Role of integrin alphav beta6 in acute lung injury induced by Pseudomonas aeruginosa.
Deletion of integrin alphav beta6 has been associated with significant protection in experiments where lung injury was induced by bleomycin, lipophilic polysaccharides, and high tidal volume ventilation. This has led to the suggestion that antibody blockade of this integrin is a novel therapy for acute lung injury. We questioned whether beta6 gene deletion would also protect against Pseudomonas aeruginosa-induced acute lung injury. Wild-type and littermate beta6-null mice, as well as recombinant soluble TGF-beta receptor type II-Fc (rsTGF-betaRII-Fc) and anti-alphav beta6 treated wild-type mice, were instilled with live P. aeruginosa. Four or 8 h after bacterial instillation, the mice were euthanized, and either bronchoalveolar lavage fluid or lung homogenates were obtained. Deletion of the beta6 gene resulted in an overall increase in inflammatory cells in the lungs. Bacterial numbers from the lung homogenates of infected beta6-null mice were significantly decreased compared to the numbers in the wild-type mice (1.6 x 10(6) CFU versus 4.2 x 10(6) CFU [P < 0.01]). There were no significant differences in P. aeruginosa-mediated increases in lung endothelial permeability between wild-type and beta6-null mice. Similarly, pretreatment with the alphav beta6 antibody or with rsTGF-betaRII-Fc did not significantly affect the P. aeruginosa-induced lung injury or rate of survival compared to pretreatment with control immunoglobulin G. We conclude that deletion or inhibition of the integrin alphav beta6 did not protect animals from P. aeruginosa-induced lung injury. However, these therapies also did not increase the lung injury, suggesting that host defense was not compromised by this promising new therapy.
Song
Yuanlin
Y
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
Pittet
Jean Francois
JF
Huang
Xiaozhu
X
He
Hong
H
Lynch
Susan V
SV
Violette
Shelia M
SM
Weinreb
Paul H
PH
Horan
Gerald S
GS
Carmago
Amua
A
Sawa
Yoriko
Y
Bernstein
Xin Liu
XL
Wiener-Kronish
Jeanine P
JP
D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D016023:Integrins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000378:metabolism* / Q000382:microbiology* / Q000517:prevention & control; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D019138:Antibodies, Blocking; D000951:Antigens, Neoplasm; D016207:Cytokines; D016023:Integrins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6