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Role of Small GTPases and vβ5 Integrin in Pseudomonas aeruginosa–Induced Increase in Lung Endothelial Permeability

¹ Departments of Anesthesia and Surgery, Laboratory of Surgical Research, and ² Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; ³ Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ⁴ Departments of Anesthesiology and Critical Care Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and ⁵ Institute of Anesthesiology, University of Zurich, Zurich, Switzerland

Correspondence and requests for reprints should be addressed to Jean-Francois Pittet, M.D., Department of Anesthesia, San Francisco General Hospital, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110. E-mail: pittetj{at}anesthesia.ucsf.edu

Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe pneumonia associated with airspace flooding with protein-rich edema in critically ill patients. The type III secretion system is a major virulence factor and contributes to dissemination of P. aeruginosa. However, it is still unknown which particular bacterial toxin and which cellular pathways are responsible for the increase in lung endothelial permeability induced by P. aeruginosa. Thus, the first objective of this study was to determine the mechanisms by which this species causes an increase in lung endothelial permeability. The results showed that ExoS and ExoT, two of the four known P. aeruginosa type III cytotoxins, were primarily responsible for bacterium-induced increases in protein permeability across the lung endothelium via an inhibition of Rac1 and an activation of the RhoA signaling pathway. In addition, inhibition of the vβ5 integrin, a central regulator of lung vascular permeability, prevented these P. aeruginosa–mediated increases in albumin flux due to endothelial permeability. Finally, prior activation of the stress protein response or adenoviral gene transfer of the inducible heat shock protein Hsp72 also inhibited the damaging effects of P. aeruginosa on the barrier function of lung endothelium. Taken together, these results demonstrate the critical role of the RhoA/vβ5 integrin pathway in mediating P. aeruginosa–induced lung vascular permeability. In addition, activation of the stress protein response with pharmacologic inhibitors of Hsp90 may protect lungs against P. aeruginosa–induced permeability changes.

Key Words: lung • Pseudomonas aeruginosa • endothelial cells • integrin • heat shock response

CLINICAL RELEVANCE We demonstrate for the first time that ExoS and ExoT, type III cytotoxins of Pseudomonas aeruginosa, increase lung vascular permeability via a RhoA- and vβ5 integrin–dependent mechanism.