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Involvement of Vitronectin in Lipopolysaccaride-Induced Acute Lung Injury¹

Yuko Tsuruta^*, Young-Jun Park^*, Gene P. Siegal^,,, Gang Liu^* and Edward Abraham^2,*

^* Department of Medicine, Department of Pathology, Department of Cell Biology, and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294

Vitronectin is present in large concentrations in serum and participates in regulation of humoral responses, including coagulation, fibrinolysis, and complement activation. Because alterations in coagulation and fibrinolysis are common in acute lung injury, we examined the role of vitronectin in LPS-induced pulmonary inflammation. Vitronectin concentrations were significantly increased in the lungs after LPS administration. Neutrophil numbers and proinflammatory cytokine levels, including IL-1β, MIP-2, KC, and IL-6, were significantly reduced in bronchoalveolar lavage fluid from vitronectin-deficient (vitronectin^–/–) mice, as compared with vitronectin^+/+ mice, after LPS exposure. Similarly, LPS induced increases in lung edema, myeloperoxidase-concentrations, and pulmonary proinflammatory cytokine concentrations were significantly lower in vitronectin^–/– mice. Vitronectin^–/– neutrophils demonstrated decreased KC-induced chemotaxis as compared with neutrophils from vitronectin^+/+ mice, and incubation of vitronectin^+/+ neutrophils with vitronectin was associated with increased chemotaxis. Vitronectin^–/– neutrophils consistently produced more TNF-, MIP-2, and IL-1β after LPS exposure than did vitronectin^+/+ neutrophils and also showed greater degradation of IB- and increased LPS-induced nuclear accumulation of NF-B compared with vitronectin^+/+ neutrophils. These findings provide a novel vitronectin-dependent mechanism contributing to the development of acute lung injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported, in part, by National Institutes of Health Grants GM049222, HL062221, HL076206 (to E.A.), and AR04631 (to G.P.S.).

² Address correspondence and reprint requests to Dr. Edward Abraham, Department of Medicine, University of Alabama at Birmingham, Boshell Diabetes Building 420, 1530 3rd Avenue South, Birmingham, AL 35294-0012. E-mail address: eabraham{at}UAB.edu

³ Abbreviations used in this paper: ALI, acute lung injury; uPA, urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor 1; uPAR, urokinase plasminogen activator receptor; BAL, bronchoalveolar lavage; MPO, myeloperoxidase; MIC, Migration and Invasion Chemotaxis.

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