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Barrier Enhancing Signals in Pulmonary Edema

Konstantin G. Birukov, Noureddine Zebda, Anna A. Birukova

10.1002/cphy.c100066

Source: Volume 3, Issue 1, January 2013

Published online: January 2013

Full Article on Wiley Online Library



Abstract

Increased endothelial permeability and reduction of alveolar liquid clearance capacity are two leading pathogenic mechanisms of pulmonary edema, which is a major complication of acute lung injury, severe pneumonia, and acute respiratory distress syndrome, the pathologies characterized by unacceptably high rates of morbidity and mortality. Besides the success in protective ventilation strategies, no efficient pharmacological approaches exist to treat this devastating condition. Understanding of fundamental mechanisms involved in regulation of endothelial permeability is essential for development of barrier protective therapeutic strategies. Ongoing studies characterized specific barrier protective mechanisms and identified intracellular targets directly involved in regulation of endothelial permeability. Growing evidence suggests that, although each protective agonist triggers a unique pattern of signaling pathways, selected common mechanisms contributing to endothelial barrier protection may be shared by different barrier protective agents. Therefore, understanding of basic barrier protective mechanisms in pulmonary endothelium is essential for selection of optimal treatment of pulmonary edema of different etiology. This article focuses on mechanisms of lung vascular permeability, reviews major intracellular signaling cascades involved in endothelial monolayer barrier preservation and summarizes a current knowledge regarding recently identified compounds which either reduce pulmonary endothelial barrier disruption and hyperpermeability, or reverse preexisting lung vascular barrier compromise induced by pathologic insults. © 2013 American Physiological Society. Compr Physiol 3:429‐484, 2013.

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Figure 1. Figure 1.

Classification of pulmonary edema.
Figure 2. Figure 2.

Role of Cdc42, Rac, and Rho GTPases in actin cytoskeletal remodeling.
Figure 3. Figure 3.

Regulation of endothelial permeability by microtubule‐dependent signaling. Stable microtubules destabilization by microtubule toxins, bacterial endotoxin, cytokines, or edemagenic agonists (thrombin) causes release of Rho‐specific guanine nucleotide exchange factor GEF‐H1 leading to activation of Rho signaling, actin cytoskeletal remodeling, actomyosin contraction and endothelial permeability. Activation of GEF‐H1 may be inhibited by stabilization of microtubule or activation of Rac and its effector p21‐activated kinase 1 (PAK‐1).
Figure 4. Figure 4.

Schematic representation of focal adhesion protein complex linked via αβ‐integrin heterodimers to the extracellular matrix and via α‐actinin and vinculin linker proteins to the actin cytoskeleton.
Figure 5. Figure 5.

Scheme of adherens junction complex. Cell‐cell contacts are formed by homotypic interactions of transmembrane protein VE‐cadherin, which interacts with αβγ‐catenin complex and p120‐catenin via intracellular domains. Anchorage of adherens junctions to actin cytoskeleton is primarily controlled by α‐catenin and α‐actinin, but may also involve vinculin and ZO proteins. Interaction of Rac/Cdc42 effector IQRas GTPase‐activating protein 1 with either actin cytoskeleton, or beta‐catenin is regulated by Rac/Cdc42 activities and may represent a Rac/Cdc42‐dependent mechanism regulating adherens junction assembly and endothelial barrier.
Figure 6. Figure 6.

Structure of tight junction complex. Extracellular domains of claudin, occluding, or junctional adhesion molecule (JAM) interact with their counterparts in a homotypic fashion, and interaction of their intracellular domains with, ZO‐1, cingulin, afadin and α‐catenin complexes links tight junction with cytoskeleton.
Figure 7. Figure 7.

Rho GTPase‐activated cellular mechanisms leading to increased endothelial permeability. Activated Rho inhibits actin depolymerization and stimulates increased stress fiber formation by Rho‐associated kinase (Rho kinase)‐mediated activation of LIM kinase, which in turn phosphorylates and inactivates actin depolymerizing protein cofilin. Rho‐kinase also promotes actomyosin contraction and formation of paracellular gaps in endothelial monolayers via phosphorylation and inactivation of myosin light chain phosphatase (MLCP) leading to accumulation of phosphorylated myosin light chains. Rho induces linear actin polymerization controlled by Rho effector mDia and indirectly, via PIP 5‐kinase mediated effects on regulator of actin polymerization profilin. Rho activation engages PIP 5‐kinase and focal adhesion kinase (FAK), which stimulate interaction between vinculin, talin, FAK, p130Cas, paxillin, and other focal adhesion proteins and promote assembly of focal adhesions critical for anchorage of activated stress fibers and force development by endothelial cells leading to paracellular gap formation and increased endothelial permeability.
Figure 8. Figure 8.

Barrier protective cytoskeletal mechanisms activated by Rac and Cdc42.
Figure 9. Figure 9.

Barrier protective cytoskeletal mechanisms activated by Rap.
Figure 10. Figure 10.

Barrier protective mechanisms mediated by PI3 kinase.
Figure 11. Figure 11.

Barrier protective mechanisms induced by increase in intracellular cAMP.
Figure 12. Figure 12.

