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(American Journal of Pathology. 2002;160:2285-2294.)
© 2002 American Society for Investigative Pathology

Animal Models

Inflammatory Cytokines, Angiogenesis, and Fibrosis in the Rat Peritoneum

Peter J. Margetts^*, Martin Kolb^*, Lisa Yu^*, Catherine M. Hoff, Clifford J. Holmes, Daniel C. Anthony and Jack Gauldie^*

From the Department of Pathology and Molecular Medicine ^*and Division of Nephrology,Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada; Renal Division Scientific Affairs,Baxter Healthcare Corporation, McGaw Park, Illinois; and the CNS Inflammation Group, the University of Southampton,Southhampton, United Kingdom

Abstract

Peritonitis, a common complication of peritoneal dialysis, is followed by acute changes in the function of the peritoneum. The role of inflammatory cytokines in these processes is not clearly identified. We used adenoviral-mediated gene transfer to transiently overexpress interleukin (IL)-1ß (AdIL-1ß) or tumor necrosis factor (TNF)- (AdTNF-) in the rat peritoneum then used a modified equilibrium test to study the histological and functional changes. Overexpression of IL-1ß or TNF- led to an acute inflammatory response. Both inflammatory cytokines induced an early expression of the angiogenic cytokine, vascular endothelial growth factor, along with increased expression of the profibrotic cytokine, transforming growth factor-ß1, along with fibronectin expression and collagen deposition in peritoneal tissues. Both inflammatory cytokines induced angiogenesis, increased solute permeability, and ultrafiltration dysfunction at earlier time points. Changes in structure and function seen in AdTNF--treated animals returned to normal by 21 days after infection, whereas AdIL-1ß-treated animals had persistently increased vasculature with submesothelial thickening and fibrosis. This was associated with up-regulation TIMP-1. TNF- or IL-1ß both induce acute changes in the peritoneum that mimic those seen in peritoneal dialysis patients who experience an episode of peritonitis. These functional changes were associated with early angiogenesis that resolved rapidly after exposure to TNF-. IL-1ß exposure, however, led to a different response with sustained vascularization and fibrosis. IL-1ß inhibition may be a therapeutic goal in acute peritonitis to prevent peritoneal damage.

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