Submitted on December 18, 2007
Revised on July 31, 2008
Role of Small GPTases and 
v
5 Integrin in P. aeruginosa-induced Increase in Lung Permeability
Michael T Ganter1, Jeremie Roux2, George Su3, Susan V Lynch2, Clifford S Deutschman4, Yoram G Weiss5, Sarah C Christiaans2, Byron Myazawa2, Eric Kipnis2, Jeanine P Wiener-Kronish6, Marybeth Howard2, and Jean-Francois Pittet6*
1 Departments of Anesthesia and Surgery, University of California San Francisco, Laboratory of Surgical Research, San Francisco, CA, United States; Institute of Anesthesiology, University of Zurich, Zurich, Switzerland,
2 Departments of Anesthesia and Surgery, University of California San Francisco, Laboratory of Surgical Research, San Francisco, CA, United States,
3 Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA,
4 Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA, USA,
5 Departments of Anesthesiology and Critical Care Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel,
6 Departments of Anesthesia and Surgery, University of California San Francisco, Laboratory of Surgical Research, San Francisco, CA, United States; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
* To whom correspondence should be addressed. 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 
v
5 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/v5 integrin pathway in mediating P. aeruginosa-induced lung vascular permeability. Additionally, activation of the stress protein response with pharmacologic inhibitors of Hsp90 may protect lungs against P. aeruginosa-induced permeability changes.
