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Inter--Trypsin Inhibitor Attenuates Complement Activation and Complement-Induced Lung Injury¹

Stavros Garantziotis^2,*,, John W. Hollingsworth^*,, Rami B. Ghanayem, Sarah Timberlake^*,, Lisheng Zhuo, Koji Kimata and David A. Schwartz

^* Department of Medicine, Duke University Medical Center, Durham, NC 27710; National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; North Carolina State University, Raleigh, NC 27695; and Institute for Molecular Science of Medicine, Aichi Medical University, Aichi, Japan

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--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.

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 This work was supported by the Intramural Research Program of the National Institutes of Health; the National Institute of Environmental Health Sciences; and the National Heart, Lung, and Blood Institute.

² Address correspondence and reprint requests to Dr. Stavros Garantziotis, Box 3683, Duke University Medical Center, Durham, NC 27710. E-mail address: garan001{at}mc.duke.edu

³ Abbreviations used in this paper: IaI, inter--trypsin inhibitor; CVF, cobra venom factor; RA, rheumatoid arthritis; UTI, urinary trypsin inhibitor; vWA, von-Willebrand type A.