APT070 (Mirococept), a membrane-localised complement inhibitor, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury.
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-alpha and IL-6, but not those of IL-1beta 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.
Souza
Danielle G
DG
Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627 - Pampulha, 31270-901 Belo Horizonte, MG, Brazil.
Esser
Dirk
D
Bradford
Roberta
R
Vieira
Angélica T
AT
Teixeira
Mauro M
MM
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D003169:Complement Inactivator Proteins / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005759:Gastroenteritis / Q000097:blood / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D006454:Hemoglobins / Q000032:analysis; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply / Q000187:drug effects*; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000097:blood / Q000150:complications* / Q000378:metabolism
D003169:Complement Inactivator Proteins; D016207:Cytokines; D006454:Hemoglobins; D003165:Complement System Proteins