Barrier Enhancing Signals in Pulmonary Edema

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.

Lung Circulation

“…The thinness of the pulmonary endothelium and minimal distance between the capillary wall and alveolar epithelium are ideal for gas exchange, but also predispose the lungs to edema formation. In recent years, the barrier protective function of the pulmonary vasculature has been investigated intensely [reviewed in (53,60,327,476)]. Recent studies from several laboratories suggest that the pulmonary microvascular endothelium is much less permeable than that of capillaries in other organs and less permeable than the pulmonary macrovasculature (134,477,480,601).…”

IQGAP1 Regulates Endothelial Barrier Function via EB1-Cortactin Cross Talk

“…In turn, EC monolayer recovery and actin reorganization are characterized by cytoskeletal relaxation, dissolution of stress fibers, activation of cortical actin polymerization, and actin filament branching, leading to increased cytoskeletal motility and resealing of intercellular gaps. These events are regulated by Rac GTPase-dependent mechanisms (9).…”

“…Activated Rac1 GTPase stimulates the cytoskeletal effectors cortactin, Arp2/3, and others, which leads to cortical actin thickening, assembly of adherens junctions, and enhancement of the endothelial barrier (2,9). Emerging evidence suggests a role for cross talk between cytoskeletal elements such as microtubules (MT) and the actin network in the regulation of Rho GTPase signaling and the maintenance of cell monolayer integrity.…”

Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6

“…Increased cAMP levels enhance endothelial barrier integrity (19,20) and inhibit barrier-disruptive signaling by protein kinase A-mediated phosphorylation and inactivation of myosin light chain (MLC) kinase (21) and inactivation of the RhoA GTPase-dependent pathway of EC barrier dysfunction (22,23). PC also triggers an alternative, protein kinase A-independent mechanism of EC barrier enhancement, which involves cAMP-activated guanine nucleotide exchange factor Epac1 and its target Ras-related protein 1 (Rap1) GTPase (24,25).…”