Barrier disruptive and barrier protective mechanisms mediated by p60Src tyrosine kinase.
Figure 13. Figure 13.

Barrier protective mechanisms induced by activated protein C.
Figure 14. Figure 14.

Scheme of arachidonic acid metabolic pathway.
Figure 15. Figure 15.

Sphingomyelin metabolic pathway.
Figure 16. Figure 16.

Molecular mechanisms underlying barrier protective effects of sphingosine 1‐phosphate.
Figure 17. Figure 17.

Products of oxidation of phospholipids containing arachidonic acid.
Figure 18. Figure 18.

Barrier protective mechanisms of oxidized phospholipids.
Figure 19. Figure 19.

Barrier protective mechanisms induced by hepatocyte growth factor.
Figure 20. Figure 20.

Barrier protective mechanisms induced by ATP.


Figure 1.

Classification of pulmonary edema.



Figure 2.

Role of Cdc42, Rac, and Rho GTPases in actin cytoskeletal remodeling.



Figure 3.

Regulation of endothelial permeability by microtubule‐dependent signaling. Stable microtubules destabilization by microtubule toxins, bacterial endotoxin, cytokines, or edemagenic agonists (thrombin) causes release of Rho‐specific guanine nucleotide exchange factor GEF‐H1 leading to activation of Rho signaling, actin cytoskeletal remodeling, actomyosin contraction and endothelial permeability. Activation of GEF‐H1 may be inhibited by stabilization of microtubule or activation of Rac and its effector p21‐activated kinase 1 (PAK‐1).



Figure 4.

Schematic representation of focal adhesion protein complex linked via αβ‐integrin heterodimers to the extracellular matrix and via α‐actinin and vinculin linker proteins to the actin cytoskeleton.



Figure 5.

Scheme of adherens junction complex. Cell‐cell contacts are formed by homotypic interactions of transmembrane protein VE‐cadherin, which interacts with αβγ‐catenin complex and p120‐catenin via intracellular domains. Anchorage of adherens junctions to actin cytoskeleton is primarily controlled by α‐catenin and α‐actinin, but may also involve vinculin and ZO proteins. Interaction of Rac/Cdc42 effector IQRas GTPase‐activating protein 1 with either actin cytoskeleton, or beta‐catenin is regulated by Rac/Cdc42 activities and may represent a Rac/Cdc42‐dependent mechanism regulating adherens junction assembly and endothelial barrier.



Figure 6.

Structure of tight junction complex. Extracellular domains of claudin, occluding, or junctional adhesion molecule (JAM) interact with their counterparts in a homotypic fashion, and interaction of their intracellular domains with, ZO‐1, cingulin, afadin and α‐catenin complexes links tight junction with cytoskeleton.



Figure 7.

Rho GTPase‐activated cellular mechanisms leading to increased endothelial permeability. Activated Rho inhibits actin depolymerization and stimulates increased stress fiber formation by Rho‐associated kinase (Rho kinase)‐mediated activation of LIM kinase, which in turn phosphorylates and inactivates actin depolymerizing protein cofilin. Rho‐kinase also promotes actomyosin contraction and formation of paracellular gaps in endothelial monolayers via phosphorylation and inactivation of myosin light chain phosphatase (MLCP) leading to accumulation of phosphorylated myosin light chains. Rho induces linear actin polymerization controlled by Rho effector mDia and indirectly, via PIP 5‐kinase mediated effects on regulator of actin polymerization profilin. Rho activation engages PIP 5‐kinase and focal adhesion kinase (FAK), which stimulate interaction between vinculin, talin, FAK, p130Cas, paxillin, and other focal adhesion proteins and promote assembly of focal adhesions critical for anchorage of activated stress fibers and force development by endothelial cells leading to paracellular gap formation and increased endothelial permeability.



Figure 8.

Barrier protective cytoskeletal mechanisms activated by Rac and Cdc42.



Figure 9.

Barrier protective cytoskeletal mechanisms activated by Rap.



Figure 10.

Barrier protective mechanisms mediated by PI3 kinase.



Figure 11.

Barrier protective mechanisms induced by increase in intracellular cAMP.



Figure 12.

Barrier disruptive and barrier protective mechanisms mediated by p60Src tyrosine kinase.



Figure 13.

Barrier protective mechanisms induced by activated protein C.



Figure 14.

Scheme of arachidonic acid metabolic pathway.



Figure 15.

Sphingomyelin metabolic pathway.



Figure 16.

Molecular mechanisms underlying barrier protective effects of sphingosine 1‐phosphate.



Figure 17.

Products of oxidation of phospholipids containing arachidonic acid.



Figure 18.

Barrier protective mechanisms of oxidized phospholipids.



Figure 19.

Barrier protective mechanisms induced by hepatocyte growth factor.



Figure 20.

Barrier protective mechanisms induced by ATP.

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Article Title: Barrier Enhancing Signals in Pulmonary Edema
 

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Konstantin G. Birukov, Noureddine Zebda, Anna A. Birukova. Barrier Enhancing Signals in Pulmonary Edema. Compr Physiol 2013, 3: 429-484. doi: 10.1002/cphy.c100066