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Gastrointestinal and Liver Microcirculations: Roles in Inflammation and Immunity

Soichiro Miura, Paul Kubes, D Neil Granger

10.1002/cphy.cp020414

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 Introduction
2 Gastrointestinal Microcirculation
2.1 Microvascular perfusion and inflammation
2.2 Microvascular perfusion and the recruitment of leukocytes and platelets
3 The Microcirculation and Immune Function
3.1 Lymphocyte homing and cellular traffic in organized lymphoid tissue of intestine
3.2 Lymphoid cell traffic to intestinal immune effector sites
3.3 The microcirculation and IBD
3.4 NSAIDs: the microcirculation and neutrophil‐mediated GI injury
3.5 Helicobacter pylori (HP) infection and gastric mucosal injury
4 Liver Microcirculation
4.1 Role of inflammatory cells in liver disease
Figure 1. Figure 1.

Relationship between shear rate and the adhesion of leukocytes and platelets in rat mesenteric venules. Data from Am J Physiol 284: G123–G129. 2003.
Figure 2. Figure 2.

Schematic representation of the T lymphocyte trafficking in the intestinal immune system. The organized lymphoid tissues of the Peyer's patches (PP) and mesenteric lymph nodes (MLNs) are involved in the induction of immunity and education of intestinal tropism of lymphocytes. Naïve and central memory T lymphocytes and plasmacytoid dendritic cells (DC) migrate into PP through high endothelium of postcapillary venules (PCV). Central and effector memory T cells also migrate to the effector sites in the lamina propria of the intestine. The cell adhesion molecules used for the recruitment of lymphoid cells are shown in the frame. (See page 18 in colour section at the back of the book)
Figure 3. Figure 3.

Representative microscopic images of lymphocyte migration in the rat intestine. (A) An ileal Peyer's patch (PP) under fluorescence microscopy at 20 min after the infusion of carboxyfluorescein succinimidyl ester (CFSE)‐labeled T lymphocytes derived from intestinal lymph. The lymphocytes adhere in a relatively select portion of postcapillary venules of PP (× 10 objective lens). (B) Distribution of transmigrated CFSE‐labeled T lymphocytes in PP 1 h after the infusion. Many lymphocytes migrate into the interstitium (× 20 objective lens). (C) High‐speed video images of rat intestinal collecting lymphatics. A marked increase in lymphocyte transport through lymphatics is observed 4h after administration of olive oil. (D) Villus tips of ileal mucosa in endotoxin‐treated rats under fluorescence microscopy. Adherent T lymphocytes in arcade microvessels are observed 20 min after T lymphocyte administration (× 20 objective lens). (See page 18 in colour section at the back of the book)
Figure 4. Figure 4.

Chemokine and chemokine receptor expression in the intestinal mucosa and their possible roles in the trafficking of lymphocytes and plasma cells. Chemokine expression in organized lymphoid tissues (e.g. Peyer's patches) differs from that observed in the intestinal mucosa, and is characterized by the expression of SLC/CCL21 and CCL19/ELC in the high endothelial venules for attracting T cells and CXCL13/BLC for B cells. The small intestine expresses the specific chemokine CCL25/TECK. which attracts cells with small intestinal tropism such as CCR9+ memory T cells and CCR9+ plasma cells. During intestinal inflammation, the mechanisms controlling lymphocyte trafficking become more complex. (See page 19 in colour section at the back of the book)
Figure 5. Figure 5.

(A) illustrates that leukocytes roll in post‐sinusoidal venules due to [I] expression of adhesion molecules, and 2 diameter is not a limitation. (B) illustrates that leukocytes approach the diameter of sinusoids and the lack of selectins within these vessels prevent rolling. Only firm adhesion is seen in sinusoids.
Figure 6. Figure 6.

The role of selectins in leukocyte adhesion in sinusoids (A) and hepatic venules (B) after FMLP treatment. Liver preparations were studied in wildtype, P‐selectin defecient, and double E‐selectin/P‐selectin deficient mice. To eliminate contributions of all three selectins, some E‐selectin/P‐selectin defecient animals were also given an anti‐L‐selectin mAb intravenously (Mel‐14, 3mg/kg). Preparations were superfused continuously with bicarbonate‐buffered saline alone or 10 uM FMLP. Leukocyte adhesion was determined 60 min after FMLP treatment. Data are represented as means ± SEM. *p < 0.05 vs. wildtype; n = 18.


Figure 1.

Relationship between shear rate and the adhesion of leukocytes and platelets in rat mesenteric venules. Data from Am J Physiol 284: G123–G129. 2003.



Figure 2.

Schematic representation of the T lymphocyte trafficking in the intestinal immune system. The organized lymphoid tissues of the Peyer's patches (PP) and mesenteric lymph nodes (MLNs) are involved in the induction of immunity and education of intestinal tropism of lymphocytes. Naïve and central memory T lymphocytes and plasmacytoid dendritic cells (DC) migrate into PP through high endothelium of postcapillary venules (PCV). Central and effector memory T cells also migrate to the effector sites in the lamina propria of the intestine. The cell adhesion molecules used for the recruitment of lymphoid cells are shown in the frame. (See page 18 in colour section at the back of the book)



Figure 3.

Representative microscopic images of lymphocyte migration in the rat intestine. (A) An ileal Peyer's patch (PP) under fluorescence microscopy at 20 min after the infusion of carboxyfluorescein succinimidyl ester (CFSE)‐labeled T lymphocytes derived from intestinal lymph. The lymphocytes adhere in a relatively select portion of postcapillary venules of PP (× 10 objective lens). (B) Distribution of transmigrated CFSE‐labeled T lymphocytes in PP 1 h after the infusion. Many lymphocytes migrate into the interstitium (× 20 objective lens). (C) High‐speed video images of rat intestinal collecting lymphatics. A marked increase in lymphocyte transport through lymphatics is observed 4h after administration of olive oil. (D) Villus tips of ileal mucosa in endotoxin‐treated rats under fluorescence microscopy. Adherent T lymphocytes in arcade microvessels are observed 20 min after T lymphocyte administration (× 20 objective lens). (See page 18 in colour section at the back of the book)



Figure 4.

Chemokine and chemokine receptor expression in the intestinal mucosa and their possible roles in the trafficking of lymphocytes and plasma cells. Chemokine expression in organized lymphoid tissues (e.g. Peyer's patches) differs from that observed in the intestinal mucosa, and is characterized by the expression of SLC/CCL21 and CCL19/ELC in the high endothelial venules for attracting T cells and CXCL13/BLC for B cells. The small intestine expresses the specific chemokine CCL25/TECK. which attracts cells with small intestinal tropism such as CCR9+ memory T cells and CCR9+ plasma cells. During intestinal inflammation, the mechanisms controlling lymphocyte trafficking become more complex. (See page 19 in colour section at the back of the book)



Figure 5.

(A) illustrates that leukocytes roll in post‐sinusoidal venules due to [I] expression of adhesion molecules, and 2 diameter is not a limitation. (B) illustrates that leukocytes approach the diameter of sinusoids and the lack of selectins within these vessels prevent rolling. Only firm adhesion is seen in sinusoids.



Figure 6.

The role of selectins in leukocyte adhesion in sinusoids (A) and hepatic venules (B) after FMLP treatment. Liver preparations were studied in wildtype, P‐selectin defecient, and double E‐selectin/P‐selectin deficient mice. To eliminate contributions of all three selectins, some E‐selectin/P‐selectin defecient animals were also given an anti‐L‐selectin mAb intravenously (Mel‐14, 3mg/kg). Preparations were superfused continuously with bicarbonate‐buffered saline alone or 10 uM FMLP. Leukocyte adhesion was determined 60 min after FMLP treatment. Data are represented as means ± SEM. *p < 0.05 vs. wildtype; n = 18.

