title: Membrane complement regulators protect against fibrin exudation increases in a severe peritoneal inflammation model in rats.
abstract: 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.
authors.affiliation: Renal Replacement Therapy, Division of Nephrology, Nagoya Univ. Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan. mmizu@med.nagoya-u.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuno
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Mizuno
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D018957:CD59 Antigens / Q000276:immunology / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism*; D006706:Homeostasis / Q000276:immunology; D008297:Male; D010530:Peritoneal Dialysis / Q000009:adverse effects; D010537:Peritoneum / Q000276:immunology* / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D015054:Zymosan / Q000633:toxicity
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000954:Antigens, Surface; D018957:CD59 Antigens; C513105:Cr1l protein, rat; D011956:Receptors, Cell Surface; D005337:Fibrin; D003165:Complement System Proteins; D015054:Zymosan