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Perit Dial Int 29(3): 340-351
2009
© 2009 International Society for Peritoneal Dialysis
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Bench

TISSUE FACTOR AND FACTOR V INVOLVEMENT IN RAT PERITONEAL FIBROSIS

Hiroki Saito1, Masayuki Kitamoto1, Kozue Kato1, Ning Liu1, Hisayo Kitamura1, Kazuhide Uemura1, Fumiaki Nogaki2, Toshiya Takeda3, Noriko Mori4 and Takahiko Ono1

Division of Molecular Medicine,1 University of Shizuoka School of Pharmaceutical Sciences; Division of Nephrology,2 Shimada Municipal Hospital, Shizuoka; Dialysis Center,3 Kyoto Takeda Hospital, Kyoto; and Division of Nephrology,4 Shizuoka General Hospital, Shizuoka, Japan

Correspondence to: T. Ono, Department of Internal Medicine, Shimada Municipal Hospital, 1200-5 Noda, Shimada City 427-8502 Japan. ono{at}municipal-hospital.shimada.shizuoka.jp

{diamondsuit} Objective: Fibrin deposition on the peritoneum has been frequently observed in peritoneal fibrosis induced by long-term peritoneal dialysis. The present study was conducted to clarify the contribution of factor Xa through tissue factor and factor V expression in peritoneal fibrosis.

{diamondsuit} Methods: Wistar rats were intraperitoneally injected with chlorhexidine gluconate (CG) every day. For the interventional study, the factor Xa inhibitor fondaparinux was subcutaneously administered. After 28 days of CG injection, peritoneal specimens were examined by immunohistochemical analyses and in situ hybridization.

{diamondsuit} Results: The peritoneal submesothelial compact zone was observed to be markedly thicker in the CG-injected groups than in the normal group, and that thickness was dose dependent. Immunohistochemical study revealed massive fibrin, fibronectin, and type IV collagen depositions in the CG-injected groups, which was markedly higher than that in the normal group. Macrophage infiltration and staining for tissue factor, factor V, factor X, and protease-activated receptor-2 were intense in the CG-injected groups and negative/trace in the normal group. Tissue factor and factor V mRNAs were abundant in cells in the thickened peritoneum. A double-labeling experiment revealed that tissue factor was observed mainly in macrophages, and factor V was abundantly distributed in the fibrotic tissue together with macrophages. Fondaparinux treatment decreased the thickness of submesothelial fibrotic tissue, and size and number of CD31-positive vessels.

{diamondsuit} Conclusion: These results suggest that expression of tissue factor and factor V in infiltrated macrophages, together with factor X deposition, may progress angiogenesis and accumulation of extracellular matrix components, partly via profibrotic and procoagulant mechanisms in the peritoneum after inflammatory stimulation.

KEY WORDS: Encapsulating peritoneal sclerosis; fibrin; tissue factor; factor X; PAR2.

Received 21 March 2007; accepted 9 September 2008.






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