References
 1. Donald DE. Splanchnic circulation. In: Handbook of Physiology, Section 2: The Cardiovascular System. Volume III. The Peripheral Circulation and Organ Blood Flow, Part 1, eds Shepherd JT and Abboud FM, Bethesda, MD: The American Physiological Society, 1983. pp. 219–240.
 2. Lundgren O. Microcirculation of the gastrointestinal tract and pan creas. In: Handbook of Physiology, Section 2: The Cardiovascular System. Volume TV. Microcirculation, Part 1, eds Renkin EM and Michel CC. Bethesda, MD: The American Physiological Society, 1984, pp. 799–864.
 3. Granger DN, Kvietys PR, Korthuis RJ and Premen AJ. Microcirculation of the intestinal mucosa. In: Handbook of Physiology, Section 6: The Gastrointestinal System. Volume I. Motility and Circulation, Part 2, ed. Wood JD. Bethesda, MD: The American Physiological Society, 1989, pp. 1405–1474.
 4. Kvietys PR, Granger DN and Harper SL. Circulation of the pancreas and salivary glands. In: Handbook of Physiology, Section 6: The Gastrointestinal System. Volume 1. Motility and Circulation, Part 2, ed. Wood JD. Bethesda, MD: The American Physiological Society, 1989, pp. 1565–1596.
 5. Lautt WW. Hepatic circulation. In: Handbook of Physiology, Section 6: The Gastrointestinal System. Volume I. Motility and Circulation, Part 2, ed. Wood JD, Bethesda, MD: The American Physiological Society, 1989, pp. 1519–1564.
 6. Crissinger KD and Granger DN. Gastrointestinal blood flow. In: Textbook of Gastroenterology, 4th Edition, Vol. 1, eds Yamada T, Alpers DH, Kaplowitz N, Laine L, Owyang C and Powell DW. Philadelphia: Lippincott Williams & Wilkins, 2003, pp. 498–520.
 7. Hatoum OA, Miura H and Binion DG. The vascular contribution in the pathogenesis of inflammatory bowel disease. Am J Physiol Heart Circ Physiol 285: H1791–H1796, 2003.
 8. Korthuis RJ. Inflammatory bowel disease: role of the intestinal circulation. In: Pathophysiology of the Splanchnic Circulation, Vol. II, eds Kvietys PR, Barrowman JA and Granger DN, Boca Raton: CRC Press 1987, pp. 67–88.
 9. Guslandi M, Polli D, Sorghi M and Tittobello A. Rectal blood flow in ulcerative colitis. Am J Gastroenterol 90: 579–580, 1995.
 10. Bolondi L, Gaiani S, Brignola C, Campieri M, Rigamonti A, Zironi G, Gionchetti P, Belloli C, Miglioli M and Barbara L. Changes in splanchnic hemodynamics in inflammatory bowel disease. Noninvasive assessment by Doppler ultrasound flowmetry. Stand J Gastroenterol 27: 501–507, 1992.
 11. Hulten L, Lindhagen J, Lundgren O, Fasth S and Ahren C. Regional intestinal blood flow in ulcerative colitis and Crohn's disease. Gastroenterology 72: 388–396, 1977.
 12. Satoyoshi K, Akita Y, Nozu F, Yoshikawa N and Mitamura K. Hemodynamics in the colonic mucosa of rats with dextran sulfate‐induced colitis in the early phase. J Gastroenterol 31: 512–517, 1996.
 13. Garrelds IM, Heiligers JP, Van Meeteren ME, Duncker DJ, Saxena PR, Meijssen MA and Zijlstra FJ. Intestinal blood flow in murine colitis induced with dextran sulfate sodium. Dig Dis Sci 47: 2231–2236, 2002.
 14. Kruschewski M, Foitzik T, Perez‐Canto A, Hubotter A and Buhr HJ. Changes of colonic mucosal microcirculation and histology in two colitis models. An experimental study using intravital microscopy and a new histological scoring system. Dig Dis Sci 46: 2336–2343, 2001.
 15. Deniz M, Cetinel S and Kurtel H. Blood flow alterations in TNBS‐induced colitis: role of endothelin receptors. Inflammation res 53: 329–336, 2004.
 16. Hatoum OA, Binion DG, Otterson MF and Gutterman DD. Acquired Microvascular dysfunction in inflammatory bowel disease: loss of nitric oxide‐mediated vasodilation. Gastroenterology 125: 58–69, 2003.
 17. Granger DN, Grisham MB and Kvietys PR. Mechanisms of microvascular injury. In: Physiology of the Gastrointestinal Tract, ed. Johnson LR, New York: Raven Press, 1994, pp. 1693–1722.
 18. Bienvenu K, Granger DN and Perry MA. Flow dependence of leukocyte‐endothelial cell adhesion in postcapillary venules. In: Physiology and Pathophysiology of Leukocyte Adhesion, eds Granger DN and Schmid‐Schonbein G. New York: Oxford University Press, 1995, pp. 278–293.
 19. Atherton A and Born GVR. Relationship between the velocity of rolling granulocytes and that of the blood flow in venules. J Physiol 233: 157–165, 1973.
 20. Perry MA and Granger DN, Role of CD11/CD18 in shear rate‐dependent leukocyte‐endothelial cell interactions in cat mesenteric venules. J Clin Invest 87: 1798–1804, 1991.
 21. Nazziola E and House SD. Effects of hydrodynamic and leukocyte‐endothelium specificity on leukocyte‐endothelium interactions. Microvasc Res 44: 127–142, 1992.
 22. Granger DN and Kubes P. The microcirculation and inflammation: modulation of leukocyte‐endothelial cell adhesion. J Leukoc Biol 55: 662–675, 1994.
 23. Russell J, Cooper D, Tailor A, Stokes KY and Granger DN. Low venular shear rates promote leukocyte‐dependent recruitment of adherent platelets. Am J Physiol Gastrointest Liver Physiol 284: G123–G129, 2003.
 24. Tailor A, Cooper D and Granger DN. Platelet‐vessel wall interactions in the microcirculation. Microcirculation, 2005.
 25. Vowinkel T, Mori M, Krieglstein CF, Russell J, Saijo F, Bharwani S, Turnage RH, Davidson WS, Tso P, Granger DN and Kalogeris TJ. Apolipoprotein A‐IV inhibits experimental colitis. J Clin Invest 114: 260–269, 2004.
 26. Cooper D, Russell J, Chitman KD, Williams MC, Wolf RE and Granger DN. Leukocyte dependence of platelet adhesion in postcapillary venules. Am J Physiol 286: H1895–H1900, 2004.
 27. Tailor A and Granger DN. Hypercholesterolemia promotes leukocyte‐dependent platelet adhesion in murine postcapillary venules. Microcirculation 11: 597–603, 2004.
 28. 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. Nat Med 9: 61–67, 2003.
 29. Cerwinka WH, Cooper D, Krieglstein CF, Ross CR, McCord JM and Granger DN. Superoxide mediates endotoxin‐induced platelet‐endothelial cell adhesion in intestinal venules. Am J Physiol 284: H535–H541, 2003.
 30. Mebius RE. Organogenesis of lymphoid tissues. Nat Rev Immunol 3: 292–303, 2003.
 31. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 3: 331–341, 2003.
 32. Owen RL and Jones AL. Epithelial cell specialization within human Peyer's patches: an ultrastructural study of intestinal lymphoid follicles. Gastroenterology 66: 189–203, 1974.
 33. von Andrian UH and Mackay CR. T‐cell function and migration. Two sides of the same coin. N Engl J Med 343: 1020–1034, 2000.
 34. Briskin M, Winsor‐Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, McEvoy LM, Butcher EC, Kassam N, Mackay CR, Newman W and Ringler DJ. Human mucosal addressin cell adhesion molecule‐1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 151: 97–110, 1997.
 35. Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL and Butcher EC. alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80: 413–422, 1995.
 36. Hamann A, Andrew DP, Jablonski‐Westrich D, Holzmann B and Butcher EC. Role of alpha4‐integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 152: 3282–3293, 1994.
 37. Bargatze RF, Jutila MA and Butcher EC. Distinct roles of L‐selectin and integrins alpha 4 beta 7 and LFA‐1 in lymphocyte homing to Peyer's patch‐HEV in situ: the multistep model confirmed and refined. Immunity 3: 99–108, 1995.
 38. Fujimori H, Miura S, Koseki S, Hokari R, Komoto S, Hara Y, Hachimura S, Kaminogawa S and Ishii H. Intravital observation of adhesion of lamina propria lymphocytes to microvessels of small intestine in mice. Gastroenterology 122: 734–744, 2002.
 39. Streeter PR, Rouse BT and Butcher EC. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J Cell Biol 107: 1853–1862, 1988.
 40. Rosen SD, Hwang ST, Giblin PA and Singer MS. High‐endothelialvenule ligands for L‐selectin: identification and functions. Biochem Soc Trans 25: 428–433, 1997.
 41. Berg EL, McEvoy LM, Berlin C, Bargatze RF and Butcher EC. L‐selectin‐mediated lymphocyte rolling on MAdCAM‐1. Nature 366: 695–698, 1993.
 42. von Andrian UH and Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3: 867–878, 2003.
 43. 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.
 44. Maly P, Thall A, Petryniak B, Rogers CE, Smith PL, Marks RM, Kelly RJ, Gersten KM, Cheng G, Saunders TL, Camper SA, Camphausen RT, Sullivan FX, Isogai Y, Hindsgaul O, von Andrian UH and Lowe JB. The alpha(1–3)fucosyltransferase Fuc‐TVII controls leukocyte trafficking through an essential role in L‐, E‐, and P‐selectin ligand biosynthesis. Cell 86: 643–653, 1996.
 45. Butcher EC, Williams M, Youngman K, Rott L and Briskin M. Lymphocyte trafficking and regional immunity. Adv Immunol 72: 209–253, 1999.
 46. Ruegg C, Postigo AA, Sikorski EE, Butcher EC, Pytela R and Erle DJ. Role of integrin alpha 4 beta 7/alpha 4 beta P in lymphocyte adherence to fibronectin and VCAM‐1 and in homotypic cell clustering. J Cell Biol 117: 179–189, 1992.
 47. Williams MB and Butcher EC. Homing of naïve and memory T lymphocyte subsets to Peyer's patches, lymph nodes, and spleen. J Immunol 159: 1746–1752, 1997.
 48. Westermann J, Geismar U, Sponholz A, Bode U, Sparshott SM and Bell EB. CD4+ T cells of both the naïve and the memory pheno‐type enter rat lymph nodes and Peyer's patches via high endothelial venules: within the tissue their migratory behavior differs. Eur J Immunol 21: 3174–3181, 1997.
 49. Weninger W, Crowley MA, Manjunath N and von Andrian UH. Migratory properties of naïve, effector, and memory CD8(+) T cells. J Exp Med 194: 953–966, 2001.
 50. Weninger W, Manjunath N and von Andrian UH. Migration and differentiation of CD8+ T cells. Immunol Rev 186: 221–233, 2002.
 51. McEvoy LM, Sun H, Frelinger JG and Butcher EC. Anti‐CD43 inhibition of T cell homing. J Exp Med 185: 1493–1498, 1997.
 52. Salmi M, Tonka S, Berg EL, Butcher EC and Jalkanen S. Vascular adhesion protein I (VAP‐1) mediates lymphocyte subtype‐specific, selectin‐independeni recognition of vascular endothelium in human lymph nodes. J Exp Med 186: 589–600, 1997.
 53. Miura S, Tsuzuki Y, Fukumura D, Serizawa H, Suematsu M, Kurose I, Imaeda H, Kimura H, Nagata H, Tsuchiya M, et al. Intravital demonstration of sequential migration process of lymphocyte subpopulations in rat Peyer's patches. Gastroenterology 109: 1113–1123, 1995.
 54. 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 I‐mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J Exp Med 191: 61–76, 2000.
 55. Warnock RA, Campbell JJ, Dorf ME, Matsuzawa A, McEvoy LM and Butcher EC. The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer's patch high endothelial venules. J Exp Med 191: 77–88, 2000.
 56. Baekkevold ES, Yamanaka T, Palframan RT, Carlsen HS, Reinholt FP, von Andrian UH, Brandtzaeg P and Haraldsen G. The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J Exp Med 193: 1105–1112, 2001.
 57. 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.
 58. Tang ML, Steeber DA, Zhang XQ and Tedder TF. Intrinsic differences in L‐selectin expression levels affect T and B lymphocyte subset‐specific recirculation pathways. J Immunol 160: 5113–5121, 1998.
 59. Luther SA, Tang HL, Hyman PL, Farr AG and Cyster JG. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the pit/pit mouse. Proc Natl Acad Sci USA 97: 12694–12699, 2000.
 60. Okada T, Ngo VN, Ekland EH, Forster R, Lipp M, Littman DR and Cyster JG. Chemokine requirements for B cell entry to lymph nodes and Peyer's patches. J Exp Med 196: 65–75, 2002.
 61. Ebisuno Y, Tanaka T, Kanemitsu N, Kanda H, Yamaguchi K, Kaisho T, Akira S and Miyasaka M. Cutting edge: the B cell chemokine CXC chemokine ligand 13/B lymphocyte chemoattractant is expressed in the high endothelial venules of lymph nodes and Peyer's patches and affects B cell trafficking across high endothelial venules. J Immunol 171: 1642–1646, 2003.
 62. Anderson AO and Anderson ND. Lymphocyte emigration from high endothelial venules in rat lymph nodes. Immunology 31: 731–748, 1976.
 63. Yamaguchi K and Schoefl GI. Blood vessels of the Peyer's patch in the mouse: III. High‐endothelium venules. Anat Rec 206: 419–438, 1983.
 64. Cho Y and De Bruyn PP. Internal structure of the postcapillary high‐endothelial venules of rodent lymph nodes and Peyer's patches and the transendothelial lymphocyte passage. Am J Anat 177: 481–490, 1986.
 65. Phillips R and Ager A. Activation of pertussis toxin‐sensitive CXCL12 (SDF‐1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. Eur J Immunol 32: 837–847, 2002.
 66. Miyasaka M and Tanaka T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol 4: 360–370, 2003.
 67. Nagakubo D, Murai T, Tanaka T, Usui T, Matsumoto M, Sekiguchi K and Miyasaka M. A high endothelial venule secretory protein, mac25/angiomodulin, interacts with multiple high endothelial venule‐associated molecules including chemokinesm. J Immunol 171: 553–561, 2003.
 68. Stoll S, Delon J, Brotz TM and Germain RN. Dynamic imaging of T cell‐dendritic cell interactions in lymph nodes. Science 296: 1873–1876, 2002.
 69. Miller MJ, Wei SH, Parker I and Cahalan MD. Two‐photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296: 1869–1873, 2002.
 70. Bousso P and Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat Immunol 4: 579–585, 2003.
 71. Miller MJ, Wei SH, Cahalan MD and Parker I. Autonomous T cell trafficking examined in vivo with intravital two‐photon microscopy. Proc Natl Acad Sci USA 100: 2604–2609, 2003.
 72. Miller MJ, Hejazi AS, Wei SH, Cahalan MD and Parker I. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc Natl Acad Sci USA 101: 998–1003, 2003.
 73. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F and Lipp M, R, Forster. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 192: 1545–1552, 2000.
 74. Schaniel C, Pardali E, Sallusto F, Speletas M, Ruedl C, Shimizu T, Seidl T, Andersson J, Melchers F, Rolink AG and Sideras P. Activated murine B lymphocytes and dendritic cells produce a novel CC chemokine which acts selectively on activated T cells. J Exp Med 188: 451–463, 1998.
 75. Schaniel C, Sallusto F, Ruedl C, Sideras P, Melchers F and Rolink AG. Three chemokines with potential functions in T lymphocyte‐independent and ‐dependent B lymphocyte stimulation. Eur J Immunol 29: 2934–2947, 1999.
 76. Azzali G, Vitale M and Arcari ML. Infrastructure of absorbing peripheral lymphatic vessel (ALPA) in guinea pig Peyer's patches. Microvasc Res 64: 289–301, 2002.
 77. Azzali G. Structure, lymphatic vascularization and lymphocyte migration in mucosa‐associated lymphoid tissue. Immunol Rev 195: 178–189, 2003.
 78. Nagata H, Miyairi M, Sekizuka E, Morishita T, Tatemichi M, Miura S and Tsuchiya M. In vivo visualization of lymphatic microvessels and lymphocyte migration through rat Peyer's patches. Gastroenterology 106: 1548–1553, 1994.
 79. Rothkotter HJ, Huber T, Barman NN and Pabst R. Lymphoid cells in afferent and efferent intestinal lymph: lymphocyte subpoputations and cell migration. Clin Exp Immunol 92: 317–322, 1993.
 80. Farstad IN, Norstem J and Brandtzaeg P. Phenotypes of B and T cells in human intestinal and mesenteric lymph. Gastroenterology 112: 163–173, 1997.
 81. Miura S, Sekizuka E, Nagata H, Oshio C, Minamitani H, Suematsu M, Suzuki M, Hamada Y, Kobayashi K, Asakura H and Tsuchiya M. Increased lymphocyte transport by lipid absorption in rat mesenteric lymphatics. Am J Physiol 253: G596–G600, 1987.
 82. Tsuzuki Y, Miura S, Kurose I, Suematsu M, Higuchi H, Shigematsu T, Kimura H, Serizawa H, Hokari R, Akiba Y, Yagita H, Okumura K, Tso P, Granger DN and Ishii H. Enhanced lymphocyte interaction in postcapillary venules of Peyer's patches during fat absorption in rats. Gastroenterology 112: 813–825, 1997.
 83. Miura S, Serizawa H, Tsuzuki Y, Kurose I, Suematsu M, Higuchi H, Shigematsu T, Hokari R, Hirokawa M, Kimura H and Ishii H. Vasoactive intestinal peptide modulates T lymphocyte migration in Peyer's patches of rat small intestine. Am J Physiol 272: G92–G99, 1997.
 84. Hokari R, Miura S, Fujimori H, Tsuzuki Y, Shigematsu T, Higuchi H, Kimura H, Kurose I, Serizawa H, Suematsu M, Yagita H, Granger DN and Ishii H. Nitric oxide modulates T‐lymphocyte migration in Peyer's patches and villous submucosa of rat small intestine. Gastroenterology 115: 618–627, 1998.
 85. Irjala H, Elima K, Johansson EL, Merinen M, Kontula K, Alanen K, Grenman R, Salmi M and Jalkanen S. The same endothelial receptor controls lymphocyte traffic both in vascular and lymphatic vessels. Eur J Immunol 33: 815–824, 2003.
 86. Chiba K, Yanagawa Y, Masubuchi Y, Kataoka H, Kawaguchi T, Ohtsuki M and Hoshino Y. FTY720, a novel immunosuppressant. induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 160: 5037–5044, 1998.
 87. Henning G, Ohl L, Junt T, Reiterer P, Brinkmann V, Nakano H, Hohenberger W, Lipp M and Forster R. CC chemokine receptor 7‐dependent and ‐independent pathways for lymphocyte homing: modulation by FTY720. J Exp Med 194: 1875–1881, 2001.
 88. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W and Rosen H. Alteration of lymphocyte trafficking by sphingosine‐1‐phosphate receptor agonists. Science 296: 346–349, 2002.
 89. Honig SM, Fu S, Mao X, Yopp A, Gunn MD, Randolph GJ and Bromberg JS. FTY720 stimulates multidrug transporter‐ and cysteinyl leukotriene‐dependent T cell chemotaxis to lymph nodes. J Clin Invest 111: 627–637, 2003.
 90. Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ and Jenkins MK. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281: 96–99, 1998.
 91. Cyster JG. Chemokines and cell migration in secondary lymphoid organs. Science 286: 2098–2102, 1999.
 92. McDermott MR and Bienenstock J. Evidence for a common mucosal immunologic system. I. Migration of B immunoblasts into intestinal. respiratory, and genital tissues. J Immunol 122: 1892–1898, 1979.
 93. Mackay CR, Marston WL, Dudler L, Spertini O, Tedder TF and Hein WR. Tissue‐specific migration pathways by phenotypically distinct subpopulations of memory T cells. Eur J Immunol 22: 887–895, 1992.
 94. Kantele A, Zivny J, Hakkinen M, Elson CO and Mestecky J. Differential homing commitments of antigen‐specific T cells after oral or parenteral immunization in humans. J Immunol 162: 5173–5177, 1999.
 95. Stagg AJ, Kamm MA and Knight SC. Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur J Immunol 32: 1445–1454, 2002.
 96. Johansson‐Lindbom B, Svensson M, Wurbel MA, Malissen B, Marquez G and Agace W. Selective generation of gut tropic T cells in gut‐associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J Exp Med 198: 963–969, 2003.
 97. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M and von Andrian UH. Selective imprinting of gut‐homing T cells by Peyer's patch dendritic cells. Nature 424: 88–93, 2003.
 98. Szabo MC, Butcher EC and McEvoy LM. Specialization of mucosal follicular dendritic cells revealed by mucosal addressin‐cell adhesion molecule‐1 display. J Immunol 158: 5584–5588, 1997.
 99. Kunkel EJ and Butcher EC. Plasma‐cell homing. Nat Rev Immunol 3: 822–829, 2003.
 100. Bell EB, Sparshott SM and Ager A. Migration pathways of CD4 T cell subsets in vivo: the CD45RC‐ subset enters the thymus via alpha 4 integrin‐VCAM‐1 interaction. Int Immunol 7: 1861–1871, 1995.
 101. Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L and Butcher EC. Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest 108: 1331–1339, 2001.
 102. Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, Roberts AI, Ebert EC, Vierra MA, Goodman SB, Genovese MC, Wardlaw AJ, Greenberg HB, Parker CM, Butcher EC, Andrew DP and Agace WW. Lymphocyte CC chemokine receptor 9 and epithelial thymus‐expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue‐specific chemokines as an organizing principle in regional immunity. J Exp Med 192: 761–768, 2000.
 103. Papadakis KA, Prehn J, Moreno ST, Cheng L, Kouroumalis EA, Deem R, Breaverman T, Ponath PD, Andrew DP, Green PH, Hodge MR, Binder SW and Targan SR. CCR9‐positive lymphocytes and thymus‐expressed chemokine distinguish small bowel from colonic Crohn's disease. Gastroenterology 121: 246–254, 2001.
 104. Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P, Miazek A, Mattei MG, Malissen M, Jordan BR, Malissen B, Carrier A and Naquet P. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double‐ and single‐positive thymocytes expressing the TECK receptor CCR9. Eur J Immunol 30: 262–271, 2000.
 105. Kunkel EJ, Campbell DJ and Butcher EC. Chemokines in lymphocyte trafficking and intestinal immunity. Microcirculation 10: 313–323, 2003.
 106. Papadakis KA, Landers C, Prehn J, Kouroumalis EA, Moreno ST, Gutierrez‐Ramos JC, Hodge MR and Targan SR. CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T‐regulatory 1 cytokine profile. J Immunol 171: 159–165, 2003.
 107. Hosoe N, Miura S, Watanabe C, Tsuzuki Y, Hokari R, Oyama T, Fujiyama Y, Nagata H and Ishii H. Demonstration of functional role of TECK/CCL25 in T lymphocyte‐endothelium interaction in inflamed and uninflamed intestinal mucosa. Am J Physiol Gastrointest Liver Physiol 286: G458–G466, 2004.
 108. Suzuki K, Oida T, Hamada H, Hitotsumatsu O, Watanabe M, Hibi T, Yamamoto H, Kubota E, Kaminogawa S and Ishikawa H. Gut cryptopatches: direct evidence of extrathymic anatomical sites for intestinal T lymphopoiesis. Immunity 13: 691–702, 2000.
 109. Koseki S, Miura S, Fujimori H, Hokari R, Komoto S, Hara Y, Ogino T, Nagata H, Goto M, Hachimura S, Kaminogawa S and Ishii H. In situ demonstration of intraepithelial lymphocyte adhesion to villus microvessels of the small intestine. Int Immunol 13: 1165–1174, 2001.
 110. Wurbel MA, Malissen M, Guy‐Grand D, Meffre E, Nussenzweig MC, Richelme M, Carrier A and Malissen B. Mice lacking the CCR9 CC‐chemokine receptor show a mild impairment of early T‐ and B‐cell development and a reduction in T‐cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood 98: 2626–2632, 2001.
