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The Microcirculation in Inflammation

Klaus Ley

10.1002/cphy.cp020409

Source: Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation

Originally published: 2008

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Historical Background
2 Anatomy of the Microcirculation: Arterioles, Capillaries, and Venules
3 Special Circulations
4 Types and Ontogeny of White Blood Cells
4.1 Myeloid differentiation
4.2 Neutrophils
4.3 Monocytes
4.4 Tissue‐resident macrophages and dendritic cells
4.5 Mast cells
4.6 Eosinophils and basophils
4.7 Lymphocytes
5 Endothelial Cells in Inflammation
5.1 Endothelial heterogeneity
5.2 Endothelial surface layer
5.3 Endothelial activation
5.4 Endothelial permeability in inflammation
6 Integrated View: The Microcirculation in Inflammation
6.1 Vasomotor responses and consequences for perfusion, blood flow, shear stress
6.2 Classes of chemoattractants
6.3 Inflammatory chemokines and their receptors
6.4 Locally acting cytokines
6.5 Systemic cytokines and chemokines
6.6 Complement activation and its regulation
6.7 Eicosanoids
6.8 Other inflammatory mediators
7 Leukocyte Adhesion Cascade – General Paradigm and Exceptions
8 Leukocyte–Endothelial Interactions
8.1 Leukocyte integrins
8.2 Integrin‐associated molecules
8.3 Leukocyte immunoglobulin‐like adhesion receptors
8.4 L‐selectin
8.5 PSGL‐1 (CD162)
9 Endothelial Adhesion Molecules
9.1 P‐selectin
9.2 E‐selectin
9.3 Endothelial immunoglobulin‐like adhesion molecules
9.4 Other endothelial adhesion molecules
9.5 Signaling through adhesion molecules
9.6 Soluble adhesion molecules
10 Chemokine‐Mediated Arrest of Rolling Leukocytes
10.1 null
10.2 Differential activation of integrins
10.3 Intracellular signaling mediating arrest
11 Transmigration
11.1 null
11.2 Transmigration driven by endothelial cell activation
11.3 Paracellular route
11.4 Transcellular route
11.5 Migration through the endothelial basement membrane and pericyte sheath
11.6 Transmigration of monocytes, T cells, eosinophils
12 Migration in the Interstitial Space
13 Microvascular Damage Secondary to Inflammation
14 Oxygen‐ and Nitrogen‐Derived Radicals
14.1 Antimicrobial activities
14.2 Anti‐ and pro‐inflammatory effects of NO
14.3 Tissue damage by superoxide and other oxygen‐derived radicals
15 Regulation of Inflammatory Responses
15.1 Toll‐like receptors
15.2 Other pattern recognition receptors
15.3 Regulation of inflammation by macrophages and dendritic cells
15.4 Regulation of Inflammation by T cells
15.5 Cytokines regulating inflammation
16 Interaction Between Inflammation and Platelets
16.1 Platelet chemokines
16.2 Platelet chemokine receptors
16.3 Other platelet G‐protein‐coupled receptors
16.4 Platelet cytokines
16.5 Small molecules secreted by platelets
16.6 Platelet‐leukocyte interactions
16.7 Platelet–endothelial interactions
16.8 Enhanced leukocyte adhesion by platelets
17 Interaction Between Inflammation and Coagulation
17.1 Tissue factor
17.2 Proteases of the coagulation cascade
17.3 Fibrinolysis
17.4 Coagulation‐ and fibrinolysis‐induced effects on inflammation
17.5 Inflammation‐induced effects on coagulation and fibrinolysis
18 Resolution of Inflammation
19 Future Work
19.1 Organ‐specific inflammatory processes
19.2 Homeostatic Regulation
19.3 Interactions Between the Innate and Adaptive Immune System
19.4 Pro‐ and Anti‐Inflammatory Strategies
Figure 1. Figure 1.

One of the earliest known images of the microcirculation. Tadpole tail vessels, van Leeuwenhoek (from Ref. 6).
Figure 2. Figure 2.

First description of leukocyte rolling. “In the bright space between the flowing blood (a) and the vessel wall, which is surrounded by several parallel fibers, round, bright, and slowly moving lymphocytes can be seen.” Tongue venule of the frog rana temporaria (from Ref. 8).
Figure 3. Figure 3.

Leukocyte transmigration. Waller reported that leukocyte could transmigrate after the death of the experimental animal, thus showing that their movement was not driven by blood pressure 12. The left panel is a drawing of transmigration from Rudolf Virchow 9, the right panel is from Ref. 584.
Figure 4. Figure 4.

Leukocyte subsets. Metchnikov (also spelled Metchnikoff) described three types of leukocytes in blood. He distinguished micro‐phages and macrophages (from Ref. 16).
Figure 5. Figure 5.

(A) Weibel–Palade bodies. L = lumen. Magnification X20,000. (B) Three Weibel–Palade bodies, two in long section (arrows) showing internal microtubular elements. Note pinocytotic vesicles (arrowheads) and basal lamina (BL), X95,000. (C) A group of Weibel–Palade bodies, showing circular profiles of transversely sectioned microtubular elements. X66,000. From www.pathologyimagesinc.com
Figure 6. Figure 6.

Overlapping shear rate ranges between arterioles and venules. Rolling flux fraction (number of rolling leukocytes per 100 total leukocytes flowing through a microvessel). Top shows data for venules (small open symbols), averages (large open symbols) and arterioles (closed symbols, data from Ref. 585 (originally published as Newtonian wall shear rates) as a function of wall shear rate (1/s) given as Newtonian (8vb/d where vh is blood flow velocity and d is microvessel diameter), the estimate based on platelet tracking (2.1 times higher 586) and the most recent and most accurate estimate based on micro‐particle image velocimetry (micro‐PIV, 4.9 times higher 34). The bottom panel shows rolling flux fraction in arterioles of TNF‐α treated mouse cremaster muscle; data adapted from Ref. 587 (originally published as platelet‐based estimate). Note overlapping shear rate (and shear stress, not shown) ranges between arterioles and venules. Images adapted to match scales.
Figure 7. Figure 7.

Mechanisms of leukocyte margination. (A) In tapered tubes or microvessels (like venules), red blood cells (open symbols) tend to overtake larger leukocytes (black symbols) because of red cell deform‐ability and higher velocity, thus “pushing” the leukocytes to the wall. (B) Cross‐sectional view of a glass tube or microvessel perfused with whole blood. Aggregating red blood cells occupy the center (not shown) and push white blot cells (dots) toward the wall. (C) Leukocyte (black dot) margination at a confluence, where Q1 < Q2. The stream from Q1 becomes compressed so the leukocyte entering from venule Q1 is forced toward the wall. Note different scales of panels (from Ref. 588).
Figure 8. Figure 8.

Microcorrosion casts from normal spleen, showing three‐dimensional relationship between arterial tree (A), a lymphatic nodule (white pulp corroded away), and the surrounding marginal sinus (MS) and marginal zone (MZ). Note the sparcity of vessels within nodule, typical of normal spleens. Bar = 50μm. (B) MS consists of flattened, anastomosing vascular spaces between lymphatic nodule and MZ. Note sheetlike appearance of MS versus knobby configuration of MZ. One region of MS is fragmented (→) due to incomplete filling. The opening in MS (*) is the site where the central artery (cast accidentally broken off) entered nodule. Bar = 50mm (from Ref. 589).
Figure 9. Figure 9.

Sheet flow in the lung. (A) Transmission EM of interal‐veolar septum of the lung of the vervet monkey, Cercopithecus aethiops showing capillary blood exposed to air on all sides, w, alveolar macrophage; r, erythrocyte; ○, blood–gas barrier; a, alveoli. x3088. (B) Scanning EM of edge of an interalveolar septum of the lung of the vervet monkey, Cercopithecus aethiops, showing blood capillaries (i) and connective tissue septa (○) separating the blood capillaries. →, erythrocyte. n, interalveolar pore. x1240 (from Ref. [590).
Figure 10. Figure 10.

Liver microcirculation visualized by intravital microscopy. Concanavalin A treatment increases lymphocyte (bright cells) rolling and adhesion in the postsinusoidal venules (A) as well as sinusoids (arrows in B) (from Ref. 182).
Figure 11. Figure 11.

Kidney microcirculation visualized by corrosion casting. Normal kidney cortex depicting the parallel array of interlobular arteries, an interlobular vein (white arrow), and glomeruli (G). The peritubular capillary network homogeneously fills all the space between the other structures (A: Bar = 100μm per division; B: bar = 500μm per division) (from Ref. 591).
Figure 12. Figure 12.

Hematopoietic ontogeny in adults. Long‐term hematopoietic stem cells (LT‐HSC) can self‐renew or differentiate to short‐term (ST)‐HSC. CLP, common lymphoid progenitor: CMP. common myeloid progenitor; GMP, granulocyte macrophage progenitor; MEP. megakaryocyte/erythroid progenitor; NK, natural killer (from Ref. 1).
Figure 13. Figure 13.

(A) Neutrophils (band and segmented nucleus, human, top), a basophil (bottom left) and eosinophil (bottom right) as seen in peripheral blood smears. All from Wadsworth Center, New York State Department of Health, USA. (B) Neutrophil transmigrating through the wall of a microvessel (top left) into the tissue (bottom right), guinea pig. Freie Universität Berlin, Germany. (C) Platelet–neutrophil aggregate in blood smear. Wadsworth Center, New York State Department of Health, USA. (D) Transmission electron micrograph of a platelet. Sara J. Israels, Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada. (E) Platelet in blood, scanning electron micrograph, Monash University, Melbourne, Australia. (F) Time course of the activation of a human platelet on glass imaged with atomic force microscopy. Monika Fritz. Manfred Radmacher, Hermann E. Gaub, Technische Universität München. Germany. (See page 6 in colour section at the back of the book)
Figure 14. Figure 14.

Positive and negative regulation of peripheral T cell differentiation by TGFβ1. Transforming growth factor‐β1 (TGFβ1) has opposing effects on the differentiation of different T cell lineages. (A) Differentiation of naïve CD4+ and CD8+ T cells into T helper 1 (TH1) cells, TH2 cells or cytotoxic T lymphocytes (CTLs) is opposed by TGF31. (B) The generation of TGFβ1‐producing immunomodulatory T cells, peripheral differentiation of forkhead box P3 (FOXP3)‐expressing regulatory T (Treg) cells and interleukin‐17 (IL‐17) producing TH17 cells is promoted by TGFβ1 signaling. RORγt, retinoic acid receptor‐related orphan receptor‐γt: TR1, T regulatory 1 (from Ref. 162). (See page 6 in colour section at the back of the book)
Figure 15. Figure 15.

Endothelial heterogeneity. Peroxidase stain for adhesion molecules. (A) negative control antibody. Expression of ICAM‐1 (D), but not P‐selectin (B) or E‐selectin (C) in resting mouse cremaster venules (from Ref. 195). (E) P‐selectin expressed in venule (arrows) but not arteriole after surgical preparation trauma. (F) TNF‐α increases P‐selectin expression in venule (arrow) and induces some in arteriole (arrowhead). E‐selectin without (G) and with (H) TNF‐α (from Ref. 195). (I) Confocal image of immunofluorescently labeled P‐selectin in an intact blood perfused venule of the mouse cremaster muscle (left) and a corresponding isotype‐matched control vessel under the same imaging conditions (right) (from Ref. 196).
Figure 16. Figure 16.

Consequences of the endothelial surface layer. Nearwall velocity in venule measured by micro‐PIV 204. Delay between double exposures pre‐set in strobe. Left: Intravital microscopy of mouse cremaster venule with two images of the same microbead. ESL is not visible by intravital microscopy, but its presence influences the velocity of the microbeads (schematic diagram on right), because the fluid velocity in the ESL is much smaller than in the lumen. Arrows in diagram indicate bead velocity.
Figure 17. Figure 17.

Adhesion molecules and endothelial surface layer (ESL). Neutrophils interacting with the endothelium lined with a 500‐nm thick ESL (gray) in a postcapillary venule. In capillaries, neutrophils are deformed into a near‐cylindrical shape (A) and deform the ESL. Almost all leukocytes rolling are initiated at the beginning of postcapillary venules, where leukocytes are in close physical contact with the endothelial surface (B). Non‐interacting deformed leukocytes eventually recover their spherical shape (C), but rolling leukocytes, especially neutrophils, acquire a characteristic teardrop shape that reflects the effect of adhesive forces balanced by shear forces on the cytoskeleton (D). Rolling or adherent cells can nucleate L‐selectin‐PSGL‐1‐dependent secondary capture or tethering events (E). A close‐up of a rolling neutrophil (bottom right) shows the endothelial ESL (grey 500 nm) with endothelial adhesion molecules (E‐selectin, 30 nm, and P‐selectin, 40 nm). The black hairlike lines represent the length of a P‐selectin‐PSGL‐1 pair (100nm) completely buried in the ESL. Rolling leukocytes probably continuously deform the ESL as they roll while selectin (and integrin) bonds are formed at the leading edge (right) and broken at the trailing edge (left). Arrows indicate direction of blood flow (figure from Ref. 206). (See page 6 in colour section at the back of the book)
Figure 18. Figure 18.

Integrin affinity regulation. Conformational changes in the α and β chains (red and blue), resulting in increased affinity for monovalent ligands. Note that cytoplasmic tails move apart during affinity regulation, probably through interaction with talin (green oval) (modified from Ref. 252). (See page 6 in colour section at the back of the book)
Figure 19. Figure 19.

Integrin avidity regulation by lateral mobility/clustering. Transient release of integrins from cytoskeletal anchorage (actin filaments, represented as strings of circles) allows integrin rearrangement and clustering in the plane of the cell membrane, resulting in increased avidity for multivalent ligands. Integrins bind actin through various linker proteins (green ovals and not shown) (modified from Ref. 252). (See page 6 in colour section at the back of the book)
Figure 20. Figure 20.

Mammalian integrin subunits and their αβ associations. 8 β subunits can assort with 18 α. subunits to form 24 distinct integrins. These can be considered in several subfamilies based on evolutionary relationships (coloring of α subunits), ligand specificity and, in the case of β2 and β7 integrins, restricted expression on white blood cells, α subunits with gray hatching or stippling have inserted I domains (from Ref. 254). (See page 7 in colour section at the back of the book)
Figure 21. Figure 21.

Leukocyte rolling in mouse cremaster venules (∼25mm diameter) without (top) and with (bottom) TNF‐α treatment. In untreated venules, rolling is largely P‐selectin dependent 318,319. Although leukocyte rolling flux does not increase after TNF‐α, many more rolling neutrophils are seen per field of view, because the rolling velocity decreases dramatically through E‐selectin 346 and LFA‐1 engagement 347. Note deformation of rolling cells (arrowhead). Arrow indicates direction of flow.
Figure 22. Figure 22.

(A) Assembly of the phagocyte NADPH oxidase NOX2. In resting neutrophil granulocytes (left), NOX2 and p22phox are found primarily in the membrane of intracellular vesicles. They exist in close association, costabilizing one another. Upon activation (right), there is an exchange of GDP for GTP on Rac leading to its activation. Phosphorylation of the cytosolic p47phox subunit leads to conformational changes allowing interaction with p22phox. The movement of p47phox brings with it the other cytoplasmic subunits, p67phox and p40phox to form the active NOX2 enzyme complex. Once activated, there is a fusion of NOX2‐containing vesicles with the plasma membrane or the phagosomal membrane. The active enzyme complex transports electrons from cytoplasmic NADPH to extracellular or phagosomal oxygen to generate superoxide (O2−) (from Ref. 592). (B) Myeloperoxidase and other microbicidal products. BPI, bactericidal permeability increasing protein; H2O2, hydrogen peroxide; HOBr, hypobromous acid; HOCI. hypochlorous acid; HOI, hypoiodous acid; MMP, matrix metalloproteinase; 1O2, singlet oxygen; O2−, superoxide; O3, ozone; OH, hydroxyl radical; phox, phagocyte oxidase (from Ref. 593). (See page 7 in colour section at the back of the book)
Figure 23. Figure 23.

Leukocyte–platelet interactions. Each double arrow indicates a molecular interaction, (modified from Ref. 252). (See page 8 in colour section at the back of the book)
Figure 24. Figure 24.

Proinflammatory effects of the coagulation system. The role of protease‐activated receptors (PARs) in the crosstalk between coagulation and inflammation. Tissue factor (TF) expression within the vasculature leads to activation of the coagulation proteases factor VIIa, factor Xa, and thrombin (IIa). Thrombin activates platelets, cleaves fibrinogen, and, when bound to thrombomodulin (TM) in association with the endothelial cell protein C receptor (E). activates protein C to generate activated protein C (APC). Thrombin also activates PAR‐1 and PAR‐4. The TF‐factor VIIa‐factor Xa complex activates PAR‐1 and PAR‐2 (from Ref. 594). (See page 8 in colour section at the back of the book)


Figure 1.

One of the earliest known images of the microcirculation. Tadpole tail vessels, van Leeuwenhoek (from Ref. 6).



Figure 2.

First description of leukocyte rolling. “In the bright space between the flowing blood (a) and the vessel wall, which is surrounded by several parallel fibers, round, bright, and slowly moving lymphocytes can be seen.” Tongue venule of the frog rana temporaria (from Ref. 8).



Figure 3.

Leukocyte transmigration. Waller reported that leukocyte could transmigrate after the death of the experimental animal, thus showing that their movement was not driven by blood pressure 12. The left panel is a drawing of transmigration from Rudolf Virchow 9, the right panel is from Ref. 584.



Figure 4.

Leukocyte subsets. Metchnikov (also spelled Metchnikoff) described three types of leukocytes in blood. He distinguished micro‐phages and macrophages (from Ref. 16).



Figure 5.

(A) Weibel–Palade bodies. L = lumen. Magnification X20,000. (B) Three Weibel–Palade bodies, two in long section (arrows) showing internal microtubular elements. Note pinocytotic vesicles (arrowheads) and basal lamina (BL), X95,000. (C) A group of Weibel–Palade bodies, showing circular profiles of transversely sectioned microtubular elements. X66,000. From www.pathologyimagesinc.com



Figure 6.

Overlapping shear rate ranges between arterioles and venules. Rolling flux fraction (number of rolling leukocytes per 100 total leukocytes flowing through a microvessel). Top shows data for venules (small open symbols), averages (large open symbols) and arterioles (closed symbols, data from Ref. 585 (originally published as Newtonian wall shear rates) as a function of wall shear rate (1/s) given as Newtonian (8vb/d where vh is blood flow velocity and d is microvessel diameter), the estimate based on platelet tracking (2.1 times higher 586) and the most recent and most accurate estimate based on micro‐particle image velocimetry (micro‐PIV, 4.9 times higher 34). The bottom panel shows rolling flux fraction in arterioles of TNF‐α treated mouse cremaster muscle; data adapted from Ref. 587 (originally published as platelet‐based estimate). Note overlapping shear rate (and shear stress, not shown) ranges between arterioles and venules. Images adapted to match scales.



Figure 7.

Mechanisms of leukocyte margination. (A) In tapered tubes or microvessels (like venules), red blood cells (open symbols) tend to overtake larger leukocytes (black symbols) because of red cell deform‐ability and higher velocity, thus “pushing” the leukocytes to the wall. (B) Cross‐sectional view of a glass tube or microvessel perfused with whole blood. Aggregating red blood cells occupy the center (not shown) and push white blot cells (dots) toward the wall. (C) Leukocyte (black dot) margination at a confluence, where Q1 < Q2. The stream from Q1 becomes compressed so the leukocyte entering from venule Q1 is forced toward the wall. Note different scales of panels (from Ref. 588).



Figure 8.

Microcorrosion casts from normal spleen, showing three‐dimensional relationship between arterial tree (A), a lymphatic nodule (white pulp corroded away), and the surrounding marginal sinus (MS) and marginal zone (MZ). Note the sparcity of vessels within nodule, typical of normal spleens. Bar = 50μm. (B) MS consists of flattened, anastomosing vascular spaces between lymphatic nodule and MZ. Note sheetlike appearance of MS versus knobby configuration of MZ. One region of MS is fragmented (→) due to incomplete filling. The opening in MS (*) is the site where the central artery (cast accidentally broken off) entered nodule. Bar = 50mm (from Ref. 589).



Figure 9.

Sheet flow in the lung. (A) Transmission EM of interal‐veolar septum of the lung of the vervet monkey, Cercopithecus aethiops showing capillary blood exposed to air on all sides, w, alveolar macrophage; r, erythrocyte; ○, blood–gas barrier; a, alveoli. x3088. (B) Scanning EM of edge of an interalveolar septum of the lung of the vervet monkey, Cercopithecus aethiops, showing blood capillaries (i) and connective tissue septa (○) separating the blood capillaries. →, erythrocyte. n, interalveolar pore. x1240 (from Ref. [590).



Figure 10.

Liver microcirculation visualized by intravital microscopy. Concanavalin A treatment increases lymphocyte (bright cells) rolling and adhesion in the postsinusoidal venules (A) as well as sinusoids (arrows in B) (from Ref. 182).



Figure 11.

Kidney microcirculation visualized by corrosion casting. Normal kidney cortex depicting the parallel array of interlobular arteries, an interlobular vein (white arrow), and glomeruli (G). The peritubular capillary network homogeneously fills all the space between the other structures (A: Bar = 100μm per division; B: bar = 500μm per division) (from Ref. 591).



Figure 12.

Hematopoietic ontogeny in adults. Long‐term hematopoietic stem cells (LT‐HSC) can self‐renew or differentiate to short‐term (ST)‐HSC. CLP, common lymphoid progenitor: CMP. common myeloid progenitor; GMP, granulocyte macrophage progenitor; MEP. megakaryocyte/erythroid progenitor; NK, natural killer (from Ref. 1).



Figure 13.

(A) Neutrophils (band and segmented nucleus, human, top), a basophil (bottom left) and eosinophil (bottom right) as seen in peripheral blood smears. All from Wadsworth Center, New York State Department of Health, USA. (B) Neutrophil transmigrating through the wall of a microvessel (top left) into the tissue (bottom right), guinea pig. Freie Universität Berlin, Germany. (C) Platelet–neutrophil aggregate in blood smear. Wadsworth Center, New York State Department of Health, USA. (D) Transmission electron micrograph of a platelet. Sara J. Israels, Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada. (E) Platelet in blood, scanning electron micrograph, Monash University, Melbourne, Australia. (F) Time course of the activation of a human platelet on glass imaged with atomic force microscopy. Monika Fritz. Manfred Radmacher, Hermann E. Gaub, Technische Universität München. Germany. (See page 6 in colour section at the back of the book)



Figure 14.

Positive and negative regulation of peripheral T cell differentiation by TGFβ1. Transforming growth factor‐β1 (TGFβ1) has opposing effects on the differentiation of different T cell lineages. (A) Differentiation of naïve CD4+ and CD8+ T cells into T helper 1 (TH1) cells, TH2 cells or cytotoxic T lymphocytes (CTLs) is opposed by TGF31. (B) The generation of TGFβ1‐producing immunomodulatory T cells, peripheral differentiation of forkhead box P3 (FOXP3)‐expressing regulatory T (Treg) cells and interleukin‐17 (IL‐17) producing TH17 cells is promoted by TGFβ1 signaling. RORγt, retinoic acid receptor‐related orphan receptor‐γt: TR1, T regulatory 1 (from Ref. 162). (See page 6 in colour section at the back of the book)



Figure 15.

Endothelial heterogeneity. Peroxidase stain for adhesion molecules. (A) negative control antibody. Expression of ICAM‐1 (D), but not P‐selectin (B) or E‐selectin (C) in resting mouse cremaster venules (from Ref. 195). (E) P‐selectin expressed in venule (arrows) but not arteriole after surgical preparation trauma. (F) TNF‐α increases P‐selectin expression in venule (arrow) and induces some in arteriole (arrowhead). E‐selectin without (G) and with (H) TNF‐α (from Ref. 195). (I) Confocal image of immunofluorescently labeled P‐selectin in an intact blood perfused venule of the mouse cremaster muscle (left) and a corresponding isotype‐matched control vessel under the same imaging conditions (right) (from Ref. 196).



Figure 16.

Consequences of the endothelial surface layer. Nearwall velocity in venule measured by micro‐PIV 204. Delay between double exposures pre‐set in strobe. Left: Intravital microscopy of mouse cremaster venule with two images of the same microbead. ESL is not visible by intravital microscopy, but its presence influences the velocity of the microbeads (schematic diagram on right), because the fluid velocity in the ESL is much smaller than in the lumen. Arrows in diagram indicate bead velocity.



Figure 17.

Adhesion molecules and endothelial surface layer (ESL). Neutrophils interacting with the endothelium lined with a 500‐nm thick ESL (gray) in a postcapillary venule. In capillaries, neutrophils are deformed into a near‐cylindrical shape (A) and deform the ESL. Almost all leukocytes rolling are initiated at the beginning of postcapillary venules, where leukocytes are in close physical contact with the endothelial surface (B). Non‐interacting deformed leukocytes eventually recover their spherical shape (C), but rolling leukocytes, especially neutrophils, acquire a characteristic teardrop shape that reflects the effect of adhesive forces balanced by shear forces on the cytoskeleton (D). Rolling or adherent cells can nucleate L‐selectin‐PSGL‐1‐dependent secondary capture or tethering events (E). A close‐up of a rolling neutrophil (bottom right) shows the endothelial ESL (grey 500 nm) with endothelial adhesion molecules (E‐selectin, 30 nm, and P‐selectin, 40 nm). The black hairlike lines represent the length of a P‐selectin‐PSGL‐1 pair (100nm) completely buried in the ESL. Rolling leukocytes probably continuously deform the ESL as they roll while selectin (and integrin) bonds are formed at the leading edge (right) and broken at the trailing edge (left). Arrows indicate direction of blood flow (figure from Ref. 206). (See page 6 in colour section at the back of the book)



Figure 18.

Integrin affinity regulation. Conformational changes in the α and β chains (red and blue), resulting in increased affinity for monovalent ligands. Note that cytoplasmic tails move apart during affinity regulation, probably through interaction with talin (green oval) (modified from Ref. 252). (See page 6 in colour section at the back of the book)



Figure 19.

Integrin avidity regulation by lateral mobility/clustering. Transient release of integrins from cytoskeletal anchorage (actin filaments, represented as strings of circles) allows integrin rearrangement and clustering in the plane of the cell membrane, resulting in increased avidity for multivalent ligands. Integrins bind actin through various linker proteins (green ovals and not shown) (modified from Ref. 252). (See page 6 in colour section at the back of the book)



Figure 20.

Mammalian integrin subunits and their αβ associations. 8 β subunits can assort with 18 α. subunits to form 24 distinct integrins. These can be considered in several subfamilies based on evolutionary relationships (coloring of α subunits), ligand specificity and, in the case of β2 and β7 integrins, restricted expression on white blood cells, α subunits with gray hatching or stippling have inserted I domains (from Ref. 254). (See page 7 in colour section at the back of the book)



Figure 21.

Leukocyte rolling in mouse cremaster venules (∼25mm diameter) without (top) and with (bottom) TNF‐α treatment. In untreated venules, rolling is largely P‐selectin dependent 318,319. Although leukocyte rolling flux does not increase after TNF‐α, many more rolling neutrophils are seen per field of view, because the rolling velocity decreases dramatically through E‐selectin 346 and LFA‐1 engagement 347. Note deformation of rolling cells (arrowhead). Arrow indicates direction of flow.



Figure 22.

(A) Assembly of the phagocyte NADPH oxidase NOX2. In resting neutrophil granulocytes (left), NOX2 and p22phox are found primarily in the membrane of intracellular vesicles. They exist in close association, costabilizing one another. Upon activation (right), there is an exchange of GDP for GTP on Rac leading to its activation. Phosphorylation of the cytosolic p47phox subunit leads to conformational changes allowing interaction with p22phox. The movement of p47phox brings with it the other cytoplasmic subunits, p67phox and p40phox to form the active NOX2 enzyme complex. Once activated, there is a fusion of NOX2‐containing vesicles with the plasma membrane or the phagosomal membrane. The active enzyme complex transports electrons from cytoplasmic NADPH to extracellular or phagosomal oxygen to generate superoxide (O2−) (from Ref. 592). (B) Myeloperoxidase and other microbicidal products. BPI, bactericidal permeability increasing protein; H2O2, hydrogen peroxide; HOBr, hypobromous acid; HOCI. hypochlorous acid; HOI, hypoiodous acid; MMP, matrix metalloproteinase; 1O2, singlet oxygen; O2−, superoxide; O3, ozone; OH, hydroxyl radical; phox, phagocyte oxidase (from Ref. 593). (See page 7 in colour section at the back of the book)



Figure 23.

Leukocyte–platelet interactions. Each double arrow indicates a molecular interaction, (modified from Ref. 252). (See page 8 in colour section at the back of the book)



Figure 24.

Proinflammatory effects of the coagulation system. The role of protease‐activated receptors (PARs) in the crosstalk between coagulation and inflammation. Tissue factor (TF) expression within the vasculature leads to activation of the coagulation proteases factor VIIa, factor Xa, and thrombin (IIa). Thrombin activates platelets, cleaves fibrinogen, and, when bound to thrombomodulin (TM) in association with the endothelial cell protein C receptor (E). activates protein C to generate activated protein C (APC). Thrombin also activates PAR‐1 and PAR‐4. The TF‐factor VIIa‐factor Xa complex activates PAR‐1 and PAR‐2 (from Ref. 594). (See page 8 in colour section at the back of the book)

