C1 Inhibitor-Mediated Protection from Sepsis

Abstract

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.

Cloning and molecular characterization of lycC1INH genes in large yellow croaker (Pseudosciaena crocea)

“…V. anguillarum in the genus Vibrio caused the disease known as vibriosis, a lethal hemorrhagic septicemia. C1INH has been reported to improve the survival of sepsis by directly interacting with Gram negative bacteria [31]. The partial trout C1INH has been isolated from an SSH library infected with Aeromonas salmonicida, a virulent strain causing sepsis [32], while little report has been found in other pathogen such as virus and parasites.…”

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

“…They recruit leukocytes to the site of infection, enhance neutrophil survival, and inhibit neutrophil oxidative burst (107,186,459). In a murine sepsis model, a C1 inhibitor improved survival through complement inhibition (299). In experimental pneumococcal meningitis, inhibition of C1 resulted in reduced meningeal inflammatory responses, decreased cytokine levels, decreased bacterial outgrowth, and improved survival in rats (550).…”

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

“…In fact, deficiencies of several complement factors render the host more susceptible to bacterial infections (10). In other studies, the C1 esterase inhibitor (C1-INH), a complement regulating factor that inactivates the C1 complex, has been utilized as a therapeutic agent for sepsis (11,12). In our previous examination, we focused on the similarity of symptoms between STSS and C1-INH deficiency, and noted that a decrease in C1-INH level caused by S. pyogenes infection is associated with the pathogenesis (13,14).…”