Inter-{alpha}-Trypsin Inhibitor Attenuates Complement Activation and Complement-Induced Lung Injury.
Journal of immunology (Baltimore, Md. : 1950) 2007 Sep 15; 179(6):4187-92
Garantziotis S, Hollingsworth J JW, Ghanayem R RB, Timberlake S, Zhuo L, Kimata K, Schwartz D DA
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
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.