Renal Replacement Therapy, Division of Nephrology, Nagoya Univ. Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan.
Am J Physiol Renal Physiol. 2012 May 15;302(10):F1245-51. doi: 10.1152/ajprenal.00652.2011. Epub 2012 Feb 15.
Peritonitis and the rare sequela of encapsulating peritoneal sclerosis (EPS) are serious problems in patients on peritoneal dialysis therapy. Chronic and persistent peritoneal injuries may be a risk factor of EPS. We previously reported that a chronic, proliferative peritonitis developed when zymosan was administered intraperitoneally following scraping injury of rat peritoneum (Mizuno M, Ito Y, Hepburn N, Mizuno T, Noda Y, Yuzawa Y, Harris CL, Morgan BP, Matsuo S. J Immunol 183: 1403-1412, 2009). Peritoneal membrane complement regulators (CRegs), especially Crry and CD59, protected from injury by inhibiting local complement activation, suggesting that CRegs play important roles in maintaining homeostasis in rat peritoneum. Here, we investigated roles of complement in the development of EPS by neutralizing CReg function with monoclonal antibodies (MAbs). Proliferative peritonitis was induced by scraping the peritoneum, followed by daily intraperitoneal administration of zymosan. When either Crry or CD59 alone was neutralized by MAb, the tissue injuries were not significantly changed compared with rats without neutralizing MAb. When both Crry and CD59 were neutralized in this model, severe fibrin exudation was observed on the peritoneal surface on day 5, accompanied by inflammatory cell infiltration, resembling the early stages of development of EPS. Dense peritoneal deposition of C3 fragments and membrane attack complex were observed, along with the fibrin exudates. Intravenous administration of cobra venom factor, which profoundly activates complement, further enhanced these pathological changes. Our results show that complement activation in injured peritoneum drives peritoneal inflammation, and that enhancement of complement activation by inhibiting CReg and/or enhancing systemic activation contributes to the initiation of EPS; therefore, anti-complement agents might be of therapeutic value in humans for the treatment of EPS.
腹膜炎和罕见的包裹性腹膜硬化症（EPS）是腹膜透析治疗患者的严重问题。慢性和持续的腹膜损伤可能是 EPS 的一个风险因素。我们之前报道过，当在大鼠腹膜刮伤后腹腔内给予酵母聚糖时，会发展出慢性、增生性腹膜炎（Mizuno M、Ito Y、Hepburn N、Mizuno T、Noda Y、Yuzawa Y、Harris CL、Morgan BP、Matsuo S. J Immunol 183: 1403-1412, 2009）。腹膜膜补体调节蛋白（CRegs），特别是 Crry 和 CD59，通过抑制局部补体激活来保护免受损伤，这表明 CRegs 在维持大鼠腹膜内稳态中发挥重要作用。在这里，我们通过用单克隆抗体（MAb）中和 CReg 功能来研究补体在 EPS 发展中的作用。通过刮擦腹膜诱导增生性腹膜炎，然后每天腹腔内给予酵母聚糖。当仅用 MAb 中和 Crry 或 CD59 之一时，与未用中和 MAb 的大鼠相比，组织损伤没有明显变化。当在该模型中同时中和 Crry 和 CD59 时，在第 5 天观察到腹膜表面有严重的纤维蛋白渗出，伴有炎症细胞浸润，类似于 EPS 发展的早期阶段。观察到 C3 片段和膜攻击复合物在腹膜上的致密沉积，伴随着纤维蛋白渗出物。静脉内给予眼镜蛇毒液因子，可深度激活补体，进一步增强这些病理变化。我们的结果表明，损伤腹膜中的补体激活驱动腹膜炎症，并且通过抑制 CReg 和/或增强全身性激活来增强补体激活有助于 EPS 的启动；因此，抗补体药物可能对人类治疗 EPS 具有治疗价值。
