Complement terminal pathway inhibition reduces peritoneal injuries in a rat peritonitis model

Peritonitis and the resulting peritoneal injuries are common problems that prevent long-term peritoneal dialysis (PD) therapy in patients with end-stage kidney diseases. Previously, we have analyzed the relationship between the complement system and progression of peritoneal injuries associated with PD, particularly focusing on the early activation pathways and effects of the anaphylatoxins. We here utilized a novel mAb 2H2 that blocks assembly of the membrane attack complex (MAC) to investigate roles of the complement terminal pathway in PD-associated peritoneal injury. We intraperitoneally injected mAb 2H2 anti-C5b-7 (2.5 or 5 mg/rat) once or twice over the five-day course of the experiment to investigate the effects of inhibiting formation of MAC in a fungal rat peritonitis model caused by repeated intraperitoneal administration of zymosan after methylglyoxal pretreatment (Zy/MGO model). Rats were sacrificed on day 5 and macroscopic changes in both parietal and visceral peritoneum evaluated. Peritoneal thickness, the abundance of fibrinogen and complement C3 and MAC deposition in tissue and accumulation of inflammatory cells were pathologically assessed. The results showed that mAb 2H2, but not isotype control mAb, reduced peritoneal thickness and accumulation of inflammatory cells in a dose and frequency-dependent manner in the Zy/MGO model. These effects were accompanied by decreased C3, MAC, and fibrinogen deposition in peritoneum. In conclusion, in the rat Zy/MGO model, complement terminal pathway activation and MAC formation substantially contributed to development of peritoneal injuries, suggesting that MAC-targeted therapies might be effective in preventing development of peritoneal injuries in humans. To investigate roles of the terminal pathway (TP) of the complement system (C), we utilized a novel mAb 2H2 (anti-C5b-7) that blocks assembly of the membrane attack complex (MAC) to investigate roles of the TP in PD-associated peritoneal injury using a fungal rat peritonitis model caused by repeated intraperitoneal administration of zymosan (Zy) after methylglyoxal pretreatment (Zy/MGO model). Our results showed that mAb 2H2, but not isotype control mAb, reduced peritoneal thickness and accumulation of inflammatory cells in the Zy/MGO model, accompanied by decreased C3, MAC, and fibrinogen deposition in peritoneum. In conclusion, in the rat Zy/MGO model, TP activation and MAC formation substantially contributed to development of peritoneal injuries, suggesting that MAC-targeted therapies might be effective in preventing development of peritoneal injuries in humans. Graphical Abstract

Automated summary

In this study, we used a novel mAb 2H2 to investigate the role of the complement terminal pathway in peritoneal injuries associated with peritoneal dialysis. The results showed that blocking the assembly of the membrane attack complex (MAC) with mAb 2H2 reduced peritoneal thickness and inflammation in a dose-dependent manner. This indicates that targeting MAC might be an effective therapy for preventing peritoneal injuries in humans.