 111. Farstad IN, Haistensen TS, Lazarovits AI, Norstein J, Fausa O and Brandtzaeg P. intestinal B‐cell blasts Human, plasma cells express the mucosal homing receptor integrin alpha 4 beta 7. Scand J Immunol 42: 662–672, 1995.
 112. Bowman EP, Kuklin NA, Youngman KR, Lazarus NH, Kunkel EJ, Pan J, Greenberg HB and Butcher EC. The intestinal chemokine thymus‐expressed chemokine (CCL25) attracts IgA antibody‐secreting cells. J Exp Med 195: 269–275, 2002.
 113. Lazarus NH, Kunkel EJ, Johnston B, Wilson E, Youngman KR and Butcher EC. A common mucosal chemokine (mucosae‐associated epithelial chemokine/CCL28) selectively attracts IgA plasmablasts. J Immunol 170: 3799–3805, 2003.
 114. Kunkel EJ, Kim CH, Lazarus NH, Vierra MA, Soler D, Bowman EP and Butcher EC. CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab‐secreting cells. J Clin Invest 111: 1001–1010, 2003.
 115. Yang SK, Eckmann L, Panja A and Kagnoff MF. Differential and regulated expression of C‐X‐C, C‐C, and C‐chemokines by human colon epithelial cells. Gastroenterology 113: 1214–1223, 1997.
 116. Dwinell MB, Eckmann L, Leopard JD, Varki NM and Kagnoff MF. Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology 117: 359–367, 1999.
 117. Agace WW, Roberts Al, Wu L, Greineder C, Ebert EC and Parker CM. Human intestinal lamina propria and intraepithelial lymphocytes express receptors specific for chemokines induced by inflammation. Eur J Immunol 30: 819–826, 2000.
 118. Izadpanah A, Dwinell MB, Eckmann L, Varki NM and Kagnoff MF. Regulated MIP‐3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am J Physiol Gastrointest Liver Physiol 280: G710–G719, 2001.
 119. Dwinell MB, Lugering N, Eckmann L and Kagnoff MF. Regulated production of interferon‐inducible T‐cell chemoattractants by human intestinal epithelial cells. Gastroenterology 120: 49–59, 2001.
 120. Smith JM, Johanesen PA, Wendt MK, Binion DG and Dwinell MB. CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity. Am J Physiol Gastrointest Liver Physiol 16, 2004, Sep 9 [Epub ahead of print].
 121. Davenport MP, Grimm MC and Lloyd AR. A homing selection hypothesis for T‐cell trafficking. Immunol Today 21: 315–317, 2000.
 122. Sallusto F, Kremmer E, Palermo B, Hoy A, Ponath P, Qin S, Forster R, Lipp M and Lanzavecchia A. Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur J Immunol 29: 2037–2045, 1999.
 123. Beilhack A and Rockson SG. Immune traffic: a functional overview. Lymphatic Res Biol 1: 219–234, 2003.
 124. 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 inflammed tissues. Nature 385: 81–83, 1997.
 125. Xie H, Lim YC, Luscinskas FW and Lichtman AH. Acquisition of selectin binding and peripheral homing properties by CD4(+) and CD8(+) T cells. J Exp Med 189: 1765–1776, 1999.
 126. Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A and Sinigaglia F. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187: 129–134, 1998.
 127. Masopust D, Vezys V, Marzo AL and Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291: 2413–2417, 2001.
 128. Lee HO, Cooper CJ, Choi JH, Alnadjim Z and Barrett TA. The state of CD4+ T cell activation is a major factor for determining the kinetics and location of T cell responses to oral antigen. J Immunol 168: 3833–3838, 2002.
 129. Haddad W, Cooper CJ, Zhang Z, Brown JB, Zhu Y, Issekutz A, Fuss I, Lee HO, Kansas GS and Barrett TA. P‐selectin and PSGL‐1 are major determinants for Th1 cell recruitment to nonlymphoid effector sites in the intestinal lamina propria. J Exp Med 198: 369–377, 2003.
 130. Papadakis KA. Chemokines in inflammatory bowel disease. Curr Allergy Asthma Rep 4: 83–89, 2004.
 131. Watanabe C, Miura S, Hokari R, Teramoto K, Ogino T, Komoto S, Hara Y, Koseki S, Tsuzuki Y, Nagata H, Granger DN and Ishii H. Spatial heterogeneity of TNF‐alpha‐induced T cell migration to colonic mucosa is mediated by MAdCAM‐1 and VCAM‐1. Am J Physiol Gastrointest Liver Physiol 283: G1379–G1387, 2002.
 132. Randolph GJ, Inaba K, Robbiani DF, Steinman RM and Muller WA. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11: 753–761, 1999.
 133. Rotta G, Edwards EW, Sangaietti S, Bennett C, Ronzoni S, Colombo MP, Steinman RM, Randolph GJ and Rescigno M. Lipopolysaccharide or whole bacteria block the conversion of inflammatory monocytes into dendritic cells in vivo. J Exp Med 198: 1253–1263, 2003.
 134. Geissmann F, Jung S and Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71–82, 2003.
 135. McEvoy LM, Jutila MA, Tsao PS, Cooke JP and Butcher EC. Anti‐CD43 inhibits monocyte‐endothelial adhesion in inflammation and atherogenesis. Blood 90: 3587–3594, 1997.
 136. Ishii N, Tsuzuki Y, Matsuzaki K, Miyazaki J, Okada Y, Hokari R, Kawaguchi A, Nagao S, Itoh K and Miura S. Endotoxin stimulates monocyte‐endothelial cell interactions in mouse intestinal Peyer's patches and villus mucosa. Clin Exp Immunol 135: 226–232, 2004.
 137. Taub DD, Lloyd AR, Conlon K, Wang JM, Ortaldo JR, Harada A, Matsushima K, Kelvin DJ and Oppenheim JJ. Recombinant human interferon‐inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med 177: 1809–1814, 1993.
 138. Gerszten RE, Garcia‐Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA, Jr., 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.
 139. 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.
 140. Janatpour MJ, Hudak S, Sathe M, Sedgwick JD and McEvoy LM. Tumor necrosis factor‐dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment. J Exp Med 194: 1375–1384, 2001.
 141. Iwasaki A and Kelsall BL. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)‐3alpha, MIP‐3beta, and secondary lymphoid organ chemokine. J Exp Med 191: 1381–1394, 2000.
 142. Iwasaki A and Kelsall BL. Unique functions of CD11b+, CD8 alpha+, and double‐negative Peyer's patch dendritic cells. J Immunol 166: 4884–4890, 2001.
 143. Shreedhar VK, Kelsall BL and Neutra MR. Cholera toxin induces migration of dendritic cells from the subepithelial dome region to T‐ and B‐cell areas of Peyer's patches. Infect Immun 71: 504–509, 2003.
 144. Cook DN, Prosser DM, Forster R, Zhang J, Kuklin NA, Abbondanzo SJ, Niu XD, Chen SC, Manfra DJ, Wiekowski MT, Sullivan LM, Smith SR, Greenberg HB, Narula SK and Lipp M, S.A. Lira, CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 12: 495–503, 2000.
 145. Varona R, Villares R, Carramolino L, Goya I, Zaballos A, Gutierrez J, Torres M, Martinez‐A C and Marquez G. CCR6‐deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed‐type hypersensitivity responses. J Clin Invest 107: R37–R45, 2001.
 146. Bilsborough J, George TC, Norment A and Viney JL. Mucosal CD8alpha+ DC, with a plasmacytoid phenotype. induce differentiation and support function of T cells with regulatory properties. Immunology 108: 481–492, 2003.
 147. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A and Colonna M. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5: 919–923, 1999.
 148. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP and Ricciardi‐Castagnoli P. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2: 361–367, 2001.
 149. Becker C, Wirtz S, Blessing M, Pirhonen J, Strand D, Bechthold O, Frick J, Galle PR, Autenrieth I and Neurath MF. Constitutive p40 promoter activation and IL‐23 production in the terminal ileum mediated by dendritic cells. J Clin Invest 112: 693–706, 2003.
 150. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR, Qin S and Lanzavecchia A. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 28: 2760–2769, 1998.
 151. Gunn MD, Kyuwa S, Tarn C, Kakiuchi T, Matsuzawa A, Williams LT and Nakano H. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 189: 451–460, 1999.
 152. Robbiani DF, Finch RA, Jager D, Muller WA, Sartorelli AC and Randolph GJ. The leukotriene C(4) transporter MRPI regulates CCL19 (MIP‐3beta, ELC)‐dependent mobilization of dendritic cells to lymph nodes. Cell 103: 757–768, 2000.
 153. Xu H, Guan H, Zu G, Bullard D, Hanson J, Slater M and Elmets CA. The role of ICAM‐1 molecule in the migration of Langerhans cells in the skin and regional lymph node. Eur J Immunol 31: 3085–3093, 2001.
 154. Pugh CW, MacPherson GG and Steer HW. Characterization of non‐lymphoid cells derived from rat peripheral lymph. J Exp Med 157: 1758–1779, 1983.
 155. Turnbull E and MacPherson G. lmmunobiology of dendritic cells in the rat. Immunol Rev 184: 58–68, 2001.
 156. MacPherson GG, Jenkins CD, Stein MJ and Edwards C. Endotoxin‐mediated dendritic cell release from the intestine. Characterization of released dendritic cells and TNF dependence. J Immunol 154: 1317–1322, 1995.
 157. Martln‐Fontecha A, Sebastiani S, Hopken UE, Uguccioni M, Lipp M, Lanzavecchia A and Sallusto F. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198: 615–621, 2003.
 158. Kobayashi H, Miura S, Nagata H, Tsuzuki Y, Hokari R, Ogino T, Watanabe C, Azuma T and Ishii H. In situ demonstration of dendritic cell migration from rat intestine to mesenteric lymph nodes: relationships to maturation and role of chemokines. J Leukoc Biol 75: 434–442, 2004.
 159. Huang FP, Platt N, Wykes M, Major JR, Powell TJ, Jenkins CD and MacPherson GG. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med 191: 435–444, 2000.
 160. Lyoda T, Shimoyama S, Liu K, Omatsu Y, Akiyama Y, Maeda Y, Takahara K, Steinman RM and Inaba K. The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 195: 1289–1302, 2002.
 161. Mishra A, Hogan SP, Lee JJ, Foster PS and Rothenberg ME. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest 103: 1719–1727, 1999.
 162. Rothenberg ME, Mishra A, Brandt EB and Hogan SP. Gastrointestinal eosinophils. Immunol Rev 179: 139–155, 2001.
 163. Grisham FS and Laroux MB. Immunological basis of inflammatory bowel disease: Role of the microcirculation. Microcirculation 8: 283–301, 2001.
 164. Middleton SJ, Shorthouse M and Hunter JO. Increased nitric oxide synthesis in ulcerative colitis. Lancet 341: 465–466, 1993.
 165. Rachmilewitz D, Stamler JS, Bachwich D, Karmeli F, Ackerman Z and Podolsky DK. Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Gut 36: 718–723, 1995.
 166. Kimura H, Miura S, Shigematsu T, Ohkubo N, Tsuzuki Y, Kurose I, Higuchi H, Akiba Y, Hokari R, Hirokawa M, Serizawa H and Ishii H. Increased nitric oxide production and inducible nitric oxide synthase activity in colonic mucosa of patients with active ulcerative colitis and Crohn's disease. Dig Dis Sci 42: 1047–1054, 1999.
 167. Binion DG, Fu S, Ramanujam KS, Chai YC, Dweik RA, Drazba JA, Wade JG, Ziats NP, Erzurum SC and Wilson KT. iNOS expression in human intestinal microvascular endothelial cells inhibits leukocyte adhesion. Am J Physiol 275: G592–G603, 1998.
