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Zymosan, but Not Lipopolysaccharide, Triggers Severe and Progressive Peritoneal Injury Accompanied by Complement Activation in a Rat Peritonitis Model¹

Masashi Mizuno^*,,2, Yasuhiko Ito^*,, Natalie Hepburn, Tomohiro Mizuno, Yukihiro Noda, Yukio Yuzawa, Claire L. Harris, B. Paul Morgan and Seiichi Matsuo

*Renal Replacement Therapy and Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya, Japan; and Complement Biology Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff, United Kingdom

Fungal peritonitis is an important complication in peritoneal dialysis patients; either continuous or recurrent peritonitis may enhance peritoneal damage. Even when the peritoneal dialysis catheter is removed in patients with fungal peritonitis, peritoneal fibrosis can progress and evolve into encapsular peritoneal sclerosis. It is unclear why fungal infections are worse than bacterial in these respects. Zymosan is a cell wall component of yeast that strongly activates the complement system. In this study, we compared the effects of zymosan and bacterial LPS on peritoneal inflammation in a rat peritoneal injury model induced by mechanical scraping. Intraperitoneal administration of zymosan, but not LPS or vehicle, caused markedly enhanced peritonitis with massive infiltration of cells and deposition of complement activation products C3b and membrane attack complex on day 5. In rats administered zymosan and sacrificed on days 18 or 36, peritoneal inflammation persisted with accumulation of ED-1-positive cells, small deposits of C3b and membrane attack complex, exudation of fibrinogen, and capillary proliferation in subperitoneal tissues. When zymosan was administered daily for 5 days after peritoneal scrape, there was even greater peritoneal inflammation with peritoneal thickening, inflammatory cell accumulation, and complement deposition. Inhibition of systemic complement by pretreatment with cobra venom factor or local inhibition by i.p. administration of the recombinant complement regulator Crry-Ig reduced peritoneal inflammation in zymosan-treated rats. Our results show that yeast components augment inflammation in the injured peritoneum by causing complement activation within the peritoneal cavity. Local anticomplement therapy may therefore protect from peritoneal damage during fungal infection of the peritoneum.

² Address correspondence and reprint requests to Dr. Masashi Mizuno, Renal Replacement Therapy and Division of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Japan. E-mail address: mmizu{at}med.nagoya-u.ac.jp or masashim1jp{at}yahoo.co.jp

¹ This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry Education, Science, and Culture, Japan (no. 19590946) and the 2006 research grant from the Aichi Kidney Foundation. B.P.M. was supported by a Programme Grant from the Wellcome Trust (Grant 068590) and C.L.H. and N.J.H. were supported by the Wellcome Trust (Grant 068823) and the Welsh Office of Research and Development (Grant DTA01/1/014).