Role of Integrin αvβ6 in Acute Lung Injury Induced byPseudomonas aeruginosa

Abstract

Deletion of integrin αvβ6 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 β6 gene deletion would also protect againstPseudomonas aeruginosa-induced acute lung injury. Wild-type and littermate β6-null mice, as well as recombinant soluble TGF-β receptor type II-Fc (rsTGF-βRII-Fc) and anti-αvβ6 treated wild-type mice, were instilled with liveP. 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 β6 gene resulted in an overall increase in inflammatory cells in the lungs. Bacterial numbers from the lung homogenates of infected β6-null mice were significantly decreased compared to the numbers in the wild-type mice (1.6 × 10⁶CFU versus 4.2 × 10⁶CFU [P< 0.01]). There were no significant differences inP. aeruginosa-mediated increases in lung endothelial permeability between wild-type and β6-null mice. Similarly, pretreatment with the αvβ6 antibody or with rsTGF-βRII-Fc did not significantly affect theP. aeruginosa-induced lung injury or rate of survival compared to pretreatment with control immunoglobulin G. We conclude that deletion or inhibition of the integrin αvβ6 didnotprotect animals fromP. 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.