References
 1. Ley K Physiology of Inflammation. New York: Oxford University Press, 2001, 1–546 pp.
 2. Eisen V. Past and present views of inflammation. Agents Actions Suppl 3: 9–16, 1977.
 3. Anonymous, Galen on abnormal swellings. J Hist Med Allied Sci 33: 531–549, 1978.
 4. Jarcho S. Boerhaave on inflammation. II. Am. J Cardiol 25: 480–482, 1970.
 5. Jarcho S. Gaubius on inflammation. I. Am J Cardiol 26: 192–195, 1970.
 6. van Leeuwenhoek A. Epistolae ad societatem regiam anglicam. Leiden: Joh Arnold. 1719, 1–316 pp.
 7. Dutrochet H. Recherches anatomiques et physiologiques sur la structure intime des animaux et des vigétaux. et sur leur motilité. Paris: Bailliere et fils, 1824.
 8. Wagner R. Erläuterungstafeln zur Physiologie und Entwicklungsgeschichte. Leipzig: Leopold Voss, 1839, Tab. XIV pp.
 9. Virchow R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Berlin: August Hirschwald Verlag, 1871.
 10. Jarcho S. Augustus Volney Waller on blood vessels and inflammation. II. Am J Cardiol 28: 712–714, 1971.
 11. Jarcho S. William Addison on blood vessels and inflammation (1841–43). Am J Cardiol 28: 223–225, 1971.
 12. Waller A. Microscopic examination of some of the principal tissues of the animal frame, as observed in the tongue of the living frog, toad, etc. Phil Mag 29: 271–287, 1846.
 13. Cohnheim J. Lectures on General Pathology: A Handbook for Practitioners and Students. London: The New Sydenham Society, 1889.
 14. Cohnheim J. Vorlesungen über allgemeine Pathologic Berlin: August Hirschwald Verlag, 1877.
 15. Schultze M. Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes. Archiv f mikroskop Anatomic 1: 1–42, 1865.
 16. Metchnikoff ME. Lectures on the Comparative Pathology of Inflammation. London: Kegan Paul, Trench & Truebner & Co., 1893.
 17. Ehrlich P. Über die spezifischen Granulationen des Blutes. Arch Anat Physiol (Leipzig) 3: 571–579, 1879.
 18. Ehrlich P. Farbenanalytische Untersuchungen zur Histologic und Klinik des Blutes. Berlin: August Hirschwald, 1891, 1–137 pp.
 19. Arthus M. Injections repetees de serum de cheval cuez le lapin. Seances et Memoire de la Societe de Biologie 55: 817–825, 1903.
 20. Clark ER and Clark EL. Observations on changes in blood vascular endothelium in the living animal. Am J Anat 57: 385–438, 1935.
 21. Dale HH. Some chemical factors in the control of the circulation. Lancet 1: 1233–1237, 1929.
 22. Rocha e Silva M. A brief survey of the history of inflammation. Agents Actions 8: 45–49, 1978.
 23. Nicoll PA and Webb RR. Blood circulation in the subcutaneous tissue of the living bat's wing. Ann NY Acad Sci 46: 697–711, 1946.
 24. Mayrovitz HN, Wiedeman MP and Tuma RF. Factors influencing leukocyte adherence in microvessels. Thromb Haemostas (Stuttgart) 38: 823–830, 1977.
 25. Vejlens G The distribution of leukocytes in the vascular system. Acta Pathol Microbiol Scand Suppl. 33: 1–239, 1938.
 26. FShraeus R. The suspension stability of the blood. Physiol Rev 9: 241–274, 1929.
 27. Weibel ER and Palade GE. New cytoplasmic components in arterial endothelia. J Cell Biol 23: 101–112, 1964.
 28. Marchesi VT and Florey HW. Electron micrographic observations on the emigration of leukocytes. Quart J Exp Physiol Cog Med Sci 45: 343–348, 1960.
 29. Marchesi VT and Gowans JL. The migration of lymphocytes through the endothelium of venules in lymph‐nodes: an electron microscopic study. Proc R Soc Lond [Biol] 159: 282–290, 1964.
 30. Happel J and Byrne BJ. Motion of a sphere and fluid in a cylindrical tube. Ind Engin Chem 46: 181–1186, 1954.
 31. Goldman AJ, Cox RG and Brenner H. Slow viscous motion of a sphere parallel to a plane wall ‐ II. Couette flow. Chem Eng Sci 22: 653–660, 1967.
 32. Baker M and Wayland H. On‐line volume flow rate and velocity profile measurement for blood in microvessels. Microvasc Res 7: 131–143, 1974.
 33. Pittman RN and Ellsworth ML. Estimation of red cell flow in microvessels: consequences of the Baker‐Wayland spatial averaging model. Microvasc Res 32: 371–388, 1986.
 34. Long DS, Smith ML, Pries AR, Ley K and Damiano ER. Microviscometry reveals reduced blood viscosity and altered shear rate and shear stress profiles in microvessels after hemodilution. Proc Natl Acad Sci USA 101: 10060–10065, 2004.
 35. Atherton A and Born GVR. Quantitative investigations of the adhesiveness of circulating polymorphonuclear leukocytes to blood vessels. J Physiol (Lond) 222: 447–474, 1972.
 36. Atherton A and Born GVR. Relationship between the velocity of rolling granulocytes and that of the blood flow in venules. J Physiol (Lond) 233: 157–165, 1973.
 37. Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM and Dinarello CA. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci USA 81: 7907–7911, 1984.
 38. Liu CC, Steffen M, King F and Young JD. Identification, isolation, and characterization of a novel cytotoxin in murine cytolytic lymphocytes. Cell 51: 393–403, 1987.
 39. Ruddle NH, Li CB, Tang WL, Gray PW and McGrath KM. Lymphotoxin: cloning, regulation and mechanism of killing. Ciba Found Symp 131: 64–82, 1987.
 40. Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS and Gimbrone MA, Jr. Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest 76: 2003–2011, 1985.
 41. Bevilacqua MP, Pober JS, Mendrick DL, Cotran RS and Gimbrone MA, Jr. Identification of an inducible endothelial‐leukocyte adhesion molecule. Proc Natl Acad Sci USA 84: 9238–9242, 1987.
 42. Stamper HB and Woodruff JJ. Lymphocyte homing into lymph nodes: in vitro demonstration of the selective affinities of recirculating lymphocytes for high‐endothelial venules. J Exp Med 144: 828–833, 1976.
 43. Gowans JL and Knight JL. The route of recirculation of lymphocytes in the rat. Proc R Soc Lond [Biol] 159: 257–282, 1964.
 44. Gallatin WM, Weissman IL and Butcher EC. A cell‐surface molecule involved in organ‐specific homing of lymphocytes. Nature 304: 30–34, 1983.
 45. Anderson DC, Hughes BJ and Smith CW. Abnormal mobility of neonatal polymorphonuclear granulocytes. Relationship to impaired redistribution of surface adhesion sites by chemotaetic factors or colchicine. J Clin Invest 68: 863–874, 1981.
 46. Springer TA, Thompson WS, Miller LJ, Schmalstieg FC and Anderson DC. Inherited of the Mac‐1, LFA‐1, p150,95 glycoprotein family and its molecular basis. J Exp Med 160: 1901–1918, 1984.
 47. Buchanan MR, Crowley CA, Rosin RE, Gimbrone MA, Jr. and Babior BM. Studies on the interaction between GP‐180‐deficient neutrophils and vascular endothelium. Blood 60: 160–165, 1982.
 48. Arnaout MA, Spits H, Terhorst C, Pitt J and Todd RF. Deficiency of a leukocyte surface glycoprotein (LFA‐1) in two patients with Mol deficiency. Effects of cell activation on Mol/LFA‐1 surface expression in normal and deficient leukocytes. J Clin Invest 74: 1291–1300, 1984.
 49. Dana N, Todd RF, Pitt J, Springer TA and Arnaout MA. Deficiency of a surface membrane glycoprotein (Mol) in man. J Clin Invest 73: 153–159, 1984.
 50. Davignon D, Martz E, Reynolds T, Kurzinger K and Springer TA. Lymphocyte function‐associated antigen 1 (LFA‐1): a surface antigen distinct from Lyt‐2.3 that participates in T‐lymphocyte mediated killing. Proc Natl Acad Sci USA 78: 4535–4539, 1981.
 51. Beller DI, Springer TA and Schreiber RD. Anti‐Mac‐1 selectively inhibits the mouse and human type three complement receptor. J Exp Med 156: 1000–1009, 1982.
 52. Wright SD, Rao PE, Van Voorhis WC, Craigmyle LS, Iida K, Talle MA, Westberg EF, Goldstein GW and Silverstein SC. Identification of the C3bi receptor of human monocytes and macrophages by using monoclonal antibodies. Proc Natl Acad Sci USA 80: 5699–5703, 1983.
 53. Hemler ME, Huang C, Takada Y, Schwarz L, Strominger JL and Clabby ML. Characterization of the cell surface heterodimer VLA‐4 and related peptides. J Biol Chem 262: 11478–11485, 1987.
 54. Dustin ML, Rothlein R, Bhan AK, Dinarello CA and Springer TA. Induction by IL‐1 and interferon‐gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM‐1). J Immunol 137: 245–254, 1986.
 55. Dustin ML and Springer TA. Lymphocyte function‐associated antigen‐1 (LFA‐1) interaction with intercellular adhesion molecule‐1 (ICAM‐1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol 107: 321–331, 1988.
 56. Staunton DE, Dustin ML and Springer TA. Functional cloning of ICAM‐2, a cell adhesion ligand for LFA‐1 homologous to ICAM‐1. Nature 339: 61–64, 1989.
 57. Rice GE and Bevilacqua MP. An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science 246: 1303–1306, 1989.
 58. Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi‐Rosso G and Lobb RR. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine‐induced endothelial protein that binds to lymphocytes. Cell 59: 1203–1211, 1989.
 59. Capecchi MR. Altering the genome by homologous recombination. Science 244: 1288–1292, 1989.
 60. Durum SK and Muegge K. Cytokine Knockouts. Totowa, NJ: Humana, 1998, 1–466 pp.
 61. Ley K. Gene‐targeted mice in leukocyte adhesion research. Microcirculation 2: 141–150, 1995.
 62. Schwarz MK and Wells TNC. Interfering with chemokine networks ‐ the hope for new therapeutics. Curr Opin Chem Biol 3: 407–417, 1999.
 63. Shepro D and Morel NM. Pericyte physiology. FASEB J 7: 1031–1038, 1993.
 64. Chien S, Usami S and Skalak R. Blood flow in small tubes. In: Handbook of Physiology. The Cardiovascular System. Microcirculation. eds Renkin EM and Michel CC, Bethesda. MD: American Physiological Society, 1984, pp. 217–249.
 65. Schmid‐Schonbein GW, Usami S, Skalak R and Chien S. The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels. Microvasc Res 19: 45–70, 1980.
 66. Nobis U, Priss AR, Cokelet GR and Gaehtgens P. Radial distribution of white cells during blood flow in small tubes. Microvasc Res 29: 295–304, 1985.
 67. Goldsmith HL and Spain S. Margination of leukocytes in blood flow through small tubes. Microvasc Res 27: 204–222, 1984.
 68. Nazziola E and House SD. Effects of hydrodynamics and leukocyte‐endothelium specificity on leukocyte‐endothelium interactions. Microvasc Res 44: 127–142, 1992.
 69. Mazo IB and von Andrian UH. Adhesion and homing of blood‐borne cells in bone marrow microvessels. J Leukocyte Biol 66: 25–32, 1999.
 70. Downey GP, Worthen GS, Henson PM and Hyde DM. Neutrophil sequestration and migration in localized pulmonary inflammation. Capillary localization and migration across the interalveolar septum. Am Rev Respir Dis 147: 168–176, 1993.
 71. Doerschuk CM. Mechanisms of leukocyte sequestration in inflamed lungs. Microcirculation 8: 71–88, 2001.
 72. Horie Y, Wolf R, Russell J, Shanley TP and Granger DN. Role of kupffer cells in gut ischemia/reperfusion‐induced hepatic microvascular dysfunction in mice. Hepatology 26: 1499–1505, 1997.
 73. Kubes P, Payne D and Woodman RC. Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation. Am J Physiol Gastmintest Liver Physiol 283: G139–G147, 2002.
 74. Salmi M, Tohka S and Jalkanen S. Human vascular adhesion protein‐1 (VAP‐I) plays a critical role in lymphocyte‐endothelial cell adhesion cascade under shear. Ore Res 86: 1245–1251, 2000.
 75. Bautista AP. Neutrophilic infiltration in alcoholic hepatitis. Alcohol 27: 17–21, 2002.
 76. Jaeschke H, Mechanisms of Liver Injury, II. Mechanisms of neutrophil‐induced liver cell injury during hepatic ischemia‐reperfusion and other acute inflammatory conditions. Am J Physiol Gastmintest Liver Physiol 290: G1083–G1088, 2006.
 77. Singbartl K and Ley K. Protection from ischemia‐reperfusion induced severe acute renal failure by blocking E‐selectin. Crit Care Med 28: 2507–2514, 2000.
 78. Singbartl K and Ley K. Leukocyte recruitment and acute renal failure. J Mol Med 82: 91–101, 2004.
 79. Mayadas TN, Rosenkranz A and Cotran RS. Glomerular inflammation: Use of genetically deficient mice to elucidate the roles of leukocyte adhesion molecules and Fc‐gamma receptors in vivo. Curr Opin Nephrol Hypertens 8: 293–298, 1999.
 80. Eddy AA. Progression in chronic kidney disease. Adv Chronic Kidney Dis 12: 353–365, 2005.
 81. Paul WE. Fundamental Immunology. Lippincott Williams & Wilkins, 2003, 1–1701 pp.
 82. Metcalf D. Lineage commitment and maturation in hematopoietic cells: the case for extrinsic regulation. Blood 92: 345–347, 1998.
 83. Hoang T. The origin of hematopoietic cell type diversity. Oncogene 23: 7188–7198, 2004.
 84. Enver T, Heyworth CM and Dexter TM. Do stem cells play dice? Blood 92: 348–351, 1998.
 85. Beutler E, Lichtman MA, Coller B, Kipps T and Seligsohn U. Williams Hematology. New York: McGraw‐Hill, 2001.
 86. Demetri GD and Griffin JD. Granulocyte colony‐stimulating factor and its receptor. Blood 78: 2791–2808, 1991, 7.
 87. Lieschke GJ, Grail D, Hodgson G, Metcalf D, Stanley E, Cheers C, Fowler KJ, Basu S, Zhan YF and Dunn AR. Mice lacking granulocyte colony‐stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84: 1737–1746, 1994.
 88. Liu F, Wu HY, Wesselschmidt R, Kornaga T and Link DC. Impaired production and increased apoptosis of neutrophils in granulocyte colony‐stimulating factor receptor‐deficient mice. Immunity 5: 491–501, 1996.
 89. Barreda DR, Hanington PC and Belosevic M. Regulation of myeloid development and function by colony stimulating factors. Dev Comp Immunol 28: 509–554, 2004.
 90. Seymour JF, Lieschke GJ, Grail D, Quilici C, Hodgson G and Dunn AR. Mice lacking both granulocyte colony‐stimulating factor (CSF) and granulocyte‐macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long‐term survival. Blood 90: 3037–3049, 1997.
 91. Liu F, Poursine‐Laurent J, Wu HY and Link DC. Interleukin‐6 and the granulocyte colony‐stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood 90: 2583–2590, 1997.
 92. Dalrymple SA, Lucian LA, Slattery R, McNeil T, Aud DM, Fuchino S, Lee F and Murray R. Interleukin‐6‐deficient mice are highly susceptible to listeria monocytogenes infection: correlation with inefficient neutrophilia. Infect Immun 63: 2262–2268, 1995.
 93. Stanley E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, Maher DW, Cebon J, Sinickas V and Dunn AR. Granulocyte/macrophage colony‐stimulating factor‐deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA 91: 5592–5596, 1994.
 94. Ward AC, Loeb DM, Soede‐Bobok AA, Touw IP and Friedman AD. Regulation of granulopoiesis by transcription factors and cytokine signals. Leukemia 14: 973–990, 2000.
 95. Scott EW, Simon MC, Anastasi J and Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265: 1573–1577, 1994.
 96. DeKoter RP and Singh H. Regulation of B lymphocyte and macrophage development by graded expression of PU. I. Science 288: 1439–1441, 2000.
 97. Mclvor Z, Hein S, Fiegler H, Schroeder T, Stocking C, Just U and Cross M. Transient expression of PU. 1 commits multipotent progenitors to a myeloid fate whereas continued expression favors macrophage over granulocyte differentiation. Exp Hematol 31: 39–47, 2003.
 98. Rekhtman N, Radparvar F, Evans T and Skoultchi AI. Direct interaction of hematopoietic transcription factors PU.I and GATA‐1: functional antagonism in erythroid cells. Genes Dev 13: 1398–1411, 1999.
 99. Zhang P, Behre G, Pan J, Iwama A, Wara‐Aswapati N, Radomska HS, Auron PE, Tenen DG and Sun Z. Negative cross‐talk between hematopoietic regulators: GATA proteins repress PU.1. Proc Natl Acad Sci USA 96: 8705–8710, 1999.
 100. Friedman AD. Transcriptional regulation of granulocyte and monocyte development. Oncogene 21: 3377–3390, 2002.
 101. Dahl R, Walsh JC, Lancki D, Laslo P, Iyer SR, Singh H and Simon MC. Regulation of macrophage and neutrophil cell fates by the PU.l: C/EBPalpha ratio and granulocyte colony‐stimulating factor. Nat Immunol 4: 1029–1036, 2003.
 102. Dahl R and Simon MC. The importance of PU.l concentration in hematopoietic lineage commitment and maturation. Blood Cells Mol Dis 31: 229–233, 2003.
 103. McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemsz M, Feeney AJ, Wu GE, Paige CJ and Maki RA. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15: 5647–5658, 1996.
 104. Zhang P, Iwama A, Datta MW, Darlington GJ, Link DC and Tenen DG. Upregulation of interleukin 6 and granulocyte colony‐stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis. J Exp Med 188: 1173–1184, 1998.
 105. McKinstry WJ, Li CL, Rasko JE, Nicola NA, Johnson GR and Metcalf D. Cytokine receptor expression on hematopoietic stem and progenitor cells. Blood 89: 65–71, 1997.
 106. Anderson KL, Smith KA, Perkin H, Hermanson G, Anderson CG, Jolly DJ, Maki RA and Torbett BE. PU.1 and the granulocyte‐ and macrophage colony‐stimulating factor receptors play distinct roles in late‐stage myeloid cell differentiation. Blood 94: 2310–2318, 1999.
 107. Martin C, Burdon PC, Bridger G, Gutierrez‐Ramos JC, Williams TJ and Rankin SM. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19: 583–593, 2003.
 108. Suratt BT, Petty JM, Young SK, Malcolm KC, Lieber JG, Nick JA, Gonzalo JA, Henson PM and Worthen GS. Role of the CXCR4/SDF‐I chemokine axis in circulating neutrophil homeostasis. Blood 104: 565–571, 2004.
 109. Ley K, Baker JB, Cybulsky Ml, Gimbrone MA, Jr. and Luscinskas FW. Intravenous interleukin‐8 inhibits granulocyte emigration from rabbit mesenteric venules without altering L‐selectin expression or leukocyte rolling. J Immunol 151: 6347–6357, 1993.
 110. Serbina NV and Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7: 311–317, 2006.
 111. Zhang P, Quinton LJ, Gamble L, Bagby GJ, Summer WR and Nelson S. The granulopoietic cytokine response and enhancement of granulopoiesis in mice during endotoxemia. Shock 23: 344–352, 2005.
 112. Quinton LJ, Nelson S, Zhang P, Boe DM, Happel KI, Pan W and Bagby GJ. Selective transport of cytokine‐induced neutrophil chemoattractant from the lung to the blood facilitates pulmonary neutrophil recruitment. Am J Physiol Lung Cell Mol Physiol 286: L465–L472, 2004.
 113. Lord BI, Bronchud MH, Owens S, Chang J, Howell A, Souza L and Dexter TM. The kinetics of human granulopoiesis following treatment with granulocyte colony‐stimulating factor in vivo. Proc Natl Acad Sci USA 86: 9499–9503, 1989.
 114. Semerad CL, Liu F, Gregory AD, Stumpf K and Link DC. G‐CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17: 413–423, 2002.
 115. Basu S, Hodgson G, Katz M and Dunn AR. Evaluation of role of G‐CSF in the production, survival, and release of neutrophils from bone marrow into circulation. Blood 100: 854–861, 2002.
 116. Semerad CL, Poursine‐Laurent J, Liu F and Link DC. A role for G‐CSF receptor signaling in the regulation of hematopoietic cell function but not lineage commitment or differentiation. Immunity 11: 153–161, 1999.
 117. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS and Ley K. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL‐23 and IL‐17. Immunity 22: 285–294, 2005.
 118. Anderson DC, Schmalstieg FC, Shearer W, Becker‐Freeman K, Kohl S, Smith CW, Tosi MF and Springer TA. Leukocyte LFA‐1, OKM1, p150, 95 deficiency syndrome: functional and biosynthetic studies of three kindreds. Fed Proc 44: 2671–2677, 1985.
 119. Walzog B, Weinmann P, Jeblonski F, Scharffetter‐Kochanek K, Bommert K and Gaehtgens P. A role for β2 integrins (CD11/CD18) in the regulation of cytokine gene expression of polymorphonuclear neutrophils during the inflammatory response. FASEB J 13: 1855–1865, 1999.
 120. Lindemann SW, Yost CC, Denis MM, McIntyre TM, Weyrich AS and Zimmerman GA. Neutrophils alter the inflammatory milieu by signal‐dependent translation of constitutive messenger RNAs. Proc Natl Acad Sci USA 101: 7076–7081, 2004.
 121. Hochmuth RM and Needham D. The viscosity of neutrophils and their transit through small pores. Biorheol 27: 817–828, 1990.
 122. Glasser L and Fiederlein RL. The effect of various cell separation procedures on assays of neutrophil function. A critical appraisal. Am J Clin Pathol 93: 662–669, 1990.
 123. Forsyth KD and Levinsky RJ. Preparative procedures of cooling and re‐warming increase leukocyte integrin expression and function on neutrophils. J Immunol Methods 128: 159–163, 1990.
 124. Kuijpers TW, Tool ATJ, van der School CE, Ginsel LA, Onderwater JJM, Roos D and Verhoeven AJ. Membrane surface antigen expression on neutrophils: a reappraisal of the use of surface markers for neutrophil activation. Blood 78: 1105–1111, 1991.
 125. Warnke KC and Skalak TC. In vivo measurement of leukocyte viscosity during capillary plugging. J Biomech Eng 114: 533–538, 1992.
 126. Lipowsky HH, Riedel D and Shi GS. In vivo mechanical properties of leukocytes during adhesion to venular endothelium. Biorheol 28: 53–64, 1991.
 127. Tsai MA, Frank RS and Waugh RE. Passive mechanical behavior of human neutrophils: power‐law fluid. Biophys J 65: 2078–2088, 1994.
 128. Firrell JC and Lipowsky HH. Leukocyte margination and deformation in mesenteric venules of rat. Am J Physiol 256: H1667–H1674, 1989.
 129. Damiano ER, Westheider J, Tözeren A and Ley K. Variation in the velocity, deformation, and adhesion energy density of leukocytes rolling within venules. Circ Res 79: 1122–1130, 1996.
 130. Schmidtke DW and Diamond SL. Direct observation of membrane tethers formed during neutrophil attachment to platelets or P‐selectin under physiological flow. J Cell Biol 149: 719–730, 2000.
 131. Sperandio M, Smith ML, Forlow SB, Olson TS, Xia L, McEver RP and Ley K. P‐selectin glycoprotein ligand‐1 mediates L‐selectin‐dependent leukocyte rolling in venules. J Exp Med 197: 1355–1363, 2003.
 132. Park EY, Smith MJ, Stropp ES, Snapp KR, DiVietro JA, Walker WF, Schmidtke DW, Diamond SL and Lawrence MB. Comparison of PSGL‐1 microbead and neutrophil rolling: microvillus elongation stabilizes P‐selectin bond clusters. Biophys J 82: 1835–1847, 2002.
 133. Wiktor‐Jedrzejezak W, Bartocci A, Ferrante AW, Jr., Ahmed‐Ansari A, Sell KW, Pollard JW and Stanley ER. Total absence of colony‐stimulating factor 1 in the macrophage‐deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87: 4828–4832, 1990.
 134. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD and Nishikawa S. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345: 442–444, 1990.
 135. Passlick B, Flieger D and Ziegler‐Heitbrock HW. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood 74: 2527–2534, 1989.
 136. Geissmann F, Jung S and Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71–82, 2003.
 137. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A and Geissmann F. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311: 83–87, 2006.
 138. Raud J, Linclbom L, Dahlen S‐E and Hedqvist P. Periarteriolar localization of mast cells promotes oriented interstitial migration of leukocytes in the hamster cheek pouch. Am J Pathol 134: 161, 1989.
 139. Lindner JR, Kahn ML, Coughlin SR, Sambrano GR, Schauble E, Bernstein D, Foy D, Hafezi‐Moghadam A and Ley K. Delayed onset of inflammation in protease‐activated receptor‐2‐ deficient mice. J Immunol 165: 6504–6510, 2000.
 140. Montefort S, Gratziou C, Goulding D, Polosa R, Haskard DO, Howarth PHHS and Carroll MP. Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte‐endothelial cell adhesion mobcules 6 hours after local allergen challenge of sensitized asthmatic airways. J Clin Invest 93: 1411–1421, 1994.
 141. Schwartz LE. Mast cells: function and contents. Curr Opin Immunol 6: 91–97, 1994.
 142. Okayama Y and Kawakami T. Development, migration, and survival of mast cells. Immunol Res 34: 97–115, 2006.
 143. Bochner BS and Schleimer RP. Mast cells, basophils, and eosinophils: distinct but overlapping pathways for recruitment. Immunol Rev 179: 5–15, 2001.
 144. Torii I, Morikawa S, Harada T and Kitamura Y. Two distinct types of cellular mechanisms in the development of delayed hypersensitivity in mice: requirement of either mast cells or macrophages for elicitation of the response. Immunology 78: 482–490, 1993.
 145. Matis WL, Lavker RM and Murphy GF, Substance P. induces the expression of an endothelial‐leukocyte adhesion molecule by microvascular endothelium. J Invest Dermatol 94: 492–495, 1990.
 146. Kanwar S, Hickey MJ and Kubes P. Postischemic inflammation ‐ a role for mast cells in intestine but not in skeletal muscle. Am J Physiol Gastrointest Liver Physiol 38: G212–G218, 1998.
 147. Thorlacius H, Raud J, Rosengren‐Beezley S, Forrest MJ, Hedqvist P and Lindbom L. Mast cell activation induces P‐selectin‐dependent leukocyte rolling and adhesion in postcapillary venules in vivo. Biochem Biophys Res Commun 203: 1043–1049, 1994.
 148. Ley K. Histamine can induce leukocyte rolling in rat mesenteric venules. Am J Physiol 267: H1017–H1023, 1994.
 149. Kubes P and Kanwar S. Histamine induces leukocyte rolling in post‐capillary venules: a P‐selectin mediated event. J Immunol 152: 3570–3577, 1994.
 150. Guo Y, Lindbom L and Hedqvist P. Spontaneous leukocyte rolling in rat and mouse microvessels is independent of mast cell activity. Inflamm Res 49: 325–329, 2000.
 151. Zhang Y, Ramos BF and Jakschik BA. Augmentation of reverse arthus reaction by mast cells in mice. J Clin Invest 88: 841–846, 1991.
 152. Nienartowicz A, Sobaniec‐Lotowska ME, Jarocka‐Cyrta E and Lemancewicz D. Mast cells in neoangiogenesis. Med Sci Monit 12: RA53–RA56, 2006.
 153. Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino‐Lagos K, Scott ZA, Coyle AJ, Reed JL, Van SJ, Strom TB, Zheng XX and Noelle RJ. Mast cells are essential intermediaries in regulatory T‐cell tolerance. Nature 442: 997–1002, 2006.
 154. Rothenberg ME and Hogan SP. The eosinophil. Annu Rev Immunol 24: 147–174, 2006.
 155. Larbi KY, Dangerfield JP, Culley FJ, Marshall D, Haskard DO, Jose PJ, Williams TJ and Nourshargh S. P‐selectin mediates IL‐13‐induced eosinophil transmigration but not eotaxin generation in vivo: a comparative study with IL‐4‐elicited responses. J Leukoc Biol 73: 65–73, 2003.
 156. Teixeira MM, Williams TJ and Hellewell PG. Mechanisms and pharmacological manipulation of eosinophil accumulation in vivo. Trends Pharmacol Sci 16: 418–423, 1995.
 157. Gurish MF and Boyce JA. Mast cells: ontogeny, homing, and recruitment of a unique innate effector cell. J Allergy Clin Immunol 117: 1285–1291, 2006.
 158. von Andrian UH and McKay CR. T‐cell function and migration. New Engl J Med 343: 1020–1034, 2000.
 159. Ley K and Kansas GS. Selectins in T‐cell recruitment to non‐lymphoid tissues and sites of inflammation. Nat Rev Immunol 2004 4: 325–335, 2004.
 160. Kim MR, Manoukian R, Yeh R, Silbiger SM, Danilenko DM, Scully S, Sun J, DeRose ML, Stolina M, Chang D, Van GY, Clarkin K, Nguyen HQ, Yu YB, Jing S, Senaldi G, Elliott G and Medlock ES. Transgenic overexpression of human IL‐17E results in eosinophilia, B‐lymphocyte hyperplasia, and altered antibody production. Blood 100: 2330–2340, 2002.
 161. Zheng Y and Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol 8: 457–462, 2007.
 162. Rubtsov YP and Rudensky AY. TGFbeta signalling in control of T‐cell‐mediated self‐reactivity. Nat Rev Immunol 7: 443–453, 2007.
 163. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM and Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL‐17‐producing T cells. Immunity 24: 179–189, 2006.
 164. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA and Cua DJ. IL‐23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201: 233–240, 2005.
 165. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q and Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6: 1133–1141, 2005.
 166. Haring JS, Badovinac VP and Harty JT. Inflaming the CD8+ T cell response. Immunity 25: 19–29, 2006.
 167. Enelow RI, Mohammed AZ, Stoler MH, Liu AN, Young JS, Lou YH and Braciale TJ. Structural and functional consequences of alveolar cell recognition by CD8+ T lymphocytes in experimental lung disease. J Clin Invest 102: 1653–1661, 1998.
 168. Thatte J, Dabak V, Williams MB, Braciale TJ and Ley K. LFA‐1 is required for retention of effector CD8 T cells in mouse lungs. Blood 101: 4916–4922, 2003.
 169. Galkina E, Thatte J, Dabak V, Williams MB, Ley K and Braciale TJ. Preferential migration of effector CD8+ T cells into the interstitium of the normal lung. J Clin Invest 115: 3473–3483, 2005.
 170. Yoneda R, Yokono K, Nagata M, Tominaga Y, Moriyama H, Tsukamoto K, Miki M, Okamoto N, Yasuda H, Amano K and Kasuga M. CD8 cytotoxic T‐cell clone rapidly transfers autoimmune diabetes in very young NOD and MHC class 1‐compatible scid mice. Diabetologia 40: 1044–1052, 1997.
 171. Lefrancois L, Parker CM, Olson S, Muller W, Wagner N and Puddington L. The role of β7 integrins in CDS T cell trafficking during an antiviral immune response. J Exp Med 189: 1631–1638, 1999.
 172. Cerwenka A, Morgan TM, Harmsen AG and Dutton RW. Migration kinetics and final destination of type 1 and type 2 CD8 effector cells predict protection against pulmonary virus infection. J Exp Med 189: 423–434, 1999.
 173. Munz C, Steinman RM and Fujii S. Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity. J Exp Med 202: 203–207, 2005.
 174. Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML and Littman DR. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol 3: e113, 2005.
 175. Brutkiewicz RR. CD1d ligands: the good, the bad, and the ugly. J Immunol 177: 769–775, 2006.
 176. Kinjo Y, Tupin E, Wu D, Fujio M, Garcia‐Navarro R, Benhnia MR, Zajonc DM, Ben‐Menachem G, Ainge GD, Painter GF, Khurana A, Hoebe K, Behar SM, Beutler B, Wilson IA, Tsuji M, Sellati TJ, Wong CH and Kronenberg M. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7: 978–986, 2006.
 177. Moser B and Eberl M. Gammadelta T cells: novel initiators of adaptive immunity. Immunol Rev 215: 89–102, 2007, 89–102.
 178. Singbartl K, Thatte J, Smith ML, Day K and Ley K. A CD2‐GFP transgenic mouse reveals VLA‐4 dependent CD8+ lymphocyte rolling in the inflamed microcirculation. J Immunol 166: 7520–7526, 2001.
 179. Reinhardt RL, Bullard DC, Weaver CT and Jenkins MK. Preferential accumulation of antigen‐specific effector CD4 T cells at an antigen injection site involves CD62E‐dependent migration but not local proliferation. J Exp Med 197: 751–762, 2003.
 180. Mikhak Z, Fleming CM, Medoff BD, Thomas SY, Tager AM, Campanella GS and Luster AD. STAT1 in peripheral tissue differentially regulates homing of antigen‐specific Th1 and Th2 cells. J Immunol 176: 4959–4967, 2006.
 181. Tager AM, Bromley SK, Medoff BD, Islam SA, Bercury SD, Friedrich EB, Carafone AD, Gerszten RE and Luster AD. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol 4: 982–990, 2003.
 182. Bonder CS, Norman MU, Swain MG, Zbytnuik LD, Yamanouchi J, Santamaria P, Ajuebor M, Salmi M, Jalkanen S and Kubes P. Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha‐4 integrin and vascular adhesion protein‐1. Immunity 23: 153–163, 2005.
 183. Engelhardt B, Vestweber D, Hallmann R and Schulz M. E‐ and P‐selectin are not involved in the recruitment of inflammatory cells across the blood‐brain barrier in experimental autoimmune encephalomyelitis. Blood 90: 4459–4472, 1997.
 184. Kerfoot SM and Kubes P. Overlapping roles of P‐selectin and α4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis. J Immunol 169: 1000–1006, 2002.
 185. Fagarasan S, Watanabe N and Honjo T. Generation, expansion, migration and activation of mouse B1 cells. Immunol Rev 176: 205–215, 2000.
 186. Olson TS, Bamias G, Naganuma M, Rivera‐Nieves J, Burcin TL, Ross W, Morris MA, Pizarro TT, Ernst PB, Cominelli F and Ley K. Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease. J Clin Invest 114: 389–398, 2004.
 187. Caligiuri G, Nicoletti A, Poirier B and Hansson GK. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest 109: 745–753, 2002.
 188. Rodrigo MJ and von Andrian UH. Specificity and plasticity of memory lymphocyte migration. Curr Top Microbiol Immunol 308: 83–116, 2006, 83–116.
 189. Ghitescu L and Robert M. Diversity in unity: the biochemical composition of the endothelial cell surface varies between the vascular beds. Microsc Res Tech 57: 381–389, 2002.
 190. Garlanda C and Dejana E. Heterogeneity of endothelial cells. Specific markers. Arterioscler Thromb Vasc Biol 17: 1193–1202, 1997.
 191. Gerritsen ME and Bloor CM. Endothelial cell gene expression in response to injury. FASEB J 7: 523–532, 1993.
 192. Hartel S, Gossrau R, Hanski C and Reutter W. Dipeptidyl peptidase (DPP) IV in rat organs. Histochemistry 89: 151–161, 1988.
 193. Spanel‐Borowski K. Diversity of ultrastructure in different phenotypes of cultured microvessel endothelial cells isolated from bovine corpus luteum. Cell Tissue Res 266: 37–49, 1991.
 194. Ley K, Gaehtgens P and Spanel‐Borowski K. Differential adhesion of granulocytes to five distinct phenotypes of cultured microvascular endothelial cells. Microvasc Res 43: 119–133, 1992.
 195. Jung U and Ley K. Regulation of E‐selectin, P‐selectin and ICAM‐1 expression in mouse cremaster muscle vasculature. Microcirculation 4: 311–319, 1997.
 196. Kim MB and Sarelius IH. Role of shear forces and adhesion molecule distribution on P‐selectin‐mediated leukocyte rolling in postcapillary venules. Am J Physiol Heart Circ Physiol 287: H2705–H2711, 2004.
 197. Racanelli V and Rehermann B. The liver as an immunological organ. Hepatology 43: S54–S62, 2006.
 198. Bailey SL, Carpentier PA, McMahon EJ, Begolka WS and Miller SD. Innate and adaptive immune responses of the central nervous system. Crit Rev Immunol 26: 149–188, 2006.
 199. Minagar A, Jy W, Jimenez JJ and Alexander JS. Multiple sclerosis as a vascular disease. Neurol Res 28: 230–235, 2006.
 200. Alitalo K, Tammela T and Petrova TV. Lymphangiogenesis in development and human disease. Nature 438: 946–953, 2005.
 201. Pries AR and Kuebler WM. Normal endothelium. Handb Exp Pharmacol: 1–40, 2006.
 202. Vink H and Duling BR. Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ Res 79: 581–589, 1996.
 203. Damiano ER, Duling BR, Ley K and Skalak TC. Axisymmetric pressure‐driven flow of rigid pellets through a cylindrical tube lined with a deformable porous wall layer. J Fluid Mech 314: 163–189, 1996.
 204. Smith ML, Long DS, Damiano ER and Ley K. Near‐wall micro‐PIV reveals a hydrodynamically relevant endothelial surface layer in venules in vivo. Biophys J 85: 637–645, 2003.
 205. Weinbaum S, Zhang X, Han Y, Vink H and Cowin SC. Mechanotransduction and flow across the endothelial glycocalyx. Proc Natl Acad Sci USA 100: 7988–7995, 2003.
 206. Ley K. Adhesion molecules and the recruitment of leukocytes in postcapillary venules. In: Microvascular Research: Biology and Pathology. ed. Shepro D. Elsevier, 2005, pp. 317–322.
 207. Vink H, Constantinescu AA and Spaan JA. Oxidized lipoproteins degrade the endothelial surface layer : implications for platelet‐endothelial cell adhesion. Circulation 101: 1500–1502, 2000.
 208. Henry B and Duling BR. TNF‐alpha increases entry of macromolecules into luminal endothelial cell glycocalyx. Am J Physiol Heart Circ Physiol 279: H2815–H2823, 2000.
 209. Reinhart WH, Boulanger CM, Luscher TF, Haeberli A and Straub PW. Influence of endothelial surface on flow velocity in vitro. Am J Physiol 265: H523–H529, 1993.
 210. Potter DR, Tien J and Damiano ER. Using fluorescent micro‐particle image velocimetry to interrogate the surface glycocalyx on cultured endothelial cells in collagen microchannels. FASEB J 20, 2006, 460, 17.
 211. Mulivor AW and Lipowsky HH. Role of glycocalyx in leukocyte‐endothelial cell adhesion. Am J Physiol Heart Circ Physiol 283: H1282–H1291, 2002.
 212. Geng JG, Bevilacqua MP, Moore KL, McIntyre TM, Prescott SM, Kim JM, Bliss GA, Zimmerman GA and McEver RP. Rapid neutrophil adhesion to activated endothelium mediated by GMP‐140. Nature 343: 757–760, 1990.
 213. Cybulsky MI, McComb DJ and Movat HZ. Protein synthesis dependent and independent mechanisms of neutrophil emigration. Am J Pathol 135: 227–237, 1989.
 214. Reutershan J, Morris MA, Burcin T, Smith DF, Chang D, Saprito MS and Ley K. Critical role of endothelial CXCR2 in LPS‐induced neutrophil migration into the lung. J Clin Invest 116: 695–702, 2006.
 215. Zarbock A, Singbartl K and Ley K. Complete reversal of acid‐induced acute lung injury by blocking of platelet‐neutrophil aggregation. J Clin Invest 116: 3211–3219, 2006.
 216. Duijvestijn A, Horst E, Pals ST, Rouse BN, Steere AC, Picker LJ, Meijer CJLM and Butcher EC. High endothelial differentiation in human lymphoid and inflammatory tissue defined by monoclonal antibody HECA‐452. Am J Pathol 130: 147–155, 1988.
 217. Drayton DL, Ying X, Lee J, Lesslauer W and Ruddle NH. Ectopic LTαβ directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV‐restricted sulfotransferase. J Exp Med 197: 1153–1163, 2003.
 218. Drayton DL, Liao S, Mounzer RH and Ruddle NH. Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7: 344–353, 2006.
 219. Yuan SY. Protein kinase signaling in the modulation of microvascular permeability. Vascul Pharmacol 39: 213–223, 2002.
 220. Jung U, Norman KE, Ramos CL, Scharffetter‐Kochanek K, Beaudet AL and Ley K. Transit time of leukocytes rolling through venules controls cytokine‐induced inflammatory cell recruitment in vivo. J Clin Invest 102: 1526–1533, 1998.
 221. Li Y, Karlin A, Loike JD and Silverstein SC. Determination of the critical concentration of neutrophils required to block bacterial growth in tissues. J Exp Med 200: 613–622, 2004.
 222. Olson TS and Ley K. Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integ Comp Physiol 283: R7–R28, 2002.
 223. Proudfoot AE. Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol 2: 106–115, 2002.
 224. Mantovani A, Bonecchi R and Locati M. Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol 6: 907–918, 2006.
 225. Morris MA, Gibb DR, Picard F, Brinkmann V, Straume M and Ley K. Transient T cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720. Eur J Immunol 35: 3570–3580, 2005.
 226. Gunn MD. Chemokine mediated control of dendritic cell migration and function. Semin Immunol 15: 271–276, 2003.
 227. Cho H, Shashkin P, Dunson D, Jain N, Lee J, Miller Y and Ley K. Induction of dendritic cell‐like phenotype in macrophages during foam cell formation. Physiol Genom Rev, 2006.
 228. Martinez FO, Gordon S, Locati M and Mantovani A. Transcriptional profiling of the human monocyte‐to‐macrophage differentiation and polarization: New molecules and patterns of gene expression. J Immunol 177: 7303–7311, 2006.
 229. Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83: 447S–455S, 2006.
 230. DeLong WG, Jr. and Born CT. Cytokines in patients with polytrauma. Clin Orthop Relat Res: 57–65, 2004.
 231. Morgan BP. Complement in inflammation. In: Physiology of Inflammation, ed. Ley K. Oxford: Oxford University Press, 2001, pp. 131–145.
 232. Hopken UE, Lu B, Gerard NP and Gerard C. The C5a chemoattrac‐tant receptor mediates mucosal defence to infection. Nature 383: 86–89, 1996.
 233. Li S, Boackle SA, Holers VM, Lambris JD and Blatteis CM. Complement component C5a is integral to the febrile response of mice to lipopolysaccharide. Neuroimmunomodulation 12: 67–80, 2005.
 234. Mastellos D, Papadimitriou JC, Franchini S, Tsonis PA and Lambris JD. A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J Immunol 166: 2479–2486, 2001.
 235. Paulson JC, Weinstein J, Dorland L, van Halbeck H and Vliegenthart FG. Newcastle disease virus contains a linkage‐specific glycoprotein sialidase. J Biol Chem 257: 12734–12738, 1982.
 236. Toapanta FR and Ross TM. Complement‐mediated activation of the adaptive immune responses: role of C3d in linking the innate and adaptive immunity. Immunol Res 36: 197–210, 2006.
 237. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294: 1871–1875, 2001.
 238. Hata AN and Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 103: 147–166, 2004.
 239. Feletou M and Vanhoutte PM. Endothelium‐derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol 26: 1215–1225, 2006.
 240. Node K, Huo Y, Ruan X, Yang B, Ley K, Zeldin DC and Liao JK. Anti‐inflammatory properties of cytochrome P450 epoxygenase‐derived eicosanoids. Science 285: 1276–1279, 1999.
 241. Chien S, Usami S, Dellenback RJ and Gregersen MI. Shear‐dependent interaction of plasma proteins with erythrocytes in blood rheology. Am J Physiol 219: 143–153, 1970.
 242. Ohta K, Gotoh F, Tomita M, Tanahashi N, Kobari M, Shinohara TTY, Mihara B and Takeda H. Animal species differences in erythrocyte aggregability. Am J Physiol 262: H1009–H1012, 1992.
 243. Libby P and Ridker PM. Inflammation and atherosclerosis: role of C‐reactive protein in risk assessment. Am J Med 116 Suppl 6A: 9S–16S, 2004.
 244. Miller YI, Chang MK, Binder CJ, Shaw PX and Witztum JL. Oxidized low density lipoprotein and innate immune receptors. Curr Opin Lipidol 14: 437–445, 2003.
 245. Walsh DA and McWilliams F. Tachykinins and the cardiovascular system. Curr Drug Targets 7: 1031–1042, 2006.
 246. Arfors K‐E, Lundberg C, Lindbom L, Lundberg K, Beatty PG and Harlan JM. A monoclonal antibody to the membrane glycoprotein complex CD 18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood 69: 338–340, 1987.
 247. Ley K, Lundgren E, Berger EM and Arfors K‐E. Shear‐dependent inhibition of granulocyte adhesion to cultured endothelium by dextran sulfate. Blood 73: 1324–1330, 1989.
 248. Ley K. Granulocyte adhesion to microvascular and cultured endothelium. Studia Biophys 134: 179–184, 1989.
 249. von Andrian UH, Chambers JD, McEvoy LM, Bargatze RF, Arfors K‐E and Butcher EC. Two step model of leukocyte‐endothelial cell interaction in inflammation: distinct roles for LECAM‐1 and the leukocyte β2 integrins in vivo. Proc Natl Acad Sci USA 88: 7538–7542, 1991.
 250. Butcher EC. Leukocyte‐endothelial cell recognition ‐ Three (or more) steps to specificity and diversity. Cell 67: 1033–1036, 1991.
 251. Vajkoczy P, Laschinger M and Engelhardt B. Alpha4‐integrin‐VCAM‐1 binding mediates G protein‐independent capture of encephalitogenic T cell blasts to CNS white matter microvessels. J Clin Invest 108: 557–565, 2001.
 252. Ley K. Monocyte‐platelet‐endothelial interactions. In: Hemostasis and Thrombosis, eds Coiman RW, Marder VJ, Clowes AW, George JN and Goldhaber SZ. Philadelphia: Lippincott Williams & Wilkins, 2006, pp. 691–706.
 253. Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 69: 11–25, 1992.
 254. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 110: 673–687, 2002.
 255. Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL and Arnaout MA. Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science 294: 339–345, 2001.
 256. Lu C, Takagi J and Springer TA. Association of the membrane proximal regions of the α and β subunit cytoplasmic domains constrains an integrin in the inactive state. J Biol Chem 276: 14642–14648, 2001.
 257. Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, Ginsberg MH and Calderwood DA. Talin binding to integrin beta tails: a final common step in integrin activation. Science 302: 103–106, 2003.
 258. Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH and Campbell ID. Structural basis of integrin activation by talin. Cell 128: 171–182, 2007.
 259. Bazzoni G and Hemler ME. Are changes in integrin affinity and conformation overemphasized? Trends Biochem Sci 23: 30–34, 1998.
 260. Laudanna C and Alon R. Right on the spot. Chemokine triggering of integrin‐mediated arrest of rolling leukocytes. Thromb Haemost 95: 5–11, 2006.
 261. Du X, Plow EF, Frelinger AL, III, O'Toole TE, Loftus JC and Ginsberg MH. Ligands “activate” integrin αIIb β3 (platelet GPIIb‐IIIa). Cell 65: 409–416, 1991.
 262. Ley K, Laudanna C, Cybulsky MI and Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007, in press.
 263. Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL and Butcher EC. α4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80: 413–422, 1995.
 264. Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S, Hemler ME and Lobb RR. VCAM‐1 on activated endothelium interacts with the leukocyte integrin VLA‐4 at a site distinct from the VLA‐4/fibronectin binding site. Cell 60: 577–584, 1990.
 265. Chigaev A, Zwartz G, Graves SW, Dwyer DC, Tsuji H, Foutz TD, Edwards BS, Prossnitz ER, Larson RS and Sklar LA. Alpha4betal integrin affinity changes govern cell adhesion. J Biol Chem 278: 38174–38182, 2003.
 266. DiVietro JA, Brown DC, Sklar LA, Larson RS and Lawrence MB. Immobilized stromal cell‐derived factor‐1 {alpha} triggers rapid VLA‐4 affinity increases to stabilize lymphocyte tethers on VCAM‐1 and subsequently initiate firm adhesion. J Immunol 178: 3903–3911, 2007.
 267. Yang YT, Rayburn H and Hynes RO. Cell adhesion events mediated by α4 integrins are essential in placental and cardiac development. Development 121: 549–560, 1995.
 268. Fassler R and Meyer M. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev 9: 1896–1908, 1995.
 269. Shih PT, Brennan ML, Vora DK, Territo MC, Strahl D, Elices MJ. Lusis AJ and Berliner JA, Blocking very late antigen‐4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet. Circ Res 84: 345–351, 1999.
 270. Campbell JJ, Hedrick J, Zlotnik A, Siani MA, Thompson DA and Butcher EC. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279: 381–384, 1998.
 271. Schmits R, Kündig TM, Baker DM, Shumaker G, Simard JJL, Duncan G, Wakeham A, Shahinian A, van der Heiden A, Bachmann MF, Ohashi PS, Mak TW and Hickstein DD. LEA‐1 deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor. J Exp Med 183: 1415–1426, 1996.
 272. Huo Y, Weber C, Forlow SB, Sperandio M, Thatte J, Mack M, Jung S, Littman DR and Ley K. The chemokine KC, but not monocyte chemoattractant protein‐1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest 108: 1307–1314, 2001.
 273. Seo SM, Mclntire LV and Smith CW. Effects of IL‐8, Gro‐alpha, and LTB(4) on the adhesive kinetics of LFA‐1 and Mac‐1 on human neutrophils. Am J Physiol Cell Physiol 281: C1568–C1578, 2001.
 274. Dunne JL, Ballantyne CM, Beaudet AL and Ley K. Control of leukocyte rolling velocity in TNF‐α induced inflammation by LFA‐1 and Mac‐1. Blood 99: 336–341, 2002.
 275. Coxon A, Rieu P, Barkalow FJ, Askari S, Sharpe AH, von Andrian UH, Arnaout MA and Mayadas TN. A novel role for the beta‐2 integrin CD11b/CD18 in neutrophil apoptosis ‐ a homeostafic mechanism in inflammation. Immunity 5: 653–666, 1996.
 276. Altieri DC, Mannucci PM and Capitanio AM. Binding of fibrinogen to human monocytes. J Clin Invest 78: 968–976, 1986.
 277. Fan S‐T and Edgington TS. Integrin regulation of leukocyte inflammatory functions: CD11b/CD18 enhancement of the tumor necrosis factor‐α responses of monocytes. J Immunol 150: 2972–2980, 1993.
 278. Davis GE. The Mac‐1 and p150,95 β2 integrins bind denatured proteins to mediate leukocyte cell substrate adhesion. Exp Cell Res 200: 242–252, 1992.
 279. Zhou M and Brown EJ. Leukocyte response integrin and integrin‐associated protein act as a signal transduction unit in generation of a phagocyte respiratory burst. J Exp Med 178: 1165–1174, 1993.
 280. Hodivala‐Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman‐Cullere M, Ross FP, Coller BS, Teitelbaum S and Hynes RO. Beta 3‐integrin‐deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103: 229–238, 1999.
 281. Hemler ME, Huang C and Schwarz L. The VLA protein family: characterization of five distinct cell surface heterodimers each with a common 130,000 Mr subunit. J Biol Chem 262: 3300–3309, 1987.
 282. Briskin MJ, McEvoy LM and Butcher EC. MAdCAM‐1 has homology to immunoglobulin and mucin‐like adhesion receptors and to IgAI. Nature 363: 461–464, 1993.
 283. Ossowskj L and Aguirre‐Ghiso JA. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol 12: 613–620, 2000.
 284. Hemler ME. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol 19: 397–422, 2003.
 285. Cooper D, Lindberg FP, Gamble JR, Brown EJ and Vadas MA. Transendothelial migration of neutrophils involves integrin‐ associated protein (CD47). Proc Natl Acad Sci USA 92: 3978–3982, 1995.
 286. Porter JC and Hogg N. Integrins take partners: cross‐talk between integrins and other membrane receptors. Trends Cell Biol 8: 390–396, 1998.
 287. Sendo F and Araki Y. Regulation of leukocyte adherence and migration by glycosylphosphatidyl‐inositol‐anchored proteins. J Leukoc Biol 66: 369–374, 1999.
 288. Duperray A, Languino LR, Plescia J, McDowall A, Hogg N, Craig AG, Berendt AR and Altieri DC. Molecular identification of a novel fibrinogen binding site on the first domain of ICAM‐1 regulating leukocyte‐endothelium bridging. J Biol Chem 272: 435–441, 1997.
 289. Xu H, Gonzalo JA, St. Pierre Y, Williams IR, Kupper TS, Cotran RS, Springer TA and Gutierrez‐Ramos J‐C. Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1‐deficient mice. J Exp Med 180: 95–109, 1994.
 290. Sligh JE, Jr., Ballantyne CM, Rich SS, Hawkins HK, Smith CW, Bradley A and Beaudet AL. Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci USA 90: 8529–8533, 1993.
 291. Dunne JL, Collins RG, Beaudet AL, Ballantyne CM and Ley K. Mac‐1, but not LFA‐1, uses intercellular adhesion molecule‐1 to mediate slow leukocyte rolling in TNF‐alpha‐induced inflammation. J Immunol 171: 6105–6111, 2003.
 292. Muller WA, Weigl SA, Deng X and Phillips DM. PECAM‐1 is required for iransendothelial migration of leukocytes. J Exp Med 178: 449–460, 1993.
 293. Elias CG, Spellberg JP, Karantamir B, Lin CH, Wang YJ, Mckenna PJ, Muller WA, Zukowski MM and Andrew DP. Ligation of CD31/PECAM‐1 modulates the function of lymphocytes, monocytes and neutrophils, Eur J Immunol 28: 1948–1958, 1998.
 294. Duncan GS, Andrew DP, Takimoto H, Kaufman SA, Yoshida H, Spellberg J, de la Pompa JL, Elia A, Wakeham A, Karan‐Tamir B, Muller WA, Senaldi G, Zukowski MM and Mak TW. Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule‐1 (PECAM‐1): CD31‐ deficient mice reveal PECAM‐1‐dependent and PECAM‐1‐independent functions. J Immunol 162: 3022–3030, 1999.
 295. Schenkel AR Chew TW and Muller WA. Platelet endothelial cell adhesion molecule deficiency or blockade significantly reduces leukocyte emigration in a majority of mouse strains. J Immunol 173: 6403–6408, 2004.
 296. Chavakis T, Preissner KT and Santoso S. Leukocyte trans‐endothelial migration: JAMs add new pieces to the puzzle. Thromb Haemost 89: 13–17, 2003.
 297. Arbones ML, Ord DC, Ley K, Ratech H, Maynard‐Curry C, Otten G, Capon DJ and Tedder TF. Lymphocyte homing and leukocyte rolling and migration are impaired in L‐selectin‐deficient mice. Immunity 1: 247–260, 1994.
 298. Lewinsohn DM, Bargatze RF and Butcher EC. Leukocyte‐endothelial cell recognition: evidence of a common molecular mechanism shared by neutrophils, lymphocytes, and other leukocytes. J Immunol 138: 4313–4321, 1987.
 299. Tözeren A and Ley K. How do selectins mediate leukocyte rolling in venules? Biophys J 63: 700–709, 1992.
 300. Ley K. Arrest chemokines. Microcirculation 10: 289–295, 2003.
 301. Alon R, Grabovsky V and Feigelson S. Chemokine induction of integrin avidity on rolling and arrested leukocytes: local signaling events or global stepwise activation? Microcirculation 10: 297–311, 2003.
 302. von Andrian UH, Hasslen SR, Nelson RD, Erlandsen SL and Butcher EC. A central role for microvillous receptor presentation in leukocyte adhesion under flow. Cell 82: 989–999, 1995.
 303. Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ and Black RA. An essential role for ectodomain shedding in mammalian development. Science 282: 1281–1284, 1998.
 304. Lim YC, Snapp K, Kansas GS, Camphausen R, Ding H and Luscinskas FW. Important contributions of P‐selectin Glycoprotein Ligand‐I‐ mediated secondary capture to human monocyte adhesion to P‐ selectin, E‐selectin, and TNF‐alpha‐activated endothelium under flow in vitro. J Immunol 161: 2501–2508, 1998.
 305. Eriksson EE, Xie X, Werr J, Thoren P and Lindbom L. Importance of primary capture and L‐selectin‐dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. J Exp Med 194: 205–218, 2001.
 306. Kunkel EJ, Chomas JE and Ley K. Role of primary and secondary capture for leukocyte accumulation in vivo. Cin? Res 82: 30–38, 1998.
 307. Yang J, Furie BC and Furie B. The biology of P‐selectin Glycoprotein Ligand‐1: its role as a selectin counterreceptor in leukocyte‐endothelial and leukocyte‐ platelet interaction. Thromb Haemostasis 81: 1–7, 1999.
 308. Veerman KM, Williams MJ, Uchimura K, Singer MS, Merzaban JS, Naus S, Carlow DA, Owen P, Rivera‐Nieves J, Rosen SD and Ziltener HJ. Interaction of the selectin ligand PSGL‐1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. Nat Immunol 8: 532–539, 2007.
 309. Moore KL, Patel KD, Breuhl RE, Fugang L, Johnson DA, Lichenstein HS, Cummings RD, Bainton DF and McEver RP. P‐selectin glycoprotein ligand‐1 mediates rolling of human neutrophils on P‐selectin. J Cell Biol 128: 661–671, 1995.
 310. Furie B and Furie BC. Role of platelet P‐selectin and microparticle PSGL‐1 in thrombus formation. Trends Mol Med 10: 171–178, 2004.
 311. Cambien B and Wagner DD. A new role in hemostasis for the adhesion receptor P‐selectin. Trends Mol Med 10: 179–186, 2004.
 312. Andre P, Hartwell D, Hrachovinova I, Saffaripour S and Wagner DD. Pro‐coagulant state resulting from high levels of soluble P‐selectin in blood. Proc Natl Acad Sci USA 97: 13835–13840, 2000.
 313. Yang J, Hirata T, Croce K, Merrill‐Skoloff G, Tchemychev B, Williams E, Flaumenhaft R, Furie BC and Furie B. Targeted gene disruption demonstrates that P‐selectin glycoprotein ligand 1 (PSGL‐1) is required for P‐selectin‐ mediated but not E‐selectin‐mediated neutrophil rolling and migration. J Exp Med 190: 1769–1782, 1999.
 314. Xia L, Sperandio M, Yago T, McDaniel M, Cummings RD, Pearson‐White S, Ley K and McEver RP. P‐selectin glycoprotein ligand‐1 deficient mice have impaired leukocyte tethering to E‐selectin under flow. J Clin Invest 109: 939–950, 2002.
 315. Rivera‐Nieves J, Burcin T, Olson TS, Morris MA, McDuffie MJ, Cominelli F and Ley K. Critical role of endothelial PSGL‐1 in chronic murine ileitis. J Exp Med 203: 907–917, 2006.
 316. Tchemychev B, Furie B and Furie BC. Peritoneal macrophages express both P‐selectin and PSGL‐1. J Cell Biol 163: 1145–1155, 2003.
 317. Li G, Sanders JM, Phan ET, Ley K and Sarembock IJ. Arterial macrophages and regenerating endothelial cells express P‐selectin in atherosclerosis‐prone apolipoprotein E‐deficient mice. Am J Pathol 167: 1511–1518, 2005.
 318. Mayadas TN, Johnson RC, Rayburn H, Hynes RO and Wagner DD. Leukocyte rolling and extravasation are severely compromised in P selectin‐deficient mice. Cell 74: 541–554, 1993.
 319. Ley K, Bullard DC, Arbones ML, Bosse R, Vestweber D, Tedder TF and Beaudet AL. Sequential contribution of L‐ and P‐selectin to leukocyte rolling in vivo. J Exp Med 181: 669–675, 1995.
 320. Frenette PS, Moyna C, Hartwell DW, Lowe JB, Hynes RO and Wagner DD. Platelet‐endothelial interactions in inflamed mesenteric venules. Blood 91: 1318–1324, 1998.
 321. Mori M, Salter JW, Vowinkel T, Krieglstein CF, Stokes KY and Granger DN. Molecular determinants of the prothrombogenic phenotype assumed by inflamed colonic venules. Am J Physiol Gastrointest Liver Physiol, 2004, in press.
 322. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C and Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nature Med 9: 61–67, 2003.
 323. Schober A, Manka D, von Hundelshausen P, Huo Y, Hanrath P, Sarembock IJ, Ley K and Weber C. Deposition of platelet RANTES triggering monocyte recruitment requires P‐selectin and is involved in neointima formation after arterial injury. Circulation 106: 1523–1529, 2002.
 324. Johnson RC, Chapman SM, Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ and Wagner DD. Absence of P‐selectin delays fatty streak formation in mice. J Clin Invest 99: 1037–1043, 1997.
 325. Manka DR, Collins RG, Ley K, Beaudet AL and Sarembock IJ. Absence of P‐selectin, but not intercellular adhesion molecule‐1, attenuates neointimal growth after arterial injury in apolipoprotein E‐deficient mice. Circulation 103: 1000–1005, 2001.
 326. Burger PC and Wagner DD. Platelet P‐selectin facilitates atherosclerotic lesion development. Blood 101: 2661–2666, 2003.
 327. Manka D, Forlow SB, Sanders JM, Hurwitz D, Bennett DK, Green SA, Ley K and Sarembock IJ. Critical role of platelet P‐selectin in the response to arterial injury in apolipoprotein‐E‐deficient mice. Arterioscler Thromb Vasc Biol 24: 1124–1129, 2004.
 328. Berger G, Hartwell DW and Wagner DD. P‐selectin and platelet clearance. Blood 92: 4446–4452, 1998.
 329. Bullard DC, Kunkel EJ, Kubo H, Hicks MJ, Lorenzo I, Doyle NA, Doerschuk CM, Ley K and Beaudet AL. Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E‐selectin and P‐selectin double mutant mice. J Exp Med 183: 2329–2336, 1996.
 330. Frenette PS, Mayadas TN, Rayburn H, Hynes RO and Wagner DD. Susceptibility to infection and altered hematopoiesis in mice deficient in both P‐ and E‐selectins. Cell 84: 563–574, 1996.
 331. Collins RG, Jung U, Ramirez M, Bullard DC, Hicks J, Smith CW, Ley K and Beaudet AL. The dermal and pulmonary inflammatory disease in E/P‐selectin double null mice is reduced in triple selectin null mice. Blood 98: 727–735, 2001.
 332. Forlow SB, Schurr JR, Kolls JK, Bagby GJ, Schwarzenberger PS and Ley K. Increased granulopoiesis through interleukin‐17 and granulocyte colony stimulating factor in adhesion molecule‐deficient mice. Blood 98: 3309–3314, 2001.
 333. Pan JL, Xia LJ and McEver RP. Comparison of promoters for the murine and human P‐selectin genes suggests species‐specific and conserved mechanisms for transcriptional regulation in endothelial cells. J Biol Chem 273: 10058–10067, 1998.
 334. Wenzel K, Felix S, Kleber FX, Brachold R, Menke T, Schattke S, Schulte KL, Glaser C, Rohde K, Baumann G, et al. E‐selectin polymorphism and atherosclerosis: an association study. Hum Mol Genet 3: 1935–1937, 1994.
 335. Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L and Beaudet AL. P‐selectin or ICAM‐1 deficiency substantially protects against atherosclerosis in apo E deficient mice. J Exp Med 191: 189–194, 2000.
 336. Urzainqui A, Serrador JM, Viedma F, Yanez‐Mo M, Rodriguez A, Corbí AL, Alonso‐Lebrero JL, Luque A, Deckert M, Vazquez J and Sanchez‐Madrid F. ITAM‐based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL‐1. Immunity 17: 401–412, 2002.
 337. Weyrich AS, Elstad MR, McEver RP, McIntyre TM, Moore KL, Morrissey JH, Prescott SM and Zimmerman GA. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 97: 1525–1534, 1996.
 338. Zanardo RC, Bonder CS, Hwang JM, Andonegui G, Liu L, Vestweber D, Zbytnuik L and Kubes P. A down regulatable E‐selectin ligand is functionally important for PSGL‐1‐independent leukocyte‐endothelial cell interactions. Blood 104: 3766–3773, 2004.
 339. Katayama Y, Hidalgo A, Chang J, Peired A and Frenette PS. CD44 is a physiological E‐selectin ligand on neutrophils. J Exp Med 201: 1183–1189, 2005.
 340. Hidalgo A, Peired AJ, Wild MK, Vestweber D and Frenette PS. Complete Identification of E‐Selectin Ligands on Neutrophils Reveals Distinct Functions of PSGL‐1, ESL‐1. and CD44. Immunity 26: 477–489, 2007.
 341. Ley K. Integration of inflammatory signals by rolling neutrophils. Immunol Rev 186: 8–18, 2002.
 342. Smith ML, Olson TS and Ley K. CXCR2‐ and E‐selectin‐induced neutrophil arrest during inflammation in vivo. J Exp Med 200: 935–939, 2004.
 343. Wagers AJ, Lowe JB and Kansas GS. An important role for the alpha‐1,3 fucosyltransferase, FucT‐VII, in leukocyte adhesion to E‐selectin. Blood 88: 2125–2132, 1996.
 344. Snapp KR, Heitzig CE, Ellies LG, Marth JD and Kansas GS. Differential requirements for the O‐linked branching enzyme core 2 β1‐6‐N‐glucosaminyltransferase in biosynthesis of ligands for E‐selectin and P‐selectin. Blood 97: 3806–3811, 2001.
 345. Lawrence MB and Springer TA. Neutrophils roll on E‐selectin. J Immunol 151: 6338–6346, 1993.
 346. Kunkel EJ and Ley K. Distinct phenotype of E‐selectin deficient mice: E‐selectin is required for slow leukocyte rolling in vivo. Circ Res 79: 1196–1204, 1996.
 347. Zarbock A, Lowell CA and Ley K. Spleen tyrosine kinase Syk is necessary for E‐selectin‐induced αLβ2 integrin mediated rolling on intercellular adhesion molecule‐1. Immunity 26: 773–783, 2007.
 348. Simon SI, Hu Y, Vestweber D and Smith CW. Neutrophil tethering on E‐selectin activates beta 2 integrin binding to ICAM‐1 through a mitogen‐activated protein kinase signal transduction pathway. J Immunol 164: 4348–4358, 2000.
 349. Chesnutt BC, Smith DF, Raffler NA, Smith ML, White EJ and Ley K. Induction of LFA‐1‐dependent neutrophil rolling on ICAM‐1 by engagement of E‐selectin. Microcirculation 13: 99–109, 2006.
 350. Gurtner GC, Davis V, Li H, McCoy MJ, Sharpe A and Cybulsky MI. Targeted disruption of the murine VCAM‐1 gene: essential role of VCAM‐1 in chorioallantoic fusion and placentation. Genes Dev 9: 1–14, 1995.
 351. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez‐Ramos JC, Connelly PW and Milstone DS. A major role for VCAM‐1, but not ICAM‐1, in early atherosclerosis. J Clin Invest 107: 1255–1262, 2001.
 352. Dansky HM, Barlow CB, Lominska C, Sikes JL, Kao C, Weinsaft J, Cybulsky MI and Smith JD. Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule‐1 gene dosage. Arterioseler Thromb Vasc Biol 21: 1662–1667, 2001.
 353. Muller WA. The role of PECAM‐1 (CD31) in leukocyte emigration: studies in vitro and in vivo. J Leukocyte Biol 57: 523–528, 1995.
 354. Nourshargh S, Krombach F and Dejana E. The role of JAM‐A and PECAM‐1 in modulating leukocyte infiltration in inflamed and ischemic tissues. J Leukoc Biol 80: 714–718, 2006.
 355. Mamdouh Z, Chen X, Pierini LM, Maxfield FR and Muller WA. Targeted recycling of PECAM from endothelial surface‐connected compartments during diapedesis. Nature 421: 748–753, 2003.
 356. Wegmann F, Petri B, Khandoga AG, Moser C, Khandoga A, Volkery S, Li H, Nasdala I, Brandau O, Fassler R, Butz S, Krombach F and Vestweber D. ESAM supports neutrophil extravasation, activation of Rho, and VEGF‐induced vascular permeability. J Exp Med 203: 1671–1677, 2006.
 357. Norris P, Poston RN, Thomas DS, Thornhill M, Hawk J and Haskard DO. The expression of endothelial leukocyte adhesion molecule‐1 (ELAM‐1), intercellular adhesion molecule‐1 (ICAM‐1), and vascular cell adhesion molecule‐1 (VCAM‐I) in experimental cutaneous inflammation: a comparison of ultraviolet‐B erythema and delayed hypersensitivity. J Invest Dermatol 96: 763–770, 1991.
 358. Hemmerich S, Butcher EC and Rosen SD. Sulfation‐dependent recognition of high endothelial venules (HEV)‐ligands by L‐selectin and MECA 79, an adhesion‐blocking monoclonal antibody. J Exp Med 180: 2219–2226, 1994.
 359. Schenkel AR, Mamdouh Z, Chen X, Liebman RM and Muller WA. CD99 plays a major role in the migration of monocytes through endothelial junctions. Nat Immunol 3: 143–150, 2002.
 360. Ley K and Zarbock A. Hold on to your endothelium: postarrest steps of the leukocyte adhesion cascade. Immunity 25: 185–187, 2006.
 361. Harris ES, McIntyre TM, Prescott SM and Zimmerman GA. The leukocyte integrins. J Biol Chem 275: 23409–23412, 2000.
 362. Giagulli C, Ottoboni L, Caveggion E, Rossi B, Lowell C, Constantin G, Laudanna C and Berton G. The Src Family Kinases Hck and Fgr are dispensable for inside‐out, chemoattractant‐induced signaling regulating beta2 Integrin affinity and valency in neutrophils, but are required for beta2 integrin‐mediated outside‐in signaling involved in sustained adhesion. J Immunol 177: 604–611, 2006.
 363. Schymeinsky J, Then C and Walzog B. The non‐receptor tyrosine kinase Syk regulates lamellipodium formation and site‐directed migration of human leukocytes. J Cell Physiol 204: 614–622, 2005.
 364. Ding A, Wright SD and Nathan C. Activation of mouse peritoneal macrophages by monoclonal antibodies to Mac‐1 (complement receptor type 3). J Exp Med 165: 733–749, 1987.
 365. Walzog B, Seifert R, Zakrzewicz A, Gaehtgens P and Ley K. Cross‐linking of CD 18 in human neutrophils induces an increase of intra cellular free Ca2+, exocytosis of azurophilic granules, quantitative up‐regulation of CD18. shedding of L‐selectin. and actin polymer ization. J Leukocyte Biol 56: 625–635, 1994.
 366. Hirahashi J, Mekala D, van Ziffle J, Xiao L, Saffaripour S, Wagner DD, Shapiro SD, Lowell CA and Mayadas TN. Mac‐1 signaling via sre‐family and syk kinases results in elastase‐dependent thrombohemorragic vasculopathy. Immunity 25: 271–283, 2006.
 367. Yoshida M, Westlin WF, Wang N, Ingber DE, Rosenzweig A, Resnick N and Gimbrone MA, Jr. Leukocyte adhesion to vascular endothelium induces E‐selectin linkage to the actin cytoskeleton. J Cell Biol 133: 445–455, 1996.
 368. Yoshida M, Szente BE, Kiely JM, Rosenzweig A and Gimbrone MA. Phosphorylation of the cytoplasmic domain of E‐selectin is regulated during leukocyte‐endothelial adhesion. J Immunol 161: 933–941, 1998.
 369. Abbal C, Lambelet M, Bertaggia D, Gerbex C, Martinez M, Arcaro A, Schapira M and Spertini O. Lipid raft adhesion receptors and Syk regulate selectin‐dependent rolling under flow conditions. Blood 108: 3352–3359, 2006.
 370. Brenner B, Gulbins E, Schlottmann K, Koppenhoefer U, Busch GL, Walzog B, Steinhausen M, Coggeshall KM, Linderkamp O and Lang F. L‐selectin activates the Ras pathway via the tyrosine kinase p56lck. Proc Natl Acad Sci USA 93: 15376–15381, 1996.
 371. Brenner B, Gulbins E, Busch GL, Koppenhoefer U, Lang F and Linderkamp O. L‐selectin regulates actin polymerisation via activation of the small g‐protein rac2. Biochem Biophys Res Comm 231: 802–807, 1997.
 372. Giblin PA, Hwang ST, Katsumoto TR and Rosen SD. Ligation of L‐selectin on T lymphocytes activates β1 integrins and promotes adhesion to fibronectin. J Immunol 159: 3498–3507, 1997.
 373. Hafezi‐Moghadam A, Thomas KL, Prorock AJ, Huo Y and Ley K. L‐selectin shedding regulates leukocyte recruitment. J Exp Med 193: 863–872, 2001.
 374. Steeber DA, Engel P, Miller AS, Sheetz MP and Tedder TF. Ligation of L‐selectin through conserved regions within the lectin domain activates signal transduction pathways and integrin function in human, mouse, and rat leukocytes. J Immunol 159: 952–963, 1997.
 375. Carveth HJ, Bohnsack JF, McIntyre TM, Baggiolini M, Prescott SM and Zimmerman GA. Neutrophil activating factor (NAF) induces polymorphonuclear leukocyte adherence to endothelial cells and to subendothelial matrix proteins. Biochem Biophys Res Comm 162: 387–393, 1989.
 376. Morgan SJ, Moore MW, Cacalano G and Ley K. Reduced leukocyte adhesion response and absence of slow leukocyte rolling in interleukin‐8 (IL‐8) receptor deficient mice. Microvasc Res 54: 188–191, 1997.
 377. Rot A. Endothelial cell binding of NAP‐1/IL‐8: role in neutrophil emigration. Immunol Today 13: 291–294, 1992.
 378. Huber AR, Kunkel SL, Todd RF and Weiss SJ. Regulation of transendothelial neutrophil migration by endogenous interleukin‐8. Science 254: 99–102, 1991.
 379. Middleton J, Neil S, Wintle J, Clark‐Lewis I, Moore H, Lam C, Auer M, Hub E and Rot A. Transcytosis and surface presentation of IL‐8 by venular endothelial cells. Cell 91: 385–395, 1997.
 380. Rainger GE, Fisher A, Shearman C and Nash GB. Adhesion of flowing neutrophils to cultured endothelial cells after hypoxia and reoxygenation in vitro. Am J Physiol Heart Circ Physiol 269: H1398–H1406, 1995.
 381. Rainger GE, Fisher AC and Nash GB. Endothelial‐borne platelet‐activating factor and interleukin‐8 rapidly immobilize rolling neutrophils. Am J Physiol Heart Circul Physiol 272: H114–H122, 1997.
 382. Lawrence MB and Springer TA. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell 65: 859–873, 1991.
 383. Kitayama J, Fuhlbrigge RC, Puri KD and Springer TA. P‐selectin, L‐selectin, and α4 integrin have distinct roles in eosinophil tethering and arrest on vascular endothelial cells under physiological flow conditions. J Immunol 159: 3929–3939, 1997.
 384. Diacovo TG, Roth SJ, Buccola JM, Bainton DF and Springer TA. Neutrophil rolling, arrest, and transmigration across activated, surface‐adherent platelets via sequential action of P‐selectin and the β2‐integrin CD11b/CD18. Blood 88: 146–157, 1996.
 385. Stein JV, Rot A, Luo Y, Narasimhaswamy M, Nakano H, Gunn MD, Matsuzawa A, Quackenbush EJ, Dorf ME and von Andrian UH. The CC chemokine thymus‐derived chemotactic agent 4 (TCA‐4, secondary lymphoid tissue chemokine, 6Ckine, exodus‐2) triggers lymphocyte function‐associated antigen 1 ‐mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J Exp Med 191: 61–76, 2000.
 386. Shamri R, Grabovsky V, Gauguet JM, Feigelson S, Manevich E, Kolanus W, Robinson MK, Staunton DE, von Andrian UH and Alon R. Lymphocyte arrest requires instantaneous induction of an extended LFA‐1 conformation mediated by endothelium‐bound chemokines. Nat Immunol 6: 497–506, 2005.
 387. Lum AF, Green CE, Lee GR. Staunton DE and Simon SI. Dynamic regulation of LFA‐1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM‐1) in shear flow. J Biol Chem 277: 20660–20670, 2002.
 388. Lupher ML, Jr., Harris EA, Beals CR, Sui LM, Liddington RC and Staunton DE. Cellular activation of leukocyte function‐associated antigen‐1 and its affinity are regulated at the I domain allosteric site. J Immunol 167: 1431–1439, 2001.
 389. Tangemann K, Gunn MD, Giblin P and Rosen SD. A high endothelial cell‐derived chemokine induces rapid, efficient, and subset‐selective arrest of rolling T lymphocytes on a reconstituted endothelial substrate. J Immunol 161: 6330–6337, 1998.
 390. Constantin G, Majeed M, Giagulli C, Piccio L, Kim JY, Butcher EC and Laudanna C. Chemokines trigger immediate beta2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. Immunity 13: 759–769, 2000.
 391. Gakidis MA, Cullere X, Olson T, Wilsbacher JL, Zhang B, Moores SL, Ley K, Swat W, Mayadas T and Brugge JS. Vav GEFs are required for beta2 integrin‐dependent functions of neutrophils. J Cell Biol 166: 273–282, 2004.
 392. Smith DF, Deem TL, Bruce A, Reutershan J, Wu D and Ley K. Leukocyte phoshoinositide‐3‐kinase gamma is required for chemokine‐induced sustained adhesion under flow in vivo. J Leukocyte Biol 80: 1491–1499, 2006.
 393. Zhang H, Schaff UY, Green CE, Chen H, Sarantos MR, Hu Y, Wara D, Simon SI and Lowell CA. Impaired integrin‐dependent function in Wiskott‐Aldrich syndrome protein‐deficient murine and human neutrophils. Immunity 25: 285–295, 2006.
 394. Schenkel AR, Mamdouh Z and Muller WA. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 5: 393–400, 2004.
 395. Phillipson M, Heit B, Colarusso P, Liu L, Ballantyne CM and Kubes P. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med 203: 2569–2575, 2006.
 396. Scharffetter‐Kochanek K, Lu HF, Norman K, Vannood N, Munoz F, Grabbe S, McArthur M, Lorenzo I, Kaplan S, Ley K, Smith CW, Montgomery CA, Rich S and Beaudet AL. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med 188: 119–131, 1998.
 397. Fitzhugh DJ, Naik S, Caughman SW and Hwang ST. Cutting edge: C‐C chemokine receptor 6 is essential for arrest of a subset of memory T cells on activated dermal microvascular endothelial cells under physiologic flow conditions in vitro. J Immunol 165: 6677–6681, 2000.
 398. DiVietro JA, Smith MJ, Smith BR, Petruzzelli L, Larson RS and Lawrence MB. Immobilized IL‐8 triggers progressive activation of neutrophils rolling in vitro on P‐selectin and intercellular adhesion molecule‐1. J Immunol 167: 4017–4025, 2001.
 399. Kunkel EJ, Dunne JL and Ley K. Leukocyte arrest during cytokine‐dependent inflammation in vivo. J Immunol 164: 3301–3308, 2000.
 400. Grabovsky V, Feigelson S, Chen C, Bleijs DA, Peled A, Cinamon G, Baleux F, Arenzana‐Seisdedos F, Lapidot T, Van Kooyk Y, Lobb RR and Alon R. Subsecond induction of α4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule‐1 under flow conditions. J Exp Med 192: 495–506, 2000.
 401. Peled A, Grabovsky V, Habler L, Sandbank J, Arenzana‐Seisdedos F, Petit I, Ben‐Hur H, Lapidot T and Alon R. The chemokine SDF‐1 stimulates integrin‐mediated arrest of CD34+ cells on vascular endothelium under shear flow. J Clin Invest 104: 1199–1211, 1999.
 402. Cinamon G, Shinder V and Alon R. Shear forces promote lymphocyte migration across vascular endothelium bearing apical chemokines. Nat Immunol 2: 515–522, 2001.
 403. Kitayama J, MacKay CR, Ponath PD and Springer TA. The C‐C chemokine receptor CCR3 participates in stimulation of eosinophil arrest on inflammatory endothelium in shear flow. J Clin Invest 101: 2017–2024, 1998.
 404. Tachimoto H, Burdick MM, Hudson SA, Kikuchi M, Konstantopoulos K and Bochner BS. CCR3‐active chemokines promote rapid detachment of eosinophils from VCAM‐1 in vitro. J Immunol 165: 2748–2754, 2000.
