title: Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan.
abstract: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA. Feg2@pitt.edu
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Koenitzer
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Tobolewski
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
authors.forename: Tim D
authors.initials: TD
authors.lastname: Oury
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017638:Asbestos, Crocidolite / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity*; D018893:Bronchoalveolar Lavage; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D013481:Superoxides / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D013481:Superoxides; D017638:Asbestos, Crocidolite; D006820:Hyaluronic Acid; C441642:SOD3 protein, human; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase