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C1 Inhibitor-Mediated Protection from Sepsis¹

Dongxu Liu^2,3,*, Fengxin Lu^*, Gangjian Qin, Stacey M. Fernandes^*, Jinan Li^*, and Alvin E. Davis, III^3,*

^* CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115; Division of Cardiovascular Research, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA 02135; and Department of Pathology, Harvard Medical School, Boston, MA 02115

C1 inhibitor (C1INH) protects mice from lethal Gram-negative bacterial LPS-induced endotoxin shock and blocks the binding of LPS to the murine macrophage cell line, RAW 264.7, via an interaction with lipid A. Using the cecal ligation and puncture (CLP) model for sepsis in mice, treatment with C1INH improved survival in comparison with untreated controls. The effect was not solely the result of inhibition of complement and contact system activation because reactive center-cleaved, inactive C1INH (iC1INH) also was effective. In vivo, C1INH and iC1INH both reduced the number of viable bacteria in the blood and peritoneal fluid and accelerated killing of bacteria by blood neutrophils and peritoneal macrophages. In vitro, C1INH bound to bacteria cultured from blood or peritoneal fluid of mice with CLP-induced sepsis, but had no direct effect on bacterial growth. However, both C1INH and iC1INH enhanced the bactericidal activity of blood neutrophils and peritoneal exudate leukocytes. C1INH-deficient mice (C1INH^–/– mice) subjected to CLP had a higher mortality than did wild-type littermate mice. Survival of C1INH^–/– mice was significantly increased with two doses of C1INH, one given immediately following CLP, and the second at 6 h post-CLP. C1INH may be important in protection from sepsis through enhancement of bacterial uptake by, and/or bactericidal capacity of, phagocytes. Treatment with C1INH may provide a useful additional therapeutic approach in some patients with peritonitis and/or sepsis.

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 U.S. Public Health Service Grants HD22082 and AI057366.

² Current address: Center for Infection and Immunity Research, School of Life Sciences, Hubei University, P. R. China.

³ Address correspondence and reprint requests to Dr. Alvin E. Davis III, CBR Institute for Biomedical Research, 800 Huntington Avenue, Boston, MA 02115; E-mail address: aldavis{at}cbrinstitute.org or Dongxu Liu, Center for Infection and Immunity Research, School of Life Sciences, Hubei University, P. R. China; E-mail address: dxliu{at}hubu.edu.cn

⁴ Abbreviations used in this paper: CLP, cecal ligation and puncture; ACD, acid citrate dextrose; C1INH, C1 inhibitor; iC1INH, reactive center-cleaved inactive C1INH.