 405. Piali L, Weber C, LaRosa G, MacKay CR, Springer TA, Clark‐Lewis I and Moser B. The chemokine receptor CXCR3 mediates rapid and shear‐resistant adhesion‐induction of effector T lymphocytes by the chemokines IP10 and Mig. Eur J Immunol 28: 961–972, 1998.
 406. Fong AM, Robinson LA, Steeber DA, Tedder TF, Yoshie O, Imai T and Patel DD. Fractalkine and CX3 CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. J Exp Med 188: 1413–1419, 1998.
 407. Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A and Littman DR. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20: 4106–4114, 2000.
 408. Teupser D, Pavlides S, Tan M, Gutierrez‐Ramos JC, Kolbeck R and Breslow JL. Major reduction of atherosclerosis in fractalkine (CX3CLl)‐deficient mice is at the brachiocephalic artery, not the aortic root. Proc Natl Acad Sci USA 101: 17795–17800, 2004.
 409. Haskell CA, Hancock WW, Salant DJ, Gao W, Csizmadia V, Peters W, Faia K, Fituri O, Rottman JB and Charo IF. Targeted deletion of CX(3)CR1 reveals a role for fractalkine in cardiac allograft rejection. J Clin Invest 108: 679–688, 2001.
 410. Campbell JJ, Qiti SX, Bacon KB, MacKay CR and Butcher EC. Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion‐triggering versus chemotactic responses in lymphoid cells. J Cell Biol 134: 255–266, 1996.
 411. Weber C, Alon R, Moser B and Springer TA. Sequential regulation of α1 β1 and α5 β1 integrin avidity by CC chemokines in monocytes ‐implications for transendothelial chemotaxis. J Cell Biol 134: 1063–1073, 1996.
 412. Weber KSC, von Hundelshausen P, Clark‐Lewis I, Weber PC and Weber C. Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow. Eur J Immunol 29: 700–712, 1999.
 413. Carr MW, Alon R and Springer TA. The C‐C chemokine MCP‐1 differentially modulates the avidity of β1 and β2 integrins on T lymphocytes. Immunity 4: 179–187, 1996.
 414. Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, Dorf M, Littman DR, Rollins BJ, Zweerink H, Rot A and von Andrian UH. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med 194: 1361–1373, 2001.
 415. Schober A, Zernecke A, Liehn EA, von HP, Knarren S, Kuziel WA and Weber C. Crucial role of the CCL2/CCR2 axis in neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early monocyte recruitment and CCL2 presentation on platelets. Circ Res 95: 1125–1133, 2004.
 416. Weber C, Weber KS, Klier C, Gu S, Wank R, Horuk R and Nelson PJ. Specialized rales of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)l‐like/CD45RO(+) T cells. Blood 97: 1144–1146, 2001.
 417. Pachynski RK, Wu SW, Gunn MD and Erle DJ, Secondary lymphoid‐tissue chemokine (SLC) stimulates integrin alpha 4 beta 7‐mediated adhesion of lymphocytes to mucosal addressin cell adhesion moecule‐1 (MAdCAM‐1) under flow. J Immunol 161: 952–956, 1998.
 418. Johnston B, Burns AR, Suematsu M, Issekutz TB, Woodman RC and Kubes P. Chronic inflammation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein‐1. J Clin Invest 103: 1269–1276, 1999.
 419. Nagai K, Larkin S, Hartnell A, Larbi K, Aghakhani MR, Windley C, Davies D, Lobb RR, Williams TJ and Nourshargh S. Human eotaxin induces eosinophil extravasation through rat mesenteric venules: role of alpha(4) integrins and vascular cell adhesion molecule‐1. Immunology 96: 176–183, 1999.
 420. Cuvelier SL and Patel KD. Shear‐dependent eosinophil transmigration on interleukin 4‐ stimulated endothelial cells: a role for endothelium‐associated eotaxin‐3. J Exp Med 194: 1699–1709, 2001.
 421. Friedrich EB, Sinha S, Li L, Dedhar S, Force T, Rosenzweig A and Gerszten RE. Role of integrin‐linked kinase in leukocyte recruitment. J Biol Chem 277: 16371–16375, 2002.
 422. Gerszten RE, Friedrich EB, Matsui T, Hung RR, Li L, Force T and Rosenzweig A. Role of phosphoinosilide 3‐kinase in monocyte recruitment under flow conditions. J Biol Chem 276: 26846–26851, 2001.
 423. Smith DF, Galkina E, Ley K and Huo Y. GRO family chemokines are specialized for monocyte arrest from flow. Am J Physiol Heart Circ Physiol 289: H1976–H1984, 2005.
 424. Gerszten RE, Garcia‐Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA, Luster AD, Luscinskas FW and Rosenzweig A. MCP‐1 and IL‐8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398: 718–723, 1999.
 425. Laudanna C, Campbell JJ and Butcher EC. Role of Rho in chemoattractant‐activated leukocyte adhesion through integrins. Science 271: 981–983, 1996.
 426. Giagulli C, Scarpini E, Ottoboni L, Narumiya S, Butcher EC, Constantin G and Laudanna C. RhoA and zeta PKC control distinct modalities of LFA‐1 activation by chemokines: critical role of LFA‐1 affinity triggering in lymphocyte in vivo homing. Immunity 20: 25–35, 2004.
 427. Zarbock A, Deem TL, Burcin TL and Ley K Gαi2 is required for chemokine‐induced neutrophil arrest. Blood, 2007, in press.
 428. Hyduk SJ, Chan JR, Duffy ST, Chen M, Peterson MD, Waddell TK, Digby GC, Szaszi K, Kapus A and Cybulsky MI. Phospholipase C, calcium and calmodulin are critical for {alpha}4{beta} 1 integrin affinity up‐regulation and monocyte arrest triggered by chemoat‐tractants. Blood 109: 176–184, 2007.
 429. Bergmeier W, George T, Wang HW, Crittenden JR, Baldwin AC, Cifuni SM, Housman DE, Graybiel AM and Wagner DD. Mice lacking the signaling molecule CalDAG‐GEFl represent a model for leukocyte adhesion deficiency type III. J Clin Invest 117: 1699–1707, 2007.
 430. Pasvolsky R, Feigelson SW, Kilic SS, Simon AJ, Tal‐Lapidot G, Grabovsky V, Crittenden JR, Amariglio N, Safran M, Graybiel AM, Rechavi G, Ben‐Dor S, Etzioni A and Alon R, A LAD‐HI syndrome is associated with defective expression of the Rap‐1 activator CalDAG‐GEFI in lymphocytes, neutrophils, and platelets. J Exp Med 204: 1571–1582, 2007.
 431. Kinashi T, Aker M, Sokolovsky‐Eisenberg M, Grabovsky V, Tanaka C, Shamri R, Feigelson S, Etzioni A and Alon R. LAD‐III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood 103: 1033–1036, 2004.
 432. Cinamon G, Shinder V, Shamri R and Alon R. Chemoattractant signals and beta 2 integrin occupancy at apical endothelial contacts combine with shear stress signals to promote transendothelial neutrophil migration. J Immunol 173: 7282–7291, 2004.
 433. Huang AJ, Manning JE, Bandak TM, Ratau MC, Hanser KR and Silverstein SC. Endothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cells. J Cell Biol 120: 1371–1380, 1993.
 434. Burns AR, Walker DC, Brown ES, Thurmon LT, Bowden RA, Keese CR, Simon SI, Entman ML and Smith CW. Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners. J Immunol 159: 2893–2903, 1997.
 435. Feng D, Nagy JA, Pyne K, Dvorak HF and Dvorak AM. Neutrophils emigrate from venules by a transendothelial cell pathway in response to fMLP. J Exp Med 187: 903–915, 1998.
 436. Ohashi KL, Tung DKL, Wilson J, Zweifach BW and Schmid‐Schonbein GW. Transvascular and interstitial migration of neutrophils in rat mesentery. Microcirculation 3: 199–210, 1996.
 437. Wang S, Voisin MB, Larbi KY, Dangerfield J, Scheiermann C, Tran M, Maxwell PH, Sorokin L and Nourshargh S. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J Exp Med 203: 1519–1532, 2006.
 438. Young RE, Thompson RD, Larbi KY, La M, Roberts CE, Shapiro SD, Perretti M and Nourshargh S. Neutrophil elastase (NE)‐deficient mice demonstrate a nonredundant role for NE in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivo. J Immunol 172: 4493–4502, 2004.
 439. Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R and Luscinskas FW. ICAM‐1 regulates neutrophil adhesion and trans‐cellular migration of TNF‐alpha‐activated vascular endothelium under flow. Blood 106: 584–592, 2005.
 440. Shaw SK, Bamba PS, Perkins BN and Luscinskas FW. Real‐time imaging of vascular endothelial‐cadherin during leukocyte transmigration across endothelium. J Immunol 167: 2323–2330, 2001.
 441. Luscinskas FW, Cybulsky Ml, Kiely J‐M, Peckins CS, Davis VM and Gimbrone MA, Jr. Cytokine‐activated human endothelial monolayers support enhanced neutrophil transmigration via a mechanism involving both endothelial‐leukocyte adhesion molecule‐1 (ELAM‐I) and intercellular adhesion‐molecule‐1 (ICAM‐I). J Immunol 146: 1617–1625, 1991.
 442. Barreiro O, Yanez‐Mo M, Serrador JM, Montoya MC, Vicente‐Manzanares M, Tejedor R, Furthmayr H and Sanchez‐Madrid F. Dynamic interaction of VCAM‐1 and ICAM‐I with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157: 1233–1245, 2002.
 443. Carman CV and Springer TA. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 167: 377–388, 2004.
 444. Greenwood J, Amos CL, Walters CE, Couraud PO, Lyck R, Engelhardt B and Adamson P. Intracellular domain of brain endothelial intercellular adhesion molecule‐1 is essential for T lymphocyte‐mediated signaling and migration. J Immunol 171: 2099–2108, 2003.
 445. Millan J and Ridley AJ. Rho GTPases and leucocyte‐induced endothelial remodelling. Biochem J 385: 329–337, 2005.
 446. Muller WA. Leukocyte‐endothelial‐cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 24: 327–334, 2003.
 447. Vestweber D, Regulation of endothelial cell contacts during leukocyte extravasation. Curr Opin Cell Biol 14: 587–593, 2002.
 448. Reymond N, Imbert AM, Devilard E, Fabre S, Chabannon C, Xerri L, Farnarier C, Cantoni C, Bottino C, Moretta A, Dubreuil P and Lopez M. DNAM‐I and PVR regulate monocyte migration through endothelial junctions. J Exp Med 199: 1331–1341, 2004.
 449. Salmi M and Jalkanen S. Cell‐surface enzymes in control of leukocyte trafficking. Nat Rev Immunol 5: 760–771, 2005.
 450. Liu L, Cara DC, Kaur J, Raharjo E, Mullaly SC, Jongstra‐Bilen J, Jongstra J and Kubes P. LSP1 is an endothelial gatekeeper of leukocyte transendothelial migration. J Exp Med 201: 409–418, 2005.
 451. Dejana E. Endothelial cell‐cell junctions: happy together. Nat Rev Mol Cell Biol 5: 261–270, 2004.
 452. Lou O, Alcaide P, Luscinskas FW and Muller WA. CD99 is a key mediator of the transendothelial migration of neutrophils. J Immunol 178: 1136–1143, 2007.
 453. Engelhardt B and Wolburg H. Mini‐review: transendothelial migration of leukocytes: through the front door or around the side of the house? Eur J Immunol 34: 2955–2963, 2004.
 454. Millan J, Hewlett L, Glyn M, Toomre D, Clark P and Ridley AJ. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM‐I to caveola‐ and F‐actin‐rich domains. Nat Cell Biol 8: 113–123, 2006.
 455. Nieminen M, Henttinen T, Merinen M, Marttila‐Ichihara F, Eriksson JE and Jalkanen S. Vimentin function in lymphocyte adhesion and transcellular migration. Nat Cell Biol 8: 156–162, 2006.
 456. Dvorak AM and Feng D. The vesiculo‐vacuolar organelle (WO). A new endothelial cell permeability organelle J Histochem Cytochem 49: 419–432, 2001.
 457. Hallmann R, Horn N, Selg M, Wendler O, Pausch Fand Sorokin LM. Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85: 979–1000, 2005.
 458. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O and Sorokin LM. Endothelial cell laminin isoforms, laminins 8 and 10. play decisive roles in T cell recruitment across the blood‐brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153: 933–946, 2001.
 459. Miyasaka M and Tanaka T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol 4: 360–370, 2004.
 460. Nourshargh S and Marelli‐Berg FM. Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol 26: 157–165, 2005.
 461. Newman PJ and Newman DK. Signal transduction pathways mediated by PECAM‐1: new roles for an old molecule in platelet and vascular cell biology. Arterioseler Thromb Vase Biol 23: 953–964, 2003.
 462. Dangerfield J, Larbi KY, Huang MT, Dewar A and Nourshargh S. PECAM‐I (CD31) homophilic interaction up‐regulates alpha‐6betal on transmigrated neutrophils in vivo and plays a functional role in the ability of alpha6 integrins to mediate leukocyte migration through the perivascular basement membrane. J Exp Med 196: 1201–1211, 2002.
 463. Werr J, Eriksson EE, Hedqvist P and Lindbom L. Engagement of 32 integrins induces surface expression of betal integrin receptors in human neutrophils. J Leukocyte Biol 68: 553–560, 2000.
 464. Adair‐Kirk TL, Atkinson JJ, Broekelmann TJ, Doi M, Tryggvason K, Miner JH, Mecham RP and Senior RM. A site on laminin alpha 5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase‐9 and chemotaxis. J Immunol 171: 398–406, 2003.
 465. Cepinskas G, Sandig M and Kvietys PR. PAF‐induced elastase‐dependent neutrophil transendothelial migration is associated with the mobilization of elastase to the neutrophil surface and localization to the migrating front. J Cell Sci 112: 1937–1945, 1999.
 466. Wang S, Dangerfield JP, Young RE and Nourshargh S. PECAM‐I. alpha6 integrins and neutrophil elastase cooperate in mediating neutrophil transmigration. J Cell Sci 118: 2067–2076, 2005.
 467. Lackie JM and Wilkinson PC. Adhesion and locomotion of neutrophil leukocytes on 2‐D substrata and in 3‐D matrices. In: White Cell Mechanics: Basic Science and Clinical Aspects, eds Meiselman HJ, Lichtman MA and LaCelle PL. New York: A. R. Liss, 1984. pp. 237–254.
 468. Friedl P, Borgmann S and Brocker EB. Amoeboid leukocyte crawling through extracellular matrix: lessons from the dictyostelium paradigm of cell movement. J Leukoc Biol 70: 491–509, 2001.
 469. Bainton DF, Miller U, Kishimoto TK and Springer TA. Leukocyte adhesion receptors are stored in peroxidase‐negative granules of human neutrophils. J Exp Med 166: 1641–1653, 1987.
 470. Kubes P, Niu X‐F, Smith CW, Kehrli ME, Reinhardt PH and Woodman RC. A novel β1 ‐dependent adhesion pathway on neutrophils: a mechanism invoked by dihydrocytochalasin B or endothelial transmigration. FASEB J 9: 1103–1111, 1995.
 471. Werr J, Johansson J, Eriksson EE, Hedqvist P, Ruoslahti E and Lindbom L. Integrin alpha(2)beta(1) (VLA‐2) is a principal receptor used by neutrophils for locomotion in extravascular tissue. Blood 95: 1804–1809, 2000.
 472. Reinhardt PH, Elliott JF and Kubes P. Neutrophils can adhere via alpha(4)beta(1)‐integrin under flow conditions. Blood 89: 3837–3846, 1997.
 473. Taooka Y, Chen J, Yednock T and Sheppard D. The integrin alpha‐9betal mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule‐1. J Cell Biol 145: 413–420, 1999.
 474. Rennke HG and Klein PS. Pathogenesis and significance of nonprimary focal and segmental glomerulosclerosis. Am J Kidney Dis 13: 443–456, 1989.
 475. Wang Q, Tang XN and Yenari MA. The inflammatory response in stroke. J Neuroimmunol 184: 53–68, 2007.
 476. Sumimoto H, Miyano K and Takeya R. Molecular composition and regulation of the NOx family NAD(P)H oxidases. Biochem Biophys Res Commun 338: 677–686, 2005.
 477. Seifert R and Schultz G. The superoxide‐forming NADPH oxidase of phagocytes: an enzyme system regulated by multiple mechanisms. Rev Physiol Biochem Pharmacol 117: 1–338, 1991.
 478. Hansson M, Olsson I and Nauseef WM. Biosynthesis, processing, and sorting of human myeloperoxidase. Arch Biochem Biophys 445: 214–224, 2006.
 479. Jackson SH, Gallin JI and Holland SM. The p47phox mouse knockout model of chronic granulomatous disease. J Exp Med 182: 751–758, 1995.
 480. Morgenstern DE, Gifford MAC, Li LL, Doerschuk CM and Dinauer MC. Absence of respiratory burst in X‐linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to aspergillus fumigatus. J Exp Med 185: 207–218, 1997.
 481. Kubes P, Suzuki M and Granger DN. Nitric oxide ‐ an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88: 4651–4655, 1991.
 482. Matsushita K, Morrell CN, Cambien B, Yang SX, Yamakuchi M, Bao C, Hara MR, Quick RA, Cao W, O'Rourke B, Lowenstein JM, Pevsner J, Wagner DD and Lowenstein CJ. Nitric oxide regulates exocytosis by S‐nitrosylation of N‐ethylmaleimide‐sensitive factor. Cell 115: 139–150, 2003.
 483. Hickey MJ. Role of inducible nitric oxide synthase in the regulation of leucocyte recruitment. Clinical Science 100: 1–12, 2001.
 484. Gay NJ and Keith FJ. Drosophila toll and IL‐1 receptor. Nature 351: 355–356, 1991.
 485. Kaisho T and Akira S. Toll‐like receptor function and signaling. J Allergy Clin Immunol 117: 979–987, 2006.
 486. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G and Flavell RA. Nod2‐dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307: 731–734, 2005.
 487. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM and Weaver CT. Interleukin 17‐producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6: 1123–1132, 2005.
 488. Ley K, Smith E and Stark MA. IL‐17A‐producing neutrophil‐regulatory Tn lymphocytes. Immunol Res 34: 229–242, 2006.
 489. Borges E, Tietz W, Steegmaier M, Moll T, Hallmann R, Hamann A and Vestweber D. P‐selectin glycoprotein ligand‐1 (PSGL‐1) on T helper 1 but not on T helper 2 cells binds to P‐selectin and supports migration into inflamed skin. J Exp Med 185: 573–578, 1997.
 490. Austrup F, Vestweber D, Borges E, Lohning M, Brauer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A and Hamann A. P‐ and E‐selectin mediate recruitment of T‐helper‐1 but not T‐helper‐2 cells into inflamed tissues. Nature 385: 81–83, 1997.
 491. Taylor A, Verhagen J, Blaser K, Akdis M and Akdis CA. Mechanisms of immune suppression by interleukin‐10 and transforming growth factor‐beta: the role of T regulatory cells. Immunology 117: 433–442, 2006.
 492. Bamias G, Martin C, Mishina M, Ross WG, Rivera‐Nieves J, Marini M and Cominelli F. Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology 128: 654–666, 2005.
 493. Scheuerer B, Ernst M, Durrbaum‐Landmann I, Fleischer J, Grage‐Griebenow E, Brandt E, Flad HD and Petersen F. The CXC‐chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 95: 1158–1166, 2000.
 494. von Hundelshausen P, Koenen RR, Sack M, Mause SF, Adriaens W, Proudfoot AE, Hackeng TM and Weber C. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 105: 924–930, 2005.
 495. Gear AR and Camerini D. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation and host defense. Microcirculation 10: 335–350, 2003.
 496. Coughlin SR. Thrombin signalling and protease‐activated receptors. Nature 407: 258–264, 2000.
 497. Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D, Moff S, Farese RV, Jr., Tarn C and Coughlin SR. A dual thrombin receptor system for platelet activation. Nature 394: 690–694, 1998.
