Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Clin Exp Immunol. 2023 Dec 12;214(2):209-218. doi: 10.1093/cei/uxad088.
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.
腹膜炎和由此导致的腹膜损伤是常见问题，会阻止终末期肾病患者进行长期腹膜透析（PD）治疗。此前，我们已经分析了补体系统与 PD 相关腹膜损伤进展之间的关系，特别是关注了早期激活途径和过敏毒素的作用。在这里，我们利用一种新型 mAb 2H2 来阻断膜攻击复合物（MAC）的组装，以研究补体末端途径在 PD 相关腹膜损伤中的作用。我们在实验的五天过程中，通过腹腔内注射 mAb 2H2 抗 C5b-7（2.5 或 5mg/大鼠）一次或两次，以研究在经过甲基乙二醛预处理后，通过重复腹腔内给予酵母聚糖引起的真菌性大鼠腹膜炎模型（Zy/MGO 模型）中，抑制 MAC 形成对腹膜损伤的影响。大鼠在第 5 天被处死，并评估壁层和脏层腹膜的大体变化。通过病理学评估腹膜厚度、纤维蛋白原和补体 C3 的丰度以及组织中 MAC 的沉积和炎症细胞的积聚。结果表明，mAb 2H2（而非同种型对照 mAb）以剂量和频率依赖性方式减少了 Zy/MGO 模型中腹膜厚度和炎症细胞的积聚。这些作用伴随着腹膜中 C3、MAC 和纤维蛋白原沉积的减少。总之，在大鼠 Zy/MGO 模型中，补体末端途径的激活和 MAC 的形成极大地促成了腹膜损伤的发展，这表明针对 MAC 的治疗方法可能有效预防人类腹膜损伤的发展。