 168. Kimura H, Hokari R, Miura S, Shigematsu T, Hirokawa M, Akiba Y, Kurose I, Higuchi H, Fujimori H, Tsuzuki Y, Serizawa H and Ishii H. Increased expression of an inducible isoform of nitric oxide synthase and the formation of peroxynitrite in colonic mucosa of patients with active ulcerative colitis. Gut 42: 180–187, 1998.
 169. Hokari R, Kato S, Matsuzaki K, Kuroki M, Iwai A, Kawaguchi A, Nagao S, Miyahara T, Itoh K, Sekizuka E, Nagata H, Ishii H and Miura S. Reduced sensitivity of inducible nitric oxide synthase‐deficient mice to chronic colitis. Free Radic Biol Med 31: 153–163, 2001.
 170. Krieglstein CF, Cerwinka WH, Laroux FS, Salter JW, Russell JM, Schuermann G, Grisham MB, Ross CR and Granger DN. Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen: divergent roles of superoxide and nitric oxide. J Exp Med 194: 1207–1218, 2001.
 171. Bonder CS and Kubes P. The future of GI and liver research: editorial perspectives: II. Modulating leukocyte recruitment to splanchnic organs to reduce inflammation. Am J Physiol Gastrointest Liver Physiol 284: G729–G733, 2003.
 172. Jones SC, Banks RE, Haidar A, Gearing AJ, Hemingway IK, Ibbotson SH, Dixon MF and Axon AT. Adhesion molecules in inflammatory bowel disease. Gut 36: 724–730, 1995.
 173. Nakamura S, Ohtani H, Watanabe Y, Fukushima K, Matsumoto T, Kitano A, Kobayashi K and Nagura H. In situ expression of the cell adhesion molecules in inflammatory bowel disease. Evidence of immunologic activation of vascular endothelial cells. Lab Invest 69: 77–85, 1993.
 174. Kawachi S, Jennings S, Panes J, Cockrell A, Laroux FS, Gray L, Perry M, van der Heyde H, Balish E, Granger DN, Specian RA and Grisham MB. Cytokine and endothelial cell adhesion molecule expression in interleukin‐10‐deficient mice. Am J Physiol Gastrointest Liver Physiol 278: G734–G743, 2000.
 175. Bendjelloul F, Maly P, Mandys V, Jtrkovska M, Prokesova L, Tuckova L and Tlaskalova‐Hogenova H. Intercellular adhesion molecule‐1 (ICAM‐1) deficiency protects mice against severe forms of experimentally induced colitis. Clin Exp Immunol 119: 57–63, 2000.
 176. Yacyshyn BR, Bowen‐Yacyshyn MB, Jewell L, Tami JA, Bennett CF, Kisner DL and Shanahan WR, Jr. A placebo‐controlled trial of ICAM‐1 antisense oligonucleotide in the treatment of Crohn's disease. Gastroenterology 114: 1133–1142, 1998.
 177. Soriano A, Salas A, Salas A, Sans M, Gironella M, Elena M, Anderson DC, Pique JM and Panes J. VCAM‐1, but not ICAM‐1 or MAdCAM‐1, immunoblockade ameliorates DSS‐induced colitis in mice. Lab Invest 80: 1541–1551, 2000.
 178. D'Agata ID, Paradis K, Chad Z, Bonny Y and Seidman E. Leucocyte adhesion deficiency presenting as a chronic ileocolitis. Gut 39: 605–608, 1996.
 179. Bums RC, Rivera‐Nieves J, Moskaluk CA, Matsumoto S, Cominelli F and Ley K. Antibody blockade of ICAM‐1 and VCAM‐1 ameliorates inflammation in the SAMP‐1/Yit adoptive transfer model of Crohn's disease in mice. Gastroenterology 121: 1428–1436, 2001.
 180. Kato S, Hokari R, Matsuzaki K, Iwai A, Kawaguchi A, Nagao S, Miyahara T, Itoh K, Ishii H and Miura S. Amelioration of murine experimental colitis by inhibition of mucosal addressin cell adhesion molecule‐1. J Pharmacol Exp Ther 295: 183–189, 2000.
 181. Shigematsu T, Specian RD, Wolf RE, Grisham MB and Granger DN. MAdCAM mediates lymphocyte‐endothelial cell adhesion in a murine model of chronic colitis. Am J Physiol Gastrointest Liver Physiol 281: G1309–G1315, 2001.
 182. Hokari R, Kato S, Matsuzaki K, Iwai A, Kawaguchi A, Nagao S, Miyahara T, Itoh K, Sekizuka E, Nagata H, Ishii H, Iizuka T, Miyasaka M and Miura S. Involvement of mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) in the pathogenesis of granulomatous colitis in rats. Clin Exp Immunol 126: 259–265, 2001.
 183. Picarella D, Hurlbut P, Rottman J, Shi X, Butcher E and Ringler DJ. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J Immunol 158: 2099–2106, 1997.
 184. Hesterberg PE, Winsor‐Hines D, Briskin MJ, Soler‐Ferran D, Merrill C, Mackay CR, Newman W and Ringler DJ. Rapid resolution of chronic colitis in the cotton‐top tamarin with an antibody to a gut‐homing integrin alpha 4 beta 7. Gastroenterology 111: 1373–1380, 1996.
 185. Gordon FH, Lai CW, Hamilton MI, Allison MC, Srivastava ED, Fouweather MG, Donoghue S, Greenlees C, Subhani J, Amlot PL and Pounder RE. A randomized placebo‐controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease. Gastroenterology 121: 268–274, 2001.
 186. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask‐Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T and Donoghue S. Natalizumab Pan‐European Study Group. Natalizumab for active Crohn's disease. N Engl J Med 348: 24–32, 2003.
 187. Feagan BG, Greenberg GR, Wild G, Fedorak RN, Pare P, McDonald JW, Dube R, Cohen A, Steinhartn AH, Landau S, Aguzzi RA, Fox IH, Vandervoort MK. Treatment of Ulcerative Colitis with a Humanized Antibody to the alpha4beta7 Integrin. N Eng J Med 352: 2499–2507.
 188. Sydora BC, Wagner N, Lohler J, Yakoub G, Kronenberg M, Muller W and Aranda R. Beta7 Integrin expression is not required for the localization of T cells to the intestine and colitis pathogenesis. Clin Exp Immunol 129: 35–42, 2002.
 189. Rijcken EM, Laukoetter MG, Anthoni C, Meier S, Mennigen R, Spiegel HU, Bruewer M, Senninger N, Vestweber D and Krieglstein CF. Immunoblockade of PSGL‐1 attenuates established experimental murine colitis by reduction of leukocyte rolling. Am J Physiol Gastrointest Liver Physiol 287: G115–G124, 2004.
 190. Collins CE and Rampton DS. Review article: platelets in inflammatory bowel disease‐pathogenetic role and therapeutic implications. Aliment Pharmacol Ther 11: 237–247, 1997.
 191. Suzuki K, Sugimura K, Hasegawa K, Yoshida K, Suzuki A, Ishizuka K, Ohtsuka K, Honma T, Narisawa R and Asakura H. Activated platelets in ulcerative colitis enhance the production of reactive oxygen species by polymorphonuclear leukocytes. Scand J Gastroenterol 36: 1301–1306, 2001.
 192. Danese S, Katz JA, Saibeni S, Papa A, Gasbarrini A, Vecchi M and Fiocchi C. Activated platelets are the source of elevated levels of soluble CD40 Iigand in the circulation of inflammatory bowel disease patients. Gut 52: 1435–1441, 2003.
 193. Danese S, de la Motte C, Sturm A, Vogel JD, West GA, Strong SA, Katz JA and Fiocchi C. Platelets trigger a CD40‐dependent inflammatory response in the microvasculature of inflammatory bowel disease patients. Gastroenterology 124: 1249–1264, 2003.
 194. 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.
 195. Vowinkel T, Mori M, Krieglstein CF, Russell J, Saijo F, Bharwani S, Turnage RH, Davidson WS, Tso P, Granger DN and Kalogeris TJ. Apolipoprotein A‐IV inhibits experimental colitis. J Clin Invest 114: 260–269, 2004.
 196. Ajuebor MN and Swain MG. Role of chemokines and chemokine receptors in the gastrointestinal tract. Immunology 105: 137–143, 2002.
 197. Mahida YR, Ceska M, Effenberger F, Kurlak L, Lindley I and Hawkey CJ. Enhanced synthesis of neutrophil‐activating peptide‐1/interleukin‐8 in active ulcerative colitis. Clin Sri (Lond) 82: 273–275, 1992.
 198. Izzo RS, Witkon K, Chen AI, Hadjiyane C, Weinstein MI and Pellecchia C. Neutrophil‐activating peptide (interleukin‐8) in colonic mucosa from patients with Crohn's disease. Scand J Gastroenterol 28: 296–300, 1993.
 199. Nielsen OH, Rudiger N, Gaustadnes M and Horn T. Intestinal interleukin‐8 concentration and gene expression in inflammatory bowel disease. Scand J Gastroenterol 32: 1028–1034, 1997.
 200. Z'Graggen K, Walz A, Mazzucchelli L, Strieter RM and Mueller C. The C‐X‐C chemokine ENA‐78 is preferentially expressed in intestinal epithelium in inflammatory bowel disease. Gastroenterology 113: 808–816, 1997.
 201. Reinecker HC, Loh EY, Ringler DJ, Mehta A, Rombeau JL and MacDermott RP, Monocyte‐chemoattractant protein 1 gene expression in intestinal epithelial cells and inflammatory bowel disease mucosa. Gastroenterology 108: 40–50, 1995.
 202. Mazzucchelli L, Hauser C, Zgraggen K, Wagner HE, Hess MW, Laissue JA and Mueller C. Differential in situ expression of the genes encoding the chemokines MCP‐1 and RANTES in human inflammatory bowel disease. J Pathol 178: 201–206, 1996.
 203. Grimm MC and Doe WF. Chemokines in IBD mucosa: expression of RANTES, MIP‐1alpha, MIP‐1beta and interferon inducible protein 10 by macrophages, lymphocytes, endothelial cells and granulomas. Inflammatory Bowel Dis 2: 88–96, 1996.
 204. Vainer B, Nielsen OH and Horn T. Expression of E‐selectin, sialyl Lewis X, and macrophage inflammatory protein‐1 alpha by colonic epithelial cells in ulcerative colitis. Dig Dis Sci 43: 596–608, 1998.
 205. Uguccioni M, Gionchetti P, Robbiani DF, Rizzello F, Peruzzo S, Campieri M and Baggiolini M. Increased expression of IP‐10, IL‐8, MCP‐I, and MCP‐3 in ulcerative colitis. Am J Pathol 155: 331–336, 1999.
 206. Banks C, Bateman A, Payne R, Johnson P and Sheron N. Chemokine expression in IBD, Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn's disease. J Pathol 199: 28–35, 2003.
 207. Andres PG, Beck PL, Mizoguchi E, Mizoguchi A, Bhan AK, Dawson T, Kuziel WA, Maeda N, MacDermott RP, Podolsky DK and Reinecker HC, Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate‐mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte‐associated Th2‐type immune response in the intestine. J Immunol 164: 6303–6312, 2001.
 208. Ajuebor MN, Hogaboam CM, Kunkel SL, Proudfoot AE and Wallace JL, The chemokine RANTES is a crucial mediator of the progression from acute to chronic colitis in the rat. J Immunol 166: 552–558, 2001.
 209. Luster AD. Chemokines regulate lymphocyte homing to the intestinal mucosa. Gastroenterology 120; 291–294, 2001.
 210. Shibahara T, Wilcox JN, Couse T and Madara JL, Characterization of epithelial chemoattractants for human intestinal intraepithelial lymphocytes. Gastroenterology 120; 60–70, 2001.
 211. Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B and Mackay CR, The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101: 746–754, 1998.
 212. Singh UP, Singh S, Taub DD and Lillard JW, Jr, Inhibition of IFN‐gamma‐inducible protein‐10 abrogates colitis in IL‐10−/− mice, J Immunol 171: 1401–1406, 2003.
 213. Sasaki S, Yoneyama H, Suzuki K, Suriki H, Aiba T, Watanabe S, Kawauchi Y, Kawachi H, Shimizu F, Matsushima K, Asakura H and Narumi S. Blockade of CXCL10 protects mice from acute colitis and enhances crypt cell survival. Eur J Immunol 32: 3197–3205, 2002.
 214. Garcia‐Zepeda EA, Rothenberg ME, Ownbey RT, Celestin J, Leder P and Luster AD. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia, Nat Med 2: 449–156, 1996.
 215. Carlsen HS, Baekkevold ES, Johansen FE, Haraldsen G and Brandtzaeg P, B cell attracting chemokine 1 (CXCLI3) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue. Gut 51: 364–371, 2002.
