title: Interleukin-1beta causes acute lung injury via alphavbeta5 and alphavbeta6 integrin-dependent mechanisms.
abstract: Interleukin (IL)-1beta has previously been shown to be among the most biologically active cytokines in the lungs of patients with acute lung injury (ALI). Furthermore, there is experimental evidence that lung vascular permeability increases after short-term exposure to IL-1 protein, although the exact mechanism is unknown. Therefore, the objective of this study was to determine the mechanisms of IL-1beta-mediated increase in lung vascular permeability and pulmonary edema following transient overexpression of this cytokine in the lungs by adenoviral gene transfer. Lung vascular permeability increased with intrapulmonary IL-1beta production with a maximal effect 7 days after instillation of the adenovirus. Furthermore, inhibition of the alphavbeta6 integrin and/or transforming growth factor-beta attenuated the IL-1beta-induced ALI. The results of in vitro studies indicated that IL-1beta caused the activation of transforming growth factor-beta via RhoA/alphavbeta6 integrin-dependent mechanisms and the inhibition of the alphavbeta6 integrin and/or transforming growth factor-beta signaling completely blocked the IL-1beta-mediated protein permeability across alveolar epithelial cell monolayers. In addition, IL-1beta increased protein permeability across lung endothelial cell monolayers via RhoA- and alphavbeta5 integrin-dependent mechanisms. The final series of in vivo experiments demonstrated that pretreatment with blocking antibodies to both the alphavbeta5 and alphavbeta6 integrins had an additive protective effect against IL-1beta-induced ALI. In summary, these results demonstrate a critical role for the alphavbeta5/beta6 integrins in mediating the IL-1beta-induced ALI and indicate that these integrins could be a potentially attractive therapeutic target in ALI.
authors.affiliation: Laboratory of Surgical Research, Department of Anesthesia, University of California, San Francisco 94110, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ganter
authors.forename: Jérémie
authors.initials: J
authors.lastname: Roux
authors.forename: Byron
authors.initials: B
authors.lastname: Miyazawa
authors.forename: Marybeth
authors.initials: M
authors.lastname: Howard
authors.forename: James A
authors.initials: JA
authors.lastname: Frank
authors.forename: George
authors.initials: G
authors.lastname: Su
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Horan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pittet
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000418:Albumins / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008907:Mink; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000418:Albumins; D000951:Antigens, Neoplasm; D016023:Integrins; D053583:Interleukin-1beta; D019030:Receptors, Vitronectin; D016211:Transforming Growth Factor alpha; C064660:integrin alphaVbeta5; C073878:integrin alphavbeta6; D020742:rhoA GTP-Binding Protein