Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan
Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan
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DOI：
10.1074/jbc.m709273200
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发表时间：
2008-03-07
影响因子：
4.8
通讯作者：
Oury, Tim D.
中科院分区：
文献类型：
--
作者：
Gao, Fei;Koenitzer, Jeffrey R.;Oury, Tim D.
细胞外超氧化物歧化酶（EC-SOD）在肺中以高水平表达。EC-SOD具有与基质中的聚阴离子成分结合的聚阳离子基质结合结构域。先前的研究表明，EC-SOD在博莱霉素和石棉诱导的肺纤维化模型中保护肺。尽管EC-SOD的保护机制尚未完全清楚，但这些研究表明EC-SOD在调节肺损伤的炎症反应中起重要作用。透明质酸是一种在细胞外基质中发现的聚阴离子高分子量多糖，对氧化剂介导的断裂敏感。最近的研究发现，低分子量透明质酸水平升高与炎症有关。我们推测EC-SOD可能通过阻止超氧化物介导的透明质酸片段化为低分子量片段而部分抑制肺部炎症。我们发现，EC-SOD直接结合透明质酸，并显着抑制氧化剂诱导的这种糖胺聚糖的降解。体外人类多态性中性粒细胞趋化性研究表明，透明质酸的氧化片段化导致多态性中性粒细胞趋化性，EC-SOD可以完全阻止这种反应。小鼠气管内注射青石棉会导致肺部炎症和损伤，而EC-SOD基因敲除小鼠的肺部炎症和损伤会加剧。值得注意的是，在石棉诱导的肺损伤后，支气管肺泡灌洗液中的透明质酸水平增加，并且这种反应在EC-SOD敲除小鼠中显著增强。这些数据表明，抑制氧化透明质酸碎片可能代表一种机制，EC-SOD抑制炎症反应的肺损伤。
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.