 216. Hjelmstrom P, Fjell J, Nakagawa T, Sacca R, Cuff CA and Ruddle NH. Lymphoid tissue homing chemokines are expressed in chronic inflammation. Am J Pathol 156: 1133–1138, 2000.
 217. Weninger W, Carlsen HS, Goodarzi M, Moazed F, Crowley MA, Baekkevold ES, Cavanagh LL and von Andrian UH. Naive T cell recruitment to nonlymphoid tissues: a role for endothelium‐expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis. J Immunol 170: 4638–4648, 2003.
 218. Spahn TW and Kucharzik T. Modulating the intestinal immune system: the role of lymphotoxin and GALT organs. Gut 53: 456–465, 2004.
 219. Mackay F, Browning JL, Lawton P, Shah SA, Comiskey M, Bhan AK, Mizoguchi E, Terhorst C and Simpson SJ. Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis. Gastroenterology 115: 1464–1475, 1998.
 220. Stopfer P, Obermeier F, Dunger N, Falk W, Farkas S, Janotta M, Moller A, Mannel DN and Hehlgans T. Blocking lymphotoxin‐beta receptor activation diminishes inflammation via reduced mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) expression and leucocyte margination in chronic DSS‐induced colitis. Clin Exp Immunol 136: 21–29, 2004.
 221. Spahn TW, Herbst H, Rennert PD, Lugering N, Maaser C, Kraft M, Fontana A, Weiner HL, Domschke W and Kucharzik T. Induction of colitis in mice deficient of Peyer's patches and mesenteric lymph nodes is associated with increased disease severity and formation of colonic lymphoid patches. Am J Pathol 161: 2273–2282, 2002.
 222. Dohi T, Rennert PD, Fujihashi K, Kiyono H, Shirai Y, Kawamura YI and Browning JL, J.R. McGhee. Elimination of colonic patches with lymphotoxin beta receptor‐Ig prevents Th2 cell‐type colitis. J Immunol 167: 2781–2790, 2001.
 223. Elson CO, Sartor RB, Tennyson GS and Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology 109: 1344–1367, 1995.
 224. Sartor RB. The influence of normal microbial flora on the development of chronic mucosal inflammation. Res Immunol 148: 567–576, 1997.
 225. Rath HC, Herfarth HH, Ikeda JS, Grenther WB, Hamm TE, Jr., Balish E, Taurog JD, Hammer RE, Wilson KH and Sartor RB. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA‐B27/human beta2 microglobulin transgenic rats. J Clin Invest 98: 945–953, 1996.
 226. Sellon RK, Tonkonogy S, Schultz M, Dieleman LA, Grenther W, Balish E, Rennick DM and Sartor RB. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin‐10‐deficient mice. Infect Immun 66: 5224–5231, 1998.
 227. Cong Y, Brandwein SL, McCabe RP, Lazenby A, Birkenmeier EH, Sundberg JP and Elson CO. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type I response and ability to transfer disease. J Exp Med 187: 855–864, 1998.
 228. Cario E and Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll‐like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68: 7010–7017, 2000.
 229. Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, Quertinmont E, Abramowicz M, Van Gossum A, Deviere J and Rutgeerts P. Deficient host‐bacteria interactions in inflammatory bowel disease? The toll‐like receptor (TLR)‐4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut 53: 987–992, 2004.
 230. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Aimer S, Tysk C, O'Morain A, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent‐Puig P, Gower‐Rousseau C, Macry J, Colombel JF, Sahbatou M and Thomas G. Association of NOD2 leucine‐rich repeat variants with susceptibility to Crohn's disease. Nature 411: 599–603, 2001.
 231. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G and Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411: 603–606, 2001.
 232. Komatsu S, Berg RD, Russell JM, Nimura Y and Granger DN. Enteric microflora contribute to constitutive ICAM‐1 expression on vascular endothelial cells. Am J Physiol Gastrointest Liver Physiol 279: G186–G191, 2000.
 233. Veltkamp C, Tonkonogy SL, De Jong YP, Albright C, Grenther WB, Balish E, Terhorst C and Sartor RB. Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tg(epsilon26) mice. Gastroenterology 120: 900–913, 2001.
 234. Waidmann M, Allemand Y, Lehmann J, di Genaro S, Bucheler N, Hamann A and Autenrieth IB. Microflora reactive IL‐10 producing regulatory T cells are present in the colon of IL‐2 deficient mice but lack efficacious inhibition of IFN‐gamma and TNF‐alpha production. Gut 50: 170–179, 2002.
 235. Fiorucci S, Antonelli E, Morelli O and Morelli A. Pathogenesis of non‐steroidal anti‐inflammatory drug gastropathy. Ital J Gastroenterol Hepatol 31 (Suppl 1): S6–S13, 1999.
 236. Kitahora T and Guth PH. Effect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation. Gastroenterology 93: 810–817, 1987.
 237. Tarnawski A, Stachura J, Gergely H and Hollander D. Gastric microvascular endothelium: a major target for aspirin‐induced injury and arachidonic acid protection. An ultrastructural analysis in the rat. Eur J Clin Invest 20: 432–440, 1990.
 238. Wallace JL, Keenan CM and Granger DN. Gastric ulceration induced by nonsteroidal anti‐inflammatory drugs is a neutrophil‐dependent process. Am J Physiol 259: G462–G467, 1990.
 239. Lee M, Aldred K, Lee E and Feldman M. Aspirin‐induced acute gastric mucosal injury is a neutrophil‐dependent process in rats. Am J Physiol 263: G920–G926, 1992.
 240. Arndt H, Palitzsch KD, Anderson DC, Rusche J, Grisham MB and Granger DN. Leucocyte‐endothelial cell adhesion in a model of intestinal inflammation. Gut 37: 374–379, 1995.
 241. Wallace JL, Arfors KE and McKnight GW. A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin‐induced gastric damage in the rabbit. Gastroenterology 100: 878–883, 1991.
 242. Yoshida N, Takemura T, Granger DN, Anderson DC, Wolf RE, McIntire LV and Kvietys PR. Molecular determinants of aspirin‐induced neutrophil adherence to endothelial cells. Gastroenterology 105: 715–724, 1993.
 243. Fiorucci S, Santucci L, Gerli R, Brunori PM, Federici B, Ugolini B, Fabbri C and Morelli A. NSAIDs upregulate beta 2‐integrin expression on human neutrophils through a calcium‐dependent pathway. Aliment Pharmacol Ther 11: 619–630, 1997.
 244. Krieglstein CF, Salter JW, Cerwinka WH, Russell JM, Schuermann G, Bruewer M, Laroux FS, Grisham MB and Granger DN. Role of intercellular adhesion molecule 1 in indomethacin‐induced ileitis. Biochem Biophys Res Commun 282: 635–642, 2001.
 245. Melarange R, Gentry C, Toseland CD, Smith PH and Fuller J. Neutropenia does not prevent etodolac‐ or indomethacin‐induced gastrointestinal damage in the rat. Dig Dis Sci 40: 2694–2703, 1995.
 246. Anthony A, Sim R, Dhillon AP, Pounder RE and Wakefield AJ. Gastric mucosal contraction and vascular injury induced by indometh‐acin precede neutrophil infiltration in the rat. Gut 39: 363–368, 1996.
 247. Anthony A, Pounder RE, Dhillon AP and Wakefield AJ. Vascular anatomy defines sites of indomethacin induced jejunal ulceration along the mesenteric margin. Gut 41: 763–770, 1997.
 248. Lee M, Kallal SM and Feldman M. Omeprazole prevents indomethacin‐induced gastric ulcers in rabbits. Aliment Pharmacol Ther 10: 571–576, 1996.
 249. Miura S, Suematsu M, Tanaka S, Nagata H, Houzawa S, Suzuki M, Kurose I, Serizawa H and Tsuchiya M. Microcirculatory disturbance in indomethacin‐induced intestinal ulcer. Am J Physiol 261: G213–G219, 1991.
 250. Kelly DA, Piasecki C, Anthony A, Dhillon AP, Pounder RE and Wakefield AJ. Focal reduction of villous blood flow in early indomethacin enteropathy: a dynamic vascular study in the rat. Gut 42: 366–373, 1998.
 251. Asako H, Kubes P, Wallace J, Gaginella T, Wolf RE and Granger DN. Indomethacin‐induced leukocyte adhesion in mesenteric venules: role of lipoxygenase products. Am J Physiol 262: G903–G908, 1992.
 252. Santucci L, Fiorucci S, Giansanti M, Brunori PM, Di Matteo FM and Morelli A. Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha. Gut 35: 909–915, 1994.
 253. Santucci L, Fiorucci S, Di Matteo FM and Morelli A. Role of tumor necrosis factor alpha release and leukocyte margination in indomethacin‐induced gastric injury in rats. Gastroenterology 108: 393–401, 1995.
 254. Appleyard CB, McCafferty DM, Tigley AW, Swain MG and Wallace JL. Tumor necrosis factor mediation of NSAID‐induced gastric damage: role of leukocyte adherence. Am J Physiol 270: G42–G48, 1996.
 255. Beck PL, Xavier R, Lu N, Nanda NN, Dinauer M, Podolsky DK and Seed B. Mechanisms of NSAID‐induced gastrointestinal injury defined using mutant mice. Gastroenterology 119: 699–705, 2000.
 256. Stadnyk AW, Dollard C, Issekutz TB and Issekutz AC. Neutrophil migration into indomethacin induced rat small intestinal injury is CD11a/CD18 and CD11b/CD18 co‐dependent. Gut 50: 629–635, 2002.
 257. Whittle BJ. Pharmacological approach to the prevention of non‐steroidal anti‐inflammatory drug‐induced gastropathy. Ital J Gastroenterol Hepatol 31 (Suppl 1): S43–S47, 1999.
 258. Wallace JL, Bak A, McKnight W, Asfaha S, Sharkey KA and MacNaughton WK. Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity. Gastroenterology 115: 101–109, 1998.
 259. Sigthorsson G, Simpson RJ, Walley M, Anthony A, Foster R, Hotz‐Behoftsitz C, Palizban A, Pombo J, Watts J, Morham SG and Bjarnason I. COX‐1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti‐inflammatory drug enteropathy in mice. Gastroenterology 122: 1913–1923, 2002.
 260. Whittle BJ, Laszlo F, Evans SM and Moncada S. Induction of nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin. Br J Pharmacol 116: 2286–2290, 1995.
 261. Evans SM and Whittle BJ. Role of bacteria and inducible nitric oxide synthase activity in the systemic inflammatory microvascular response provoked by indomethacin in the rat. Eur J Pharmacol 461: 63–71, 2003.
 262. Arndt H, Kullmann F, Reuss F, Scholmerich J and Palitzsch KD. Glutamine attenuates leukocyte‐endothelial cell adhesion in indomethacin‐induced intestinal inflammation in the rat. JPEN J Parenter Enteral Nutr 23: 12–18, 1999.
 263. Yamada T, Hoshino M, Hayakawa T, Ohhara H, Yamada H, Nakazawa T, Inagaki T, Iida M, Ogasawara T, Uchida A, Hasegawa C, Murasaki G, Miyaji M, Hirata A and Takeuchi T. Dietary diosgenin attenuates subacute intestinal inflammation associated with indomethacin in rats. Am J Physiol 273: G355–G364, 1997.
 264. Reuter BK, Davies NM and Wallace JL. Nonsteroidal antiinflammatory drug enteropathy in rats: role of permeability, bacteria. and enterohepatic circulation. Gastroenterology 112: 109–117, 1997.
 265. Wallace JL and Granger DN. The cellular and molecular basis of gastric mucosal defense. FASEB J 10: 731–740, 1996.
 266. Yoshida N, Granger DN, Evans DJ, Jr., Evans DG, Graham DY, Anderson DC, Wolf RE and Kvietys PR. Mechanisms involved in Helicobacter pylori‐induced inflammation. Gastroenterology 105: 1431–1440, 1993.
 267. Kurose I, Granger DN, Evans DJ, Jr., Evans DG, Graham DY, Miyasaka M, Anderson DC, Wolf RE, Cepinskas G and Kvietys PR. Helicobacter pylori‐induced microvascular protein leakage in rats: role of neutrophils, mast cells, and platelets. Gastroenterology 107: 70–79, 1994.
 268. Kalia N, Jacob S, Brown NJ, Reed MWR, Morton D and Bardhan KD. Studies on the gastric mucosal microcirculation, 2. Helicobacter pylori water soluble extracts induce platelet aggregation in the gastric mucosal microcirculation in vivo. Gut 41: 748–752, 1997.
 269. Elizalde JI, Gómez J, Panés J, Lozano M, Casadevall M, Ramirez J, Pizcueta P, Marco F, Rojas FD, Granger DN and Piqué JM. Platelet activation in mice and human Helicobacter pylori infection. J Clin Invest 100: 996–1005, 1997.
 270. Kalia N, Bardhan KD, Reed MWR, Jacob S and Brown NJ. Mechanisms of Helicobacter pylori‐induced rat gastric mucosal microcirculatory disturbances in vivo. Dig Dis Sci 45: 763–772, 2000.
 271. Kalia N, Bardhan KD, Reed MWR, Jacob S and Brown NJ. Effects of chronic administration of Helicobacter pylori extracts on rat gastric mucosal microcirculation in vivo. Dig Dis Sci 45: 1343–1351, 2000.
 272. Kalia N, Bardhan KD, Atherton JC and Brown NJ. Toxigenic Helicobacter pylori induces changes in the gastric mucosal microcirculation in rats. Gut 51: 641–647, 2002.
 273. Suzuki H, Mori M, Seto K, Miyazawa M, Kai A, Suematsu M, Yoneta T, Miura S and Ishii H. Polaprezinc attenuates the Helicobacter pylori‐induced gastric mucosal leucocyte activation in Mongolian gerbils—a study using intravital videomicroscopy. Aliment Pharmacol Ther 15: 715–725, 2001.
 274. Crowe SE, Alvarez L, Dytoc M, Hunt RH, Muller M, Sherman P, Patel J, Jin Y and Ernst PB. Expression of interleukin 8 and CD54 by human gastric epithelium after Helicobacter pylori infection in vitro. Gastroenterology 108: 65–74, 1995.
 275. Crabtree JE. Role of cytokines in pathogenesis of Helicobacter pylori‐induced mucosal damage. Dig Dis Sci 43 (9 Suppl): 46S–55S, 1998.
 276. Suzuki M, Miura S, Suematsu M, Fukumura D, Kurose I, Suzuki H, Kai A, Kudoh Y, Ohashi M and Tsuchiya M. Helicobacter pylori‐associated ammonia production enhances neutrophil‐dependent gastric mucosal cell injury. Am J Physiol 263: G719–G725, 1992.
 277. Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ET, Mera R, Miller MJ and Correa P. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 56: 3238–3243, 1996.
 278. Sakaguchi AA, Miura S, Takeuchi T, Hokari R, Mizumori M, Yoshida H, Higuchi H, Mori M, Kimura H, Suzuki H and Ishii H. Increased expression of inducible nitric oxide synthase and peroxynitrite in Helicobacter pylori gastric ulcer. Free Radic Biol Med 27: 781–789, 1999.
 279. Wyatt JI and Rathbone BJ. Immune response of the gastric mucosa to Campylobacter pylori. Scand J Gastroenterol Suppl 142: 44–49, 1988.
 280. Mohammadi M, Czinn S, Redline R and Nedrud J. Helicobacter‐specific cell‐mediated immune responses display a predominant Thl phenotype and promote a delayed‐type hypersensitivity response in the stomachs of mice. J Immunol 156: 4729–4738, 1996.
 281. Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK, Brooks EG, Graham DY, Reyes VE and Ernst PB. Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype. Gastroenterology 114: 482–492, 1998.
 282. Quiding‐Järbrink M, Ahlstedt I, Lindholm C, Johansson EL and Lönroth H. Homing commitment of lymphocytes activated in the human gastric and intestinal mucosa. Gut 49: 519–525, 2001.
 283. Mattsson A, Lönroth H, Quiding‐Järbrink M and Svennerholm AM. Induction of B cell responses in the stomach of Helicobacter pylori‐ infected subjects after oral cholera vaccination. J Clin Invest 102: 51–56, 1998.
 284. Yamaoka Y, Kita M, Kodama T, Sawai N, Tanahashi T, Kashima K and Imanishi J. Chemokines in the gastric mucosa in Helicobacter pylori infection. Gut 42: 609–617, 1998.
 285. Sato Y, Sugimura K, Mochizuki T, Honma T, Suriki H, Tashiro K, Ishizuka K, Narisawa R, Ichida T, Van Thiel DH and Asakura H. Regional differences on production of chemokines in gastric mucosa between Helicobacter pylori‐positive duodenal ulcer and gastric ulcer. Dig Dis Sci 44: 2390–2396, 1999.
 286. Kikuchi T, Kato K, Ohara S, Sekine H, Arikawa T, Suzuki T, Noguchi K, Saito M, Saito Y, Nagura H, Toyota T and Shimosegawa T. The relationship between persistent secretion of RANTES and residual infiltration of eosinophils and memory T lymphocytes after Helicobacter pylori eradication. J Pathol 192: 243–250, 2000.
 287. Michetti M, Kelly CP, Kraehenbuhl JP, Bouzourene H and Michetti P. Gastric mucosal alpha(4)beta(7)‐integrin‐positive CD4 T lymphocytes and immune protection against helicobacter infection in mice. Gastroenterology 119: 109–118, 2000.
 288. Hatanaka K, Hokari R, Matsuzaki K, Kato S, Kawaguchi A, Nagao S, Suzuki H, Miyazaki K, Sekizuka E, Nagata H, Ishii H and Miura S. Increased expression of mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) and lymphocyte recruitment in murine gastritis induced by Helicobacter pylori. Clin Exp Immunol 130: 183–189, 2002.
 289. Genta RM, Hamner HW and Graham DY. Gastric lymphoid follicles in Helicobacter pylori infection: frequency, distribution, and response to triple therapy. Hum Pathol 24: 577–583, 1993.
 290. Wotherspoon AC, Ortiz‐Hidalgo C, Falzon MR and Isaacson PG. Helicobacter pylori‐associated gastritis and primary B‐cell gastric lymphoma. Lancet 338: 1175–1176, 1991.
 291. Dogan A, Du M, Koulis A, Briskin MJ and Isaacson PG. Expression of lymphocyte homing receptors and vascular addressins in low‐grade gastric B‐cell lymphomas of mucosa‐associated lymphoid tissue. Am J Pathol 151: 1361–1369, 1997.
 292. Koulis A, Diss T, Isaacson PG and Dogan A. Characterization of tumor‐infiltrating T lymphocytes in B‐cell lymphomas of mucosa‐associated lymphoid tissue. Am J Pathol 151: 1353–1360, 1997.
 293. Drillenburg P, van der Voort R, Koopman G, Dragosics B, van Krieken JH, Kluin P, Meenan J, Lazarovits AI, Radaszkiewicz T and Pals ST. Preferential expression of the mucosal homing receptor integrin alpha 4 beta 7 in gastrointestinal non‐Hodgkin's lymphomas. Am J Pathol 150: 919–927, 1997.
 294. Mazzucchelli L, Blaser A, Kappeler A, Scharli P, Laissue JA, Baggiolini M and Uguccioni M. BCA‐1 is highly expressed in Helicobacter pylori‐induced mucosa‐associated lymphoid tissue and gastric lymphoma. J Clin Invest 104: R49–R54, 1999.
 295. Nishi T, Okazaki K, Kawasaki K, Fukui T, Tamaki H, Matsuura M, Asada M, Watanabe T, Uchida K, Watanabe N, Nakase H, Ohana M, Hiai H and Chiba T. Involvement of myeloid dendritic cells in the development of gastric secondary lymphoid follicles in Helicobacter pylori‐infected neonatally thymectomized BALB/c mice. Infect Immun 71: 2153–2162, 2003.
 296. Jaeschke H. Cellular adhesion molecules: regulation and functional significance in the pathogenesis of liver diseases. Am. J. Physiol. 273: G602–G611, 1997.
 297. Jaeschke H, Farhood A and Smith CW. Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo. FASEB J. 4: 3355–3359, 1990.
 298. Bonder CS, Ajuebor MN, Zbytnuik LD, Kubes P and Swain MG. Essential role for neutrophil recruitment to the liver in concanavalin A‐induced hepatitis. J. Immunol. 172: 45–53, 2004.
 299. Muhlen KA, Schumann J, Wittke F, Stenger S, van Rooijen N, van kaer L and Tiegs G. NK cells, but not NKT cells, are involved in Pseudomonas aeruginosa exotoxin A‐induced hepatotoxicity in mice. J Immunol 172: 3034–3041, 2004.
 300. Schumann J, Wolf D, Pahl A, Brune K, Papayannopoulou T, van Rooijen N and Tiegs G. Importance of Kupffer cells for T‐cell‐dependent liver injury in mice. Am J Pathol 157: 1671–1683, 2000.
 301. Tiegs G, Hentschel J and Wendel A. T cell‐dependent experimental liver injury in mice inducible by concanavalin A, J Clin Invest 90: 196–203, 1992.
 302. Springer TA and Lasky LA. Sticky sugars for selectins. Nature 349: 196–197, 1991.
 303. Patel KD, Cuvelier SL and Wiehler S. Selectins: critical mediators of leukocyte recruitment. Semin Immunol, 2001, In press.
 304. Springer TA. Traffic signals of lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell 76: 301–314, 1994.
 305. Luscinskas FW, Ma S, Nusrat A, Parkos CA and Shaw SK. Leukocyte transendothelial migration: a junctional affair. Semin Immunol, 186: 57–67, 2002.
 306. Fox‐Robichaud A and Kubes P. Molecular mechanisms of tumor necrosis factor alpha‐stimulated leukocyte recruitment into the hepatic circulation. Hepatology 31: 1123–1127, 2000.
 307. McCuskey RS. Microscopic methods for studying the microvas‐culature of internal organs. In: Physical techniques in biology and medicine microvascular technology, eds Barker CH and Nastuk WF. New York: Academic, 1986, pp. 247–264.
 308. Chosay JG, Essani NA, Dunn CJ and Jaeschke H. Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin‐induced injury. Am J Physiol 272: G1195–G1200, 1997.
 309. Wong J, Johnston B, Lee SS, Bullard DC, Smith CW, Beaudet AL and Kubes P. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest 99: 2782–2790, 1997.
 310. Li Y, Muruve DA, Collins RG, Lee SS and Kubes P. The role of selectins and integrins in adenovirus vector‐induced neutrophil recruitment to the liver. Eur J Immunol 32: 3443–3452, 2002.
 311. Shi J, Kokubo Y and Wake K. Expression of P‐selectin on hepatic endothelia and platelets promoting neutrophil removal by liver macrophages. Blood 2: 520–528, 1998.
 312. Wake K, Decker K, Kirn A, Knook DL, McCuskey RS, Bourwens L and Wisse E. Cell biology and kinetics of Kupffer cells in the liver. Int Rev Cytol 118: 173–229, 1989.
 313. Linke R, Wagner F, Terajima H, Theiry J, Teupser D, Leiderer R, and Hammer C. Prevention of initial perfusion failure during xenogeneic ex vivo liver perfusion by selectin inhibition. Transplantation 66: 1265–1272, 1998.
 314. Shi J, Kokubo Y and Wake K. Expression of P‐selectin on hepatic endothelia and platelets pro neutrophil removal by liver macrophages. Blood 92: 520–528, 1998.
 315. Massaguer A, Perez‐Del‐Pulgar S, Engel P, Serratosa J, Bosch J and Pizcueta P. Concanavalin‐A‐induced liver injury is severly impaired in mice deficient in P‐selectin. J. Leuk Biol 72: 262–270, 2002.
 316. Essani NA, Fisher MA, Simmons CA, Hoover JL, Farhood A and Jaeschke H. Increased P‐selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil‐induced liver injury in murine endotoxin shock. J Leuk Biol 63: 288–296, 1998.
 317. Klintman D, Schramm R, Menger MD and Thorlacius H. Leukocyte recruitment in hepatic injury: selectin‐mediated leukocyte rolling is a prerequisite for CD18‐dependent firm adhesion. J Hepatol 36: 53–59, 2002.
 318. Sawaya DE, Jr., Zibari GB, Minardi A, Bilton B, Bumey D, Granger DN, McDonald JC and Brown M. P‐selectin contributes to the initial recruitment of rolling and adherent leukocytes in hepatic venules after ischemia/reperfusion. Shock 12: 227–232, 1999.
 319. Surinder S, Yadav SS, Howell DN, Steeber DA, Harland RC, Tedder TR and Clavien PA. P‐selectin mediates reperfusion injury through neutrophil and platelet sequestration in the warm ischemic mouse liver. Hepatohgy 29: 1494–1502, 1999.
