Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-β signaling in a murine colitis model.

Abstract

Inflammatory bowel disease (IBD), particularly Crohn's disease, frequently causes intestinal fibrosis that ultimately leads to formation of strictures requiring bowel resection. Currently there is no effective antifibrotic therapy available for this disease. Pirfenidone is a small compound that has a broad spectrum of antifibrogenic effect and has been used for the treatment of fibrotic diseases in various organs. The present study aimed to investigate the antifibrogenic effect of pirfenidone in a dextran sulfate sodium (DSS)-induced murine colitis model. C57BL/6 mice were used and animals were randomly divided into groups receiving pirfenidone or vehicle by oral or transanal routes. Inflammation- and fibrosis-related indexes including body weight, colon length, disease activity, histological change, mRNA expression of pro-inflammatory and pro-fibrogenic cytokines were assessed. Furthermore, we performed in vitro analysis using CCD18-Co fibroblasts to evaluate cell proliferation, transdifferentiation, and viability after the cells were cultured with pirfenidone. It was found that oral administration of pirfenidone reduced deposition of collagen in colitis-associated fibrosis, and significantly suppressed the mRNA expression of col1a2, col3a1, and TGF-β. Moreover, pirfenidone inhibited the activation of TGF-β-related smad and MAPK pathways both in vitro and in vivo. Clinical and histological evaluation demonstrated that pirfenidone had no anti-inflammatory effect. The antifibrogenic effect was reduced when pirfenidone was administered in a delayed manner and was unobserved if given locally. Pirfenidone suppressed fibroblast proliferation and transdifferentiation without observed toxicity. Altogether, our results suggested that oral pirfenidone protects against fibrosis of DSS-induced colitis through inhibiting the proliferation of colonic fibroblasts and TGF-β signaling pathways.

• Authors: Guanwei Li, Jianan Ren, Qiongyuan Hu, Youming Deng, Guopu Chen, Kun Guo, Ranran Li, Yuan Li, Lei Wu, Gefei Wang, Guosheng Gu, Jieshou Li
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 117 Pg. 57-67 (Oct 01 2016) ISSN: 1873-2968 [Electronic] England
• PMID: 27498142 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Gastrointestinal Agents
• Pyridones
• Transforming Growth Factor beta
• Collagen
• pirfenidone

Topics

• Administration, Oral
• Administration, Rectal
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colitis (drug therapy, immunology, metabolism, pathology)
• Collagen (antagonists & inhibitors, biosynthesis, metabolism)
• Colon (drug effects, immunology, metabolism, pathology)
• Disease Models, Animal
• Female
• Fibrosis
• Gastrointestinal Agents (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Humans
• Intestinal Mucosa (drug effects, immunology, metabolism, pathology)
• Mice, Inbred C57BL
• Pyridones (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Random Allocation
• Signal Transduction (drug effects)
• Specific Pathogen-Free Organisms
• Transforming Growth Factor beta (antagonists & inhibitors, metabolism)