 498. Schonbeck U and Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 58: 4–43, 2001.
 499. Bodin S, Tronchere H and Payrastre B. Lipid rafts are critical membrane domains in blood platelet activation processes. Biochim Biophys Acta 1610: 247–257, 2003.
 500. Prasad KS, Andre P, Yan Y and Phillips DR. The platelet CD40L/GP Ilb‐IIIa axis in atherothrombotic disease. Curr Opin Hematol 10: 356–361, 2003.
 501. Mach F, Schonbeck U, Sukhova GK, Atkinson E and Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394: 200–203, 1998.
 502. Danese S and Fiocchi C. Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. Cril Rev Immunol 25: 103–121, 2005.
 503. Willerson JT. Serotonin and thrombotic complications. J Cardiovasc Pharmacol 17 Suppl 5: S13–S20, 1991.
 504. McIntire LV, Kukreti S and Konstantopoulos K. Biomechanics of cell interactions in shear fields. Adv Drug Deliv Rev 33: 1–2, 1998.
 505. Furman MI, Benoit SE, Barnard MR, Valeri CR, Borbone ML, Becker RC, Hechtman HB and Michelson AD. Increased platelet reactivity and circulating monocyte‐platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 31: 352–358, 1998.
 506. Michelson AD, Barnard MR, Krueger LA, Valeri CR and Furman MJ. Circulating monocyte‐platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P‐ selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 104: 1533–1537, 2001.
 507. Huo Y and Ley K. Role of platelets in the development of atherosclerosis. Trend Cardiovasc Med 14: 18–22, 2004.
 508. Weber C and Springer TA. Neutrophil accumulation on activated, surface‐adherent platelets in flow is mediated by interaction of Mac‐1 with fibrinogen bound to αIIb β3 and stimulated by platelet‐activating factor. J Clin Invest 100: 2085–2093, 1997.
 509. Larsen E, Celi A, Gilbert GE, Furie BC, Erban JK and Bonfanti R. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 590: 305–312, 1989.
 510. Diacovo TG, Puri KD, Warnock RA, Springer TA and von Andrian UH. Platelet‐mediated lymphocyte delivery to high endothelial venules. Science 273: 252–255, 1996.
 511. Frenette PS, Johnson RC, Hynes MR and Wagner DD. Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P‐selectin. Proc Natl Acad Sci USA 92: 7450–7454, 1995.
 512. Romo GM, Dong JF, Schade AJ, Gardiner EE, Kansas GS, Li CQ, McIntire LV, Berndt MC and Lopez JA. The glycoprotein Ib‐IX‐V complex is a platelet counterreceptor for P‐selectin. J Exp Med 190: 803–813, 1999.
 513. Padilla A, Moake JL, Bernardo A, Ball C, Wang Y, Arya M, Nolasco L, Turner N, Berndt MC, Anvari B, Lopez JA and Dong JF. P‐selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. Blood 103: 2150–2156, 2004.
 514. Lopez JA and Dong JF. Cleavage of von Willebrand factor by ADAMTS‐13 on endothelial cells. Semin Hematol 41: 15–23, 2004.
 515. Massberg S, Brand K, Gruner S, Page S, Muller E, Muller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B and Gawaz M. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 196: 887–896, 2002.
 516. Gutensohn K, Geidel K, Brockmann M, Siemensen M, Krueger W, Kroeger N and Kuehnl P. Binding of activated platelets to WBCs in vivo after transfusion. Transfusion 42: 1373–1380, 2002.
 517. Levi M, van der Poll T and Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 109: 2698–2704, 2004.
 518. Levi M, ten Cate H, Bauer KA, van der PT, Edgington TS, Buller HR, van Deventer SJ, Hack CE, ten Cate JW and Rosenberg RD. Inhibition of endotoxin‐induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti‐tissue factor antibody in chimpanzees. J Clin Invest 93: 114–120, 1994.
 519. Ruf W and Edgington TS. Structural biology of tissue factor, the initiator of thrombogenesis in vivo. FASEB J 8: 385–390, 1994.
 520. Pixley RA, De La CR, Page JD, Kaufman N, Wyshock EG, Chang A, Taylor FB, Jr. and Colman RW. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti‐factor XII antibody to block contact activation in baboons J Clin Invest 91: 61–68, 1993.
 521. Falati S, Liu Q, Gross P, Merrill‐Skoloff G, Chou J, Vandendries E, Celi A, Croce K, Furie BC and Furie B. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P‐selectin glycoprotein ligand I and platelet P‐selectin. J Exp Med 197: 1585–1598, 2003.
 522. Forlow SB, McEver RP and Nollert MU. Leukocyte‐leukocyte interactions mediated by platelet microparticles under flow. Blood 95: 1317–1323, 2000.
 523. Garcia BA, Smalley DM, Cho H, Shabanowitz J, Ley K and Hunt DF. The platelet microparticle proteome, 2005. Proteomics Research available online.
 524. Falati S, Gross P, Merrill‐Skoloff G, Furie BC and Furie B. Realtime in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nature Med 8: 1175–1181, 2002.
 525. Boulanger CM, Scoazec A, Ebrahimian T, Henry P, Mathieu E, Tedgui A and Mallat Z. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104: 2649–2652, 2001.
 526. Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M and Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 9: 458–462, 2003.
 527. Subramaniam M, Frenette PS, Saffaripour S, Johnson RC, Hynes RO and Wagner DD. Defects in hemostasis in P‐selectin‐deficient mice. Blood 87: 1238–1242, 1996.
 528. Hrachovinova I, Cambien B, Hafezi‐Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH, Jr., Schaub RG, McEver RP and Wagner DD. Interaction of P‐selectin and PSGL‐I generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 9: 1020–1025, 2003.
 529. Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 264: 4743–4746, 1989.
 530. Mousa SA, Fareed J, Iqbal O and Kaiser B. Tissue factor pathway inhibitor in thrombosis and beyond. Methods Mol Med 93: 133–155, 2004, 133–155.
 531. Nicholl SM, Roztocil E and Davies MG. Plasminogen activator system and vascular disease. Curr Vasc Pharmacol 4: 101–116, 2006.
 532. Cunningham MA, Romas P, Hutchinson P, Holdsworth SR and Tipping PG. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood 94: 3413–3420, 1999.
 533. de Jonge E, Friederich PW, Vlasuk GP, Rote WE, Vroom MB, Levi M and van der PT. Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL‐6) and IL‐8 release in healthy human subjects. Clin Diagn Lab Immunol 10: 495–497, 2003.
 534. Szaba FM and Smiley ST. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood 99: 1053–1059, 2002.
 535. Esmon CT. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J Exp Med 196: 561–564, 2002.
 536. Okajima K. Regulation of inflammatory responses by natural anticoagulants. Immunol Rev 184: 258–274, 2001.
 537. Conway EM, Van de WM, Pollefeyt S, Jurk K, Van Aken H, De Vriese A, Weitz JI, Weiler H, Hellings PW, Schaeffer P, Herbert JM, Collen D and Theilmeier G. The lectin‐like domain of thrombomodulin confers protection from neutrophil‐mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen‐activated protein kinase pathways. J Exp Med 196: 565–577, 2002.
 538. Bajzar L, Morser J and Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin‐thrombomodulin complex. J Biol Chem 271: 16603–16608, 1996.
 539. Vary TC and Kimball SR. Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol 262: C445–C452, 1992.
 540. Seitz R, Wolf M, Egbring R and Havemann K. The disturbance of hemostasis in septic shock: role of neutrophil elastase and thrombin, effects of antithrombin III and plasma substitution. Eur J Haematol 43: 22–28, 1989.
 541. Jagneaux T, Taylor DE and Kantrow SP. Coagulation in sepsis. Am J Med Sci 328: 196–204, 2004.
 542. Ren Y, Stuart L, Lindberg FP, Rosenkranz AR, Chen Y, Mayadas TN and Savill J. Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of beta 2 integrins. J Immunol 166: 4743–4750, 2001.
 543. Lucas M, Stuart LM, Savill J and Lacy‐Hulbert A. Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion. J Immunol 171: 2610–2615, 2003.
 544. Mempel TR, Henrickson SE and von Andrian UH. T‐cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427: 154–159, 2004.
 545. Abeles AM and Pillinger MH. Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum 54: 393–407, 2006.
 546. Schonbeck U and Libby P. Inflammation, immunity, and HMG‐CoA reductase inhibitors: statins as antiinflammatory agents? Circulation 109: 1118–1126, 2004.
 547. Slingluff CL, Jr., Engelhard VH and Ferrone S. Peptide and dendritic cell vaccines. Clin Cancer Res 12: 2342s–2345s, 2006.
 548. Gardner H, Kreidberg J, Koteliansky V and Jaenisch R. Deletion of integrin alpha 1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion. Dev Biol 175: 301–313, 1996.
 549. Pozzi A, Moberg PE, Miles LA, Wagner S, Soloway P and Gardner HA. Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci USA 97: 2202–2207, 2000.
 550. Holtkotter O, Nieswandt B, Smyth N, Muller W, Hafner M, Schulte V, Krieg T and Eckes B. Integrin alpha 2‐deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen. J Biol Chem 277: 10789–10794, 2002.
 551. Chen J, Diacovo TG, Grenache DG, Santoro SA and Zutter MM. The alpha(2) integrin subunit‐deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161: 337–344, 2002.
 552. Arroyo AG, Yang JT, Rayburn H and Hynes RO. Differential requirements for α4 integrins during fetal and adult hematopoiesis. Cell 85: 997–1008, 1996.
 553. Georges‐Labouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A and Le MM. Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet 13: 370–373, 1996.
 554. Georges‐Labouesse E, Mark M, Messaddeq N and Gansmuller A. Essential role of alpha 6 integrins in cortical and retinal lamination. Curr Biol 8: 983–986, 1998.
 555. Huang XZ, Wu JF, Ferrando R, Lee JH, Wang YL, Farese RV, Jr. and Sheppard D. Fatal bilateral chylothorax in mice lacking the integrin alpha9betal. Mol Cell Biol 20: 5208–5215, 2000.
 556. Bader BL, Rayburn H, Crowley D and Hynes RO. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95: 507–519, 1998.
 557. McCarty JH, Monahan‐Earley RA, Brown LF, Keller M, Gerhardt H, Rubin K, Shani M, Dvorak HF, Wolburg H, Bader BL, Dvorak AM and Hynes RO. Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol Cell Biol 22: 7667–7677, 2002.
 558. Tronik‐Le Roux D, Roullot V, Poujol C, Kortulewski T, Nurden P and Marguerie G. Thrombasthenic mice generated by replacement of the integrin alpha(IIb) gene: demonstration that transcriptional activation of this megakaryocytic locus precedes lineage commitment. Blood 96: 1399–1408, 2000.
 559. Tang T, Rosenkranz A, Assmann KJM, Goodman MJ, Gutierrezramcs JC, Carroll MC, Cotran RS and Mayadas TN. A role for Mac‐1 (CD lib/CD 18) in immune complex‐stimulated neutrophil function in vivo ‐ Mac‐1 deficiency abrogates sustained Fc‐gamma receptor‐dependent neutrophil adhesion and complement‐dependent proteinuria in acute glomerulonephritis. J Exp Med 186: 1853–1863, 1997.
 560. Dong ZM, Gutierrezramos JC, Coxon A, Mayadas TN and Wagner DD. A new class of obesity genes encodes leukocyte adhesion receptors. Proc Natl Acad Sci USA 94: 7526–7530, 1997.
 561. Wu H, Rodgers JR, Perrard XY, Perrard JL, Prince JE, Abe Y, Davis BK, Dietsch G, Smith CW and Ballantyne CM. Deficiency of CD11b or CD11d results in reduced staphylococcal enterotoxin‐induced T cell response and T cell phenotypic changes. J Immunol 173: 297–306, 2004.
 562. Schon MP, Arya A, Murphy EA, Adams CM, Strauch UG, Agace WW, Marsal J, Donohue JP, Her H, Beier DR, Olson S, Lefrancois L, Brenner MB, Grusby MJ and Parker CM. Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)‐deficient mice. J Immunol 162: 6641–6649, 1999.
 563. Stephens LE, Sutherland AE, Klimanskaya IV, Andrieux A, Meneses J, Pedersen RA and Damsky CH. Deletion of beta I integrins in mice results in inner cell mass failure and peri‐implantation lethality. Genes Dev 9: 1883–1895, 1995.
 564. McHugh KP, Hodivala‐Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO and Teitelbaum SL. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105: 433–440, 2000.
 565. Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, Huang X, Sheppard D, Hynes RO and Hodivala‐Dilke KM. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8: 27–34, 2002.
 566. Wagner N, Löhler J, Kunkel EJ, Ley K, Leung E, Krissansen G, Rajewsky K and Müller W. Critical role for β7 integrins in formation of the gut‐associated lymphoid tissue. Nature 382: 366–370, 1996.
 567. Plow EF and Zhang L. A mac‐1 attack: integrin functions directly challenged in knockout mice [editorial]. J Clin Invest 99: 1145–1146, 1997, 3.
 568. Ehlers MR. CR3: a general purpose adhesion‐recognition receptor essential for innate immunity. Microbes Infect 2: 289–294, 2000.
 569. Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC and Lopez JA. Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac‐1 (CD11b/CD18). J Exp Med 192: 193–204, 2000.
 570. Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT and Chavakis T. The junctional adhesion molecule 3 (JAM‐3) on human platelets is a counterreceptor for the leukocyte integrin Mac‐1. J Exp Med 196: 679–691, 2002.
 571. Xu JC, Grewal IS, Geba GP and Flavell RA. Impaired primary T cell responses in L‐selectin‐deficient mice. J Exp Med 183: 589–598, 1996.
 572. Grewal IS, Foellmer HG, Grewal KD, Wang H, Lee WP, Tumas D, Janeway CA, Jr. and Flavell RA. CD62L is required on effector cells for local interactions in the CNS to cause myelin damage in experimental allergic encephalomyelitis. Immunity 14: 291–302, 2001.
 573. Labow MA, Norton CR, Rumberger JM, Lombard‐Gillooly KM, Shuster DJ, Hubbard J, Bertko R, Knaack PA, Terry RW, Harbison ML, Kontgen F, Stewart CL, McIntyre KW, Will PC, Burns DK and Wolitzky BA. Characterization of E‐selectin‐deficient mice: demonstration of overlapping function of the endothelial selectins. Immunity 1: 709–720, 1994.
 574. Bullard DC, Qin L, Lorenzo I, Quinlin WM, Doyle NA, Bosse R, Vestweber D, Doerschuk CM and Beaudet AL. P‐selectin/ICAM‐1 double mutant mice: acute emigration of neutrophils into the peritoneum is completely absent but is normal in pulmonary alveoli. J Clin Invest 95: 1782–1788, 1995.
 575. Robinson SD, Frenetle PS, Rayburn H, Cummiskey M, Ullman‐Cullere M, Wagner DD and Hynes RO. Multiple, targeted deficiencies in selectins reveal a predominant role for P‐selectin in leukocyte recruitment. Proc Natil Acad Sci USA 96: 11452–11457, 1999.
 576. Schmits R, Filmus J, Gerwin N, Senaldi G, Kiefer F, Kundig T, Wakeham A, Shahinian A, Catzavelos C, Rak J, Furlonger C, Zakarian A, Simard JJ, Ohashi PS. Paige CJ, Gutierrez‐Ramos JC and Mak TW, CD44 regulates hematopoietic progenitor distribution, granuloma formation, and tumorigenicity. Blood 90: 2217–2233, 1997.
 577. Takeda K and Akira S. Toll‐like receptors in innate immunity. Int Immunol 17: 1–14, 2005.
 578. van der PT, Levi M, Buller HR, van Deventer SJ, de Boer JP, Hack CE and ten Cate JW. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 174: 729–732, 1991.
 579. van der PT, de Jonge E and Levi M. Regulatory role of cytokines in disseminated intravascular coagulation. Semin Thromb Hemosl 27: 639–651, 2001.
 580. Versteeg HH, Peppelenbosch MP and Spek CA. The pleiotropic effects of tissue factor: a possible role for factor Vila‐induced intracellular signalling? Thromb Haemost 86: 1353–1359, 2001.
 581. Kaneider NC, Forster E, Mosheimer B, Sturn DH and Wiedemann CJ. Syndecan‐4‐dependent signaling in the inhibition of endotoxin‐induced endothelial adherence of neutrophils by antithrombin. Thromb Haemost 90: 1150–1157, 2003.
 582. May AE, Schmidt R, Kanse SM, Chavakis T, Stephens RW, Schomig A, Preissner KT and Neumann FJ. Urokinase receptor surface expression regulates monocyte adhesion in acute myocardial infarction. Blood 100: 3611–3617, 2002.
 583. Cayatte AJ, Rupin A, Oliver‐Krasinski J, Maitland K, Sansilvestri‐Morel P, Boussard MF, Wierzbicki M, Verbeuren TJ and Cohen RA. S17834, a new inhibitor of cell adhesion and atherosclerosis that targets nadph oxidase. Arterioscler Thromb Vase Biol 21: 1577–1584, 2001.
 584. Arnold J. Ueber das Verhalten der Wandungen der Blutgefasse bei der Emigration weisser Blutkorper. Virchows Archiv 62: 487–503, 1875.
 585. Ley K and Gaehtgens P. Endothelial, not hemodynamic differences are responsible for preferential leukocyte rolling in venules. Cire Res 69: 1034–1041, 1991.
 586. Reneman RS, Woldhuis B, oude Egbrink MGA, Slaaf DW and Tangelder GJ. Concentration and velocity profiles of blood cells in the microcirculation. In: Advances in Cardiovascular Engineering. eds Hwang NHC, Turitto VT and Yen MRT. New York: Plenum Press, 1992, pp. 25–40.
 587. Kunkel EJ, Jung U and Ley K. TNF‐α induces selectin‐dependent leukocyte rolling in mouse cremaster muscle arterioles. Am J Physiol 212: H1391–H1400, 1997.
 588. Ley K. Leukocyte adhesion molecules: effectors of cell traffic in inflammation. BMES Bulletin 18: 43–17, 1995.
 589. Schmidt EE, MacDonald IC and Groom AC. Changes in splenic microcirculatory pathways in chronic idiopathic thrombocytopenic purpura. Blood 78: 1485–1489, 1991.
 590. Maina JN. Is the sheet‐flow design a ‘frozen core’ (a Bauplan) of the gas exchangers? Comparative functional morphology of the respiratory microvascular systems: illustration of the geometry and rationalization of the fractal properties. Comp Biochem Physiol A Mol Integr Physiol 126: 491–515, 2000.
 591. Wei W, Popov V, Walocha JA, Wen J and Bello‐Reuss E. Evidence of angiogenesis and microvascular regression in autosomal‐dominant polycystic kidney disease kidneys: a corrosion cast study. Kidney Int 70: 1261–1268, 2006.
 592. Bedard K and Krause KH. The NOX family of ROS‐generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87: 245–313, 2007.
 593. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6: 173–182, 2006.
 594. Pawlinski R and Mackman N. Tissue factor, coagulation proteases, and protease‐activated receptors in endotoxemia and sepsis. Crit Care Med 32: S293–S297, 2004.

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Article Title: The Microcirculation in Inflammation
 

How to Cite

Klaus Ley. The Microcirculation in Inflammation. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 387-448. First published in print 2008. doi: 10.1002/cphy.cp020409