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Hsp90 inhibitors prevent LPS‐induced endothelial hyper‐permeability by inhibiting pp60src activation and maintaining adherens junction proteins

Endothelial hyper‐permeability leading to vascular leak is an important consequence of sepsis and sepsis‐induced lung injury. We previously reported that heat shock protein (hsp) 90 inhibitor pretreatment improved pulmonary barrier dysfunction in a murine model of sepsis‐induced lung injury. We now examine the effects of hsp90 inhibitors on LPS‐mediated endothelial hyper‐permeability, as reflected in changes in transendothelial electrical resistance (TER) of bovine pulmonary aortic endothelial cells. Vehicle‐pretreated cells exposed to endotoxin exhibited a concentration‐dependent decrease in TER, activation of pp60Src , phosphorylation of the focal adhesion protein paxillin and reduced expression of the adherens junction (AJ) proteins, VE‐cadherin and β‐catenin. Pretreatment with the hsp90 inhibitor, radicicol prevented the decrease in TER, maintained VE‐cadherin and β‐catenin expression, inhibited activation of pp60Src and phosphorylation of paxillin. Similarly, when BPAEC hyper‐permeability was induced by endotoxin‐activated neutrophils, pretreatment of neutrophils and/or endothelial cells with radicicol protected against the activated neutrophil‐induced decrease in TER. These results suggest that the protective effects of hsp90 inhibitors include prevention of pp60Src activaton and maintenance of adherens junction proteins.