APT070 (Mirococept), a membrane-localised complement inhibitor, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury

Abstract

Activation of the complement system has been shown to play a major role in the mediation of reperfusion injury. Here, we assessed the effects of APT070 (Mirococept), a novel membrane-localised complement inhibitor based on a recombinant fragment of soluble CR1, on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in the rat. In a model of mild I/R injury (30 min of ischaemia and 30 min of reperfusion), APT070 dose-dependently (1-10 mg kg -1) inhibited the increase in vascular permeability of and neutrophil influx into intestine and lungs. Maximal inhibition occurred at 10 mg kg -1. Following severe I/R injury (120 min of ischaemia and 120 min of reperfusion), APT070 (10 mg kg -1) markedly prevented neutrophil influx and the increase in vascular permeability both in the intestine and the lungs. APT070 also effectively suppressed the increase of tissue (intestine and lungs) and serum concentrations of TNF-α and IL-6, but not those of IL-1β or IL-10. There was no significant reduction of mortality in the APT070 group. In conclusion, treatment with the membrane-targeted complement inhibitor APT070 significantly reduced the hyperinflammatory response after mild and severe ischaemia and reperfusion injury (I/RI) in rats. APT070 may be effective in therapeutic indications involving gut I/RI. © 2005 Nature Publishing Group All rights reserved.