Barrier‐protective effects of hsp90 inhibitors in bovine pulmonary arterial endothelial cells.

Abstract

Lung edema due to increased vascular permeability is a hallmark of acute lung injury (ALI). Recently we demonstrated that hsp90 inhibitors effectively protect the endothelium from bacterial lipopolysaccharide (LPS) injury. Since inflammatory cytokines, such as transforming growth factor β (TGFβ), are involved in the increased lung permeability associated with ALI, we tested the hypothesis that hsp90 inhibitors may restore endothelial cell (EC) permeability after injury by TGFβ. Bovine pulmonary arterial EC (BPAEC) exposed to TGFβ exhibited a time-and dose-dependent decrease in transendothelial electrical resistance (TER). Maximal decline of TER was observed 2.5–3h after TGFβ (10ng/ml) and was sustained for at least 18h. Pre-incubation of BPAEC with either of two hsp90 inhibitors, radicicol (RA; 1μg/ml) or 17-AAG (1μg/ml), for 2h did not prevent the first (1–3h) stage of decrease in TER, but progressively restored TER over the subsequent 4–18h. This data imply that RA and 17-AAG stimulate BPAEC repair after TGFβ injury. To test this hypothesis, we first exposed BPAEC to TGFβ for 3h and then added RA or 17AAG. Post-treatment of BPAEC with either inhibitor completely restored TER of BPAEC to levels even higher than in uninjured cells. We conclude that hsp90 inhibitors exert barrier protective effect on EC and therefore may have useful therapeutic value in ALI (supported by HL70214, HL80675, HL58064).