 320. Sakamoto N, Zhaoli S, Brengman ML, Maemura K, Ozaki M, Bulkley GB and Klein A. Hepatic reticuloendothelial system dysfunction after ischemia‐peperfusion: role of p‐selectin‐mediated neutrophil accumulation. Liver Transplant 9: 940–948, 2003.
 321. Kubes P, Payne D and Woodman RC. Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation. Am J Physiol Gastroimest Liver Physiol 283: G139–G147, 2002.
 322. Khandoga A, Biberthaler P, Enders G, Teupser D, Axmann SM, Luchting B, Hutter J, Messmer K and Krombach F. P‐selectin mediates platelet‐endothelial cell interactions and reperfusion injury in the mouse liver in vivo. Shock 18: 529–535, 2002.
 323. Horie Y, Wolf R, Anderson DC and Granger DN. Hepatic leukostasis and hypoxic stress in adhesion molecule‐deficient mice after gut ischemia/reperfusion. J Clin Invest 99: 781–788, 1997.
 324. Garcia‐Criado FJ, Palma‐Vargas JM. Valdunciel‐Garcia JJ, Gomez‐Alonso A, Srivastava O, Ezrin A, Anderson MB and Toledo‐Pereyra MD, Sulfo‐lewis diminishes neutrophil infiltration and free radicals with minimal effect on serum cytokines after liver ischemia and reperfusion. J Surg Res 70: 187–194, 1997.
 325. Rubio‐Avilla JM, Palma‐Vargas JM, Collins JT, Smejkal R, Mclaren J, Phillips LM and Toledo‐Pereyra LH. Sialyl lewis sup x analog improves liver function by decreasing neutrophil migration after hemorrhagic shock. J Trauma Inj Infect Crit Care 43: 313–318, 1997.
 326. Dulkanchainun TS, Goss JA, Imagawa DK, Shaw GD, Anselmo DM, Ka Wang T, Zhao D, Busuttil AA, Kato H, Murray NG, Kupiec‐Weglinski JW and Busuttil RW. Reduction of hepatic ischemia/reperfusion injury by a soluble P. glycoprotein ligand‐1. Ann Surg 227: 832–840, 1998.
 327. Green CE, Pearson DN, Camphausen RT, Staunton DE and Simon SI. Shear‐dependent capping of L‐selectin and P‐selectin glycoprote ligand 1 by E‐selectin signals activation of high‐avidity beta2‐int on neutrophils. J Immunol 172: 7780–7790, 2004.
 328. Yadav SS, Howell DN, Gao W, Steeber DA, Harland RC and Clavien PA. L‐selectin and ICAM‐1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver. Am J Gastroimest Liver Physiol 275: G1341–G1352, 1998.
 329. Walcheck B, Moore KL, McEver RP and Kishimoto TK. Neutrophil‐neutrophil interactions under hydrodynamic shear stress involve L‐selectin and PSGL‐1, A mechanism that amplifies initial leukocyte accumulation on P‐selectin in vitro. J Clin Invest 98: 1081–1087, 1999.
 330. Yao L, Setiadi H, Xia L, Laszik Z, Taylor FB and McEver RP. Divergent inducible expression of P‐selectin and E‐selectin in mice and primates. Blood 94: 3820–3828, 1999.
 331. Daneker GW, Lund SA, Caughman SW, Swerlick RA, Fishce AH and Stalo Anes EW. Culture and characterization of sinusoidal endothelial cells isola from human liver. In Vitro Cell Dev Biol Anim 34: 370–377, 1998.
 332. Steinhoff G, Behrend M, Schrader B, Duijv S, Duijvestijn AM and Wonigeit K. Expression patterns of leukocyte adhesion ligand molecules on h liver endothelia. Lack of ELAM‐I CD62 inducibility on sinu endothelia and distinct distribution of VCAM‐1, ICAM‐1, ICAM LFA‐3. Am J Pathol 142: 481–188, 1993.
 333. Adams DH, Hubscher SG, Fisher NC, Williams A and Robinson M. Expression of E‐selectin and E‐selectin ligands in human liver inflammation. Hepatohgy 24: 533–538, 1996.
 334. Lautenschlager I, Harma M, Hockerstedt K, Linnavuori K and Loginov RE. Human herpesvirus‐6 infection is associated with adhesion mole induction and lymphocyte infiltration in liver allografts. J Hepatol 37: 648–654, 2002.
 335. Li X, Klintman D, Weitz‐Schmidt G, Schramm R and Thorlacius H. Lymphocyte function antigen‐1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice. Br J Pharmacol 141: 709–716, 2004.
 336. Marubayashi S, Oshiro Y, Maeda T, Fukuma K, Okada K, Hinoi T, Ikeda M, Yamada K, Itoh H and Dohi K. Protective effect of monoclonal antibodies to adhesion molecules on rat liver ischemia‐reperfusion injury. Surgery 122: 45–52, 1997.
 337. Hamamoto I, Hossain MA, Mori S, Maeba T and Maeta H. Impact of adhesion molecules of the selectin family on liver microcirculation at reperfusion following cold ischemia. Transpl Int 9: 454–460, 1996.
 338. Jaeschke H, Farhood A, Fisher MA and Smith CW. Sequestration of neutrophils in the hepatic vasculature during endotoxemia is independent of beta 2 integrins and intercellular adhesion molecule‐1. Shock 6: 351–356, 1996.
 339. Liu P, McGuire GM, Fisher MA, Farhood A, Smith CW and Jaeschke H. Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin‐enhanced liver injury after hepatic ischemia. Shock 3: 56–62, 1995.
 340. Johnston B and Kubes P. The alpha4‐integrin: an alternative pathway for neutrophil recruitment? Immunol Today 20: 545–550, 1999.
 341. Yachida S, Kokudo Y, Wakabayashi H, Maeba T, Kaneda K and Maeta H. Morphological and functional alterations to sinusoidal endothelial cells in the early phase of endotoxin‐induced liver failure after partial hepatectomy in rats. Virchows Arch 433: 173–181, 1998.
 342. Matsumoto G, Tsunematsu S, Tsukinoki K, Ohmi Y, Iwamiya M, Lovera‐dos‐Santos A, Daisuke T, Shindo J and Penniger JM. Essential role of the adhesion receptor LFA‐1 for T cell‐dependent fulminant hepatitis. Am Assoclmmunol 169: 7087–7096, 2002.
 343. Emoto M, Mitrucker HW, Schmits R, Mak TW and Kaufmann SH. Critical role of leukocyte function‐assocatied antigen‐1 in liver accumulation of CD4+NKT cells. Am Assoc Immunol 162: 5094–5098, 1999.
 344. Garcia‐Barcina M, Lukomska Bw, Gawron W, Winnock M, Vidal‐Vanaclocha F, Bioulac‐Sage P, Balabaud C and Olszewski W. Expression of cell adhesion molecules on liver‐associated lymphocytes and their ligands on sinusoidal lining cells in patients with benign or malignant liver disease. Am J Pathol 146: 1406–1413, 1995.
 345. Wolf D, Hallmann R, Hallmann G, Sass M, Sixt S, Kuster B, Fregien C, Trautwein S and Tiegs G. INF‐a‐induces expression of adhesion molecules in the liver is under the control of TNFR1‐relevance for concanavalin a‐induced hepatitis. J Immunol 166: 1300–1307, 2001.
 346. Sakamoto S, Okanoue T, Itoh Y, Sakamoto K, Nishioji K, Nakagawa Y, Yoshida N, Yoshikawa T and Kashima K. Intercellular adhesion molecule‐1 and CD 18 are involved in neutrophil adhesion and its cytotoxicity to cultured sinusoidal endothelial cells in rats. Hepatohgy 26: 658–663, 1997.
 347. Sakamoto S, Okanoue T, Itoh Y, Nakagawa Y, Nakamura H, Morita A, Daimon Y, Sakamoto K, Yoshida N, Yoshikawa T and Kashima K. Involvement of Kupffer cells in the interaction between neutrophils and sinusoidal endothelial cells in rats. Shock 18: 152–157, 2002.
 348. Colletti LM, Cortis A, Lukacs N, Kunkel SL, Green M and Strieter RM. Tumor necrosis factor up‐regulates intercellular adhesion molecule 1, which is important in the neutrophil‐dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat. Shock 10: 182–191, 1998.
 349. Kono H, Vesugi T, Froh M, Rusyn I, Bradford BU and Thurman RG. ICAM‐1 is involved in the mechanism of alcohol‐induced liver in studies with knockout mice. Am J Physiol Gastrointest Liver Physiol 280: G1289–G1295, 2001.
 350. Hamann A, Kulgewitz K, Austrup F and Jablonski‐Westrick D. Activation induces rapid and profound alterations in the trafficking of T cells. Sur J Immunol 30: 3207–3218, 2000.
 351. Rentsch M, Post S, Palma P, Lang G, Menger MD and Messmer K. Anti‐ICAM‐1 Blockade reduces postsinusoidal WBC adherence following cold ischemia and reperfusion, but does not improve early graft function in rat liver transplantation. J Hepatol 32: 821–828, 2000.
 352. Bacchi CE, Marsh CL, Perkins JD, McVicar JP, Hudkbenjamin CD, Harlan JM, Lobb R and Alpers CE. Expression of vascular cell adhesion molecule (VCAM‐1) in liver pancreas allograft rejection. Am J Pathol 142: 579–591, 1993.
 353. Adams DH, Burr P, Burra SG, Hubscher E, Elias S and Newman W. Endothelial activation and circulating vascular adhesion molecule alcoholic liver disease. Hepatology 19: 588–594, 1994.
 354. Jaruga B, Hong F, Kim W and Gao B. IFN‐β/STAT1 acts as a proinflammatory signal in T cell‐mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF‐1. Am J Physiol Gastrointest Liver Physiol 10: 1–26, 2004.
 355. Shinichi I, Matsuzaki Y, Kimura T, Unno R, Ikegami T, Shoda J, Doy M, Fukahori M and Tanaka N. Suppression of hepatic lesions in a murine graft‐versus‐host reaction by antibodies against adhesion molecules. J Hepatol 32: 587–595, 2000.
 356. Fogler WE, Volker K, McCormick KL, Watanabe M, Ortaldo JR and Wiltrout RH. NK cell infiltration into lung, liver, and subcutaneous B16 melanoma is mediated by VCAM‐1/VLA‐4 interaction. Am Assoc Immunol 156: 4707–4714, 1996.
 357. Essani NA, Bajt ML, Farhood A, Vonderfecht SL and Jaeschke H. Transciptional activation of vascular cell adhesion molecule‐1 gene in vivo and its role in the pathophysiology of neutrophil‐induced liver injury in murine endotoxin shock. J Immunol 12: 5941–5948, 2004.
 358. McNab G, Reeves JL, Salmi M, Hubscher S, Jalkanen S and Adams DH. Vascular adhesion protein 1 mediates binding of T cells to human hepatic endothelium. Gastroenterology 110: 522–528, 1996.
 359. Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S and Adams DH. Vascular adhesion protein‐1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J Immunol 169: 983–992, 2002.
 360. Grant AJ, Lalor PF, Hubscher SG, Briskin M and Adams DH. MAdCAM‐1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM‐1 in chronic inflammatory liver disease). Hepatology 33: 1065–1072, 2001.
 361. Chosay JG, Fisher MA, Farhood A, Ready KA, Dunn CJ and Jaeschke H. Role of PECAM‐1 (CD31) in neutrophil transmigration in muri models of liver and peritoneal inflammation. Am J Physiol 274: G776–G782, 1998.
 362. Dillon P, Belchis D, Tracy T, Cilley R, Hafer L and Krummel T. Increased expression of intercellular adhesion molecules in biliary atresia. Am J Pathol 145: 263–267, 1994.
 363. Wayel J, Dicken D, Koo H, Cerundolo L, Rela M, Nigel D, Fuggle HV and Fuggle SV. Leukocyte Infiltration and Inflammatory antigen expression in cadaveric and Living‐Donor livers before. Transplant 75 (12): 2001–2007, 2003.
 364. Jeffrey R, Fox‐Robichaud A and Fox‐Robichaud S. Hepatic leukocyte recruitment in a model of acute colitis. Am Physiol Soc 283: G561–G566, 2002.

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Article Title: Gastrointestinal and Liver Microcirculations: Roles in Inflammation and Immunity
 

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Soichiro Miura, Paul Kubes, D Neil Granger. Gastrointestinal and Liver Microcirculations: Roles in Inflammation and Immunity. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 684-711. First published in print 2008. doi: 10.1002/cphy.cp020414