Role of small GTPases and alphavbeta5 integrin in Pseudomonas aeruginosa-induced increase in lung endothelial permeability.
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 alphavbeta5 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/alphavbeta5 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.
Ganter
Michael T
MT
Department of Anesthesia and Surgery, University of California San Francisco, San Francisco, California 94110, USA.
Roux
Jérémie
J
Su
George
G
Lynch
Susan V
SV
Deutschman
Clifford S
CS
Weiss
Yoram G
YG
Christiaans
Sarah C
SC
Myazawa
Byron
B
Kipnis
Eric
E
Wiener-Kronish
Jeanine P
JP
Howard
Marybeth
M
Pittet
Jean-François
JF
D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000033:anatomy & histology* / Q000382:microbiology; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D001427:Bacterial Toxins; C477521:ExoT protein, Pseudomonas aeruginosa; D020690:GTPase-Activating Proteins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D036002:ADP Ribose Transferases; C444820:exoenzyme S; D020559:Monomeric GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein