TY - JOUR
T1 - Regulators of endothelial and epithelial barrier integrity and function in acute lung injury
AU - Lucas, Rudolf
AU - Verin, Alexander D.
AU - Black, Stephen M.
AU - Catravas, John D.
PY - 2009/6/15
Y1 - 2009/6/15
N2 - 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.
AB - 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.
KW - ATP
KW - Lectin-like domain of TNF
KW - PPAR agonists
KW - Permeability edema
KW - hsp90 inhibitors
UR - http://www.scopus.com/inward/record.url?scp=67349132318&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349132318&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2009.01.014
DO - 10.1016/j.bcp.2009.01.014
M3 - Comment/debate
C2 - 19428331
AN - SCOPUS:67349132318
SN - 0006-2952
VL - 77
SP - 1763
EP - 1772
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 12
ER -