title: 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: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Guanwei
authors: G
authors: Li
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. Electronic address: jiananr@smail.nju.edu.cn.
authors: Jianan
authors: J
authors: Ren
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China; Medical School of Southeast University, No. 87 Dingjiaqiao Road, Nanjing 210009, China.
authors: Qiongyuan
authors: Q
authors: Hu
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Youming
authors: Y
authors: Deng
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Guopu
authors: G
authors: Chen
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Kun
authors: K
authors: Guo
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Ranran
authors: R
authors: Li
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Yuan
authors: Y
authors: Li
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Lei
authors: L
authors: Wu
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Gefei
authors: G
authors: Wang
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Guosheng
authors: G
authors: Gu
authors: Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors: Jieshou
authors: J
authors: Li
mesh_terms: D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005765:Gastrointestinal Agents; D011728:Pyridones; D016212:Transforming Growth Factor beta; D003094:Collagen; C093844:pirfenidone
keywords: Antifibrotic therapy; Inflammatory bowel disease; Intestinal fibrosis; Pirfenidone