Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway.

Abstract	Transplant-related lung fibrosis is characterized by excessive fibro-collagenous deposition. Induction of arginase, an enzyme that metabolizes L-arginine to urea and L-ornithine, is vital for collagen synthesis. Pirfenidone is an investigational anti-fibrotic agent shown to be effective in blocking pulmonary fibrosis. The purpose of this study was to determine if pirfenidone was protective against the development of fibro-collagenous injury in rat lung orthotopic transplants through altering L-arginine-arginase metabolic pathways. Lung transplants were performed using Lewis donors and Sprague-Dawley recipients (allografts) or the same strain (isografts). Recipients were given pirfenidone (0.5% chow) 1-21-day post-transplantation. A significantly increased peak airway pressure (PawP) with excessive collagen deposition was found in untreated lung allografts. Pirfenidone treatment decreased PawP and collagen content in lung allografts. The beneficial effects were associated with downregulation of arginase protein expression and activity. In addition, pirfenidone decreased endogenous transforming growth factor (TGF)-beta level in lung allografts, and TGF-beta stimulated arginase activity in a dose-dependent manner in both lung tissue and fibroblasts. These results suggest that pirfenidone inhibits local arginase activity possibly through suppression of endogenous TGF-beta, hence, limiting the development of fibrosis in lung allografts.
Authors	Hanzhong Liu, Peter Drew, Andrew C Gaugler, Yanping Cheng, Gary A Visner
Journal	American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 5 Issue 6 Pg. 1256-63 (Jun 2005) ISSN: 1600-6135 [Print] United States
PMID	15888029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Anti-Inflammatory Agents, Non-Steroidal Pyridones Tgfb1 protein, rat Transforming Growth Factor beta Transforming Growth Factor beta1 Tumor Necrosis Factor-alpha Collagen Arginine pirfenidone Nitric Oxide Synthase Nitric Oxide Synthase Type II Nos2 protein, rat Arginase
Topics	Animals Anti-Inflammatory Agents, Non-Steroidal (therapeutic use) Arginase (metabolism) Arginine (metabolism) Cells, Cultured Collagen (metabolism) Down-Regulation Gene Expression Regulation Graft Rejection (immunology, metabolism, pathology) Lung Transplantation (pathology) Male Nitric Oxide Synthase (metabolism) Nitric Oxide Synthase Type II Pulmonary Fibrosis (metabolism, pathology, prevention & control) Pyridones (therapeutic use) Rats Rats, Inbred Lew Rats, Sprague-Dawley Signal Transduction Transforming Growth Factor beta (metabolism) Transforming Growth Factor beta1 Transplantation, Homologous Tumor Necrosis Factor-alpha (antagonists & inhibitors)

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