Pirfenidone prevents esophageal stricture by inhibiting nucleotide binding oligomerization domain like receptor protein 3 inflammasome activation

• Published in: Journal of gastroenterology and hepatology Vol. 37; no. 6; pp. 1096 - 1106
• Main Authors: Hirano, Shinji, Higashimori, Akira, Nagami, Yasuaki, Nadatani, Yuji, Tanigawa, Tetsuya, Ominami, Masaki, Fukunaga, Shusei, Otani, Koji, Hosomi, Shuhei, Tanaka, Fumio, Kamata, Noriko, Taira, Koichi, Watanabe, Toshio, Fujiwara, Yasuhiro
• Format: Journal Article
• Language: English
• Published: Australia Wiley Subscription Services, Inc 01.06.2022
• Subjects: Acetic acid; Animals; Carrier Proteins - metabolism; Caspase; Caspase 1 - metabolism; Collagen; Constriction, Pathologic; Esophageal Stenosis - etiology; Esophageal Stenosis - prevention & control; esophageal stricture; Esophagus; Fibrosis; Humans; inflammasome; Inflammasomes; Inflammasomes - metabolism; Interleukin-1beta - metabolism; interleukin‐1β; Maturation; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nucleotides; Oligomerization; pirfenidone; Pyridones; Rats; Stricture; Ulcer; ulcer healing; Ulcers; Western blotting; ulcer healing; esophageal stricture; pirfenidone; inflammasome; interleukin-1β
• ISSN: 0815-9319; 1440-1746; 1440-1746
• DOI: 10.1111/jgh.15861

Background and Aim Esophageal injury often results in a scar, leading to refractory strictures. The NLRP3 inflammasome activates caspase‐1, causing the maturation of interleukin (IL)‐1β. Here, we aimed to investigate the preventive effect of pirfenidone (PFD), an antifibrotic drug, on esophageal stricture after ulcer healing and studied its mechanism by focusing on the activation of the NLRP3 inflammasome. Methods Esophageal ulcers were induced in rats via the local application of acetic acid in the serosa. PFD was intraperitoneally administered to the rats 3 days after ulcer induction. The effect of PFD on esophageal stricture after ulcer healing was assessed by esophagography on day 9. The protein levels of mature caspase‐1 and IL‐1β were assessed by western blotting. Results The ulcers fully developed 3 days after induction and were almost scarred by day 9 with severe strictures. PFD promoted ulcer healing and attenuated fibrotic collagen in the submucosa by suppressing the increase in NLRP3, cleaved caspase‐1, and mature IL‐1β expression, improving stricture rate (PFD vs vehicle = 55% vs 81%). Exogenous IL‐1β abolished the therapeutic effects of PFD on ulcer healing and stricture formation. Furthermore, NLRP3 and caspase‐1 inhibitors mimicked the effects of PFD on ulcer healing and stricture formation, with suppression of the increase in cleaved caspase‐1 and mature IL‐1β proteins and expression of fibrosis‐related molecules including transforming growth factor (TGF)‐β1. Conclusion The NLRP3 inflammasome promotes esophageal stricture formation following ulcer healing, and PFD exerts potential prophylactic activity against strictures, possibly via the inhibition of the NLRP3/IL‐1β/TGF‐β1 axis.