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Review
. 2009 Jun 15;77(12):1763-72.
doi: 10.1016/j.bcp.2009.01.014. Epub 2009 Feb 3.

Regulators of endothelial and epithelial barrier integrity and function in acute lung injury

Rudolf Lucas  1 , Alexander D Verin, Stephen M Black, John D Catravas
Affiliations
Review

Regulators of endothelial and epithelial barrier integrity and function in acute lung injury

Rudolf Lucas et al. Biochem Pharmacol. .

Abstract

Permeability edema is a life-threatening complication accompanying acute lung injury (ALI), severe pneumonia and the acute respiratory distress syndrome (ARDS), which can be associated with a reduced alveolar liquid clearance (ALC) capacity, a disruption of the alveolar epithelial barrier, and an increased capillary endothelial permeability. Bacterial and viral infections can directly promote pulmonary endothelial hyperpermeability and indirectly decrease the function and/or expression of ion transporters regulating ALC in type II alveolar epithelial cells, by means of inducing a strong inflammatory and oxidative stress response in the infected lungs. Apart from ventilation strategies, no standard treatment exists for permeability edema, making the search for novel regulators of endothelial and epithelial hyperpermeability and dysfunction important. Here, we present an overview of recently identified substances that inhibit and/or reverse endothelial barrier disruption and permeability or alveolar epithelial dysfunction: (1) zinc chelators, which were shown to attenuate the effects of oxidative stress on the pulmonary endothelium; (2) peroxisome proliferator activated receptor (PPAR) ligands, which have been shown to exert anti-inflammatory effects, by decreasing the expression of pro-inflammatory genes; (3) extracellular ATP, produced during inflammation, which induces a rapid and dose-dependent increase in transendothelial electrical resistance (TER) across pulmonary endothelial cells; (4) the lectin-like domain of TNF, which is spatially distinct from the receptor binding sites and which protects from hydrostatic and permeability edema and (5) Hsp90 inhibitors, which prevent and repair toxin-induced hyperpermeability. Unraveling the mechanism of action of these agents could contribute to the development of novel therapeutic strategies to combat permeability edema.

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Figures

Scheme 1
Scheme 1
Signal transduction pathways implicated in ATP-mediated endothelial barrier enhancement.
Scheme 2
Scheme 2
Dichotomous activity of TNF in alveolar liquid clearance and barrier protection during ALL TNF, which is induced during ALI, causes a downregulation of ENaC expression in type II alveolar epithelial cells, upon activating TNF-R1 [55, 56]. Moreover, TNF increases permeability, by means of interfering with tight junctions (TJ) in both alveolar epithelial (AEC) and capillary endothelial cells (MVEC). ROS, the generation of which is frequently increased during ALI, were also shown to downregulate ENaC and Na+-K+-ATPase expression [53] and moreover also lead to decreased endothelial barrier integrity. The TIP peptide, mimicking the lectin-like domain of TNF, is able to increase sodium uptake in alveolar epithelial cells and to restore endothelial barrier integrity, as such providing a significant protection against the development of permeability edema (red lines: inhibition, green arrows: activation).
Scheme 3
Scheme 3
Proposed mechanism of action for the anti-inflammatory and barrier-protective actions of hsp90 inhibitors.
Scheme 4
Scheme 4
Frequently used hsp 90 inhibitors.
See this image and copyright information in PMC

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