Inter-α-trypsin inhibitor attenuates complement activation and complement-induced lung injury
Inter-α-trypsin inhibitor attenuates complement activation and complement-induced lung injury
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DOI：
10.4049/jimmunol.179.6.4187
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发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Schwartzt, David A.
中科院分区：
文献类型：
--
作者：
Garantziotis, Stavros;Hollingsworth, John W.;Schwartzt, David A.
补体激活是炎症和脓毒症的核心组成部分，可导致显著的组织损伤。补体因子是血清蛋白，通过级联的蛋白水解反应放大促炎信号。间α-胰蛋白酶抑制剂（Inter-alpha-trypsin inhibitor，IAPs）是一种丰富的血清蛋白酶抑制剂，含有潜在的补体结合结构域，在动物脓毒症模型中可提高存活率。我们假设，Ifos可以结合补体并抑制补体激活，从而改善补体依赖性炎症。我们在体外补体激活试验和体内补体依赖性肺损伤小鼠模型中评估了这一假设。我们发现，Iceland通过经典和替代途径抑制补体激活，抑制补体依赖性吞噬作用在体外，并减少补体依赖性肺损伤在体内。这种新的功能，提供了一个机制的解释，其观察到的有益效果，败血症，并开辟了新的可能性，其作为一种治疗剂，在炎症性疾病。
Complement activation is a central component of inflammation and sepsis and can lead to significant tissue injury. Complement factors are serum proteins that work through a cascade of proteolytic reactions to amplify proinflammatory signals. Inter-alpha-trypsin inhibitor (IaI) is an abundant serum protease inhibitor that contains potential complement-binding domains, and has been shown to improve survival in animal sepsis models. We hypothesized that IaI can bind complement and inhibit complement activation, thus ameliorating complement-dependent inflammation. We evaluated this hypothesis with in vitro complement activation assays and in vivo in a murine model of complement-dependent lung injury. We found that IaI inhibited complement activation through the classical and alternative pathways, inhibited complement-dependent phagocytosis in vitro, and reduced complement-dependent lung injury in vivo. This novel function of IaI provides a mechanistic explanation for its observed salutary effects in sepsis and opens new possibilities for its use as a treatment agent in inflammatory diseases.