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J. Biol. Chem., Vol. 283, Issue 10, 6058-6066, March 7, 2008

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Extracellular Superoxide Dismutase Inhibits Inflammation by Preventing Oxidative Fragmentation of Hyaluronan^*

Fei Gao¹, Jeffrey R. Koenitzer, Jacob M. Tobolewski, Dianhua Jiang, Jiurong Liang, Paul W. Noble, and Tim D. Oury

From the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 and the Department of Medicine, Duke University, Durham, North Carolina 27708

Extracellular superoxide dismutase (EC-SOD) is expressed at high levels in lungs. EC-SOD has a polycationic matrix-binding domain that binds to polyanionic constituents in the matrix. Previous studies indicate that EC-SOD protects the lung in both bleomycin- and asbestos-induced models of pulmonary fibrosis. Although the mechanism of EC-SOD protection is not fully understood, these studies indicate that EC-SOD plays an important role in regulating inflammatory responses to pulmonary injury. Hyaluronan is a polyanionic high molecular mass polysaccharide found in the extracellular matrix that is sensitive to oxidant-mediated fragmentation. Recent studies found that elevated levels of low molecular mass hyaluronan are associated with inflammatory conditions. We hypothesize that EC-SOD may inhibit pulmonary inflammation in part by preventing superoxide-mediated fragmentation of hyaluronan to low molecular mass fragments. We found that EC-SOD directly binds to hyaluronan and significantly inhibits oxidant-induced degradation of this glycosaminoglycan. In vitro human polymorphic neutrophil chemotaxis studies indicate that oxidative fragmentation of hyaluronan results in polymorphic neutrophil chemotaxis and that EC-SOD can completely prevent this response. Intratracheal injection of crocidolite asbestos in mice leads to pulmonary inflammation and injury that is enhanced in EC-SOD knock-out mice. Notably, hyaluronan levels are increased in the bronchoalveolar lavage fluid after asbestos-induced pulmonary injury, and this response is markedly enhanced in EC-SOD knock-out mice. These data indicate that inhibition of oxidative hyaluronan fragmentation probably represents one mechanism by which EC-SOD inhibits inflammation in response to lung injury.

Received for publication, November 12, 2007

^* This work was supported by NIEHS, National Institutes of Health Grant F32 ES015383-01 (to F. G.) and National Institutes of Health Grant R01 HL63700 (to T. D. O.). 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 To whom correspondence should be addressed: Dept. of Pathology, University of Pittsburgh, W905 BST, 200 Lothrop St., Dept. of Pathology, Pittsburgh, PA 15261. Tel.: 412-624-8888; Fax: 412-648-9172; E-mail: Feg2{at}pitt.edu.

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