Cigarette smoke increases susceptibility to lung edema: Implication of RhoA and FAK‐mediated disassembly of endothelial cytoskeleton and cell contacts

Abstract

Cigarette smoke (CS) is a major risk factor for chronic lung and heart diseases. Whether CS is a risk factor for acute lung injury (ALI) remains controversial. Using mice exposed to acute CS and cultured lung endothelial cells exposed to cigarette smoke extract (CSE), we have shown that CS causes endothelial barrier dysfunction and exacerbates lipopolysaccharide (LPS)‐induced increase in vascular permeability in vitro and in vivo. CSE‐induced barrier dysfunction is mediated via oxidative stressinduced inhibition of RhoA and focal adhesion kinase (FAK). The aim of this study is to further address the effect and mechanism of CS on susceptibility to ALI. We found that similar to acute exposure, chronic CS exposure, which caused mild emphysema, increased susceptibility to LPS‐induced lung edema. However, chronic CS exposure alone did not increase lung vascular permeability. We also found that CSE disrupted focal adhesion complexes (FAC), F‐actin fibers and adherens junctions (AJ) via inhibition of RhoA and FAK. In addition, CSE caused disassembly of microtubule (MT) and MT stabilizer, taxol, blunted CSE‐induced barrier dysfunction. Our data suggest that CS causes endothelial barrier dysfunction via disassembly of cytoskeleton and cell contacts. Increased susceptibility to lung edema may be yet another health consequence of CS. Supported Finding: VA Merit Review (Rounds), HL64936 (Rounds), ATS/PHA grant (Lu)