Prevention of esophageal stricture using antifibrotic drug

• Project/Area Number: 17K09480
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka City University
• Principal Investigator: Nagami Yasuaki 大阪市立大学, 大学院医学研究科, 准教授 (70464633)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 食道狭窄 / ピルフェニドン / 狭窄 / Pirfenidone / ESD / 食道癌 / 抗線維化薬

Outline of Final Research Achievements

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 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%).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.

Academic Significance and Societal Importance of the Research Achievements

食道癌に対する内視鏡切除後に狭窄を生じることがあり、食事摂取が難しくなるため問題とされます。この狭窄の予防治療についてピルフェニドンという抗線維化薬の効果を明らかにしました。ブタでの実験が困難となったため、ラットを使用して、ピルフェニドンが抗線維化作用を示して、狭窄を予防することを明らかにしました。今後、さらに大型の動物や人への応用について検討していく必要があると考えますが、新たな狭窄予防薬の開発は内視鏡切除後だけではなく、その他の原因によって生じる食道狭窄や、その他の消化管狭窄の予防にも役立つものと考えています。

Research Products

• [Journal Article] Pirfenidone prevents experimental esophageal stricture after ulcer healing by inhibiting NLRP3 inflammasome activation (2022)
  • Author(s): Shinji Hirano, Akira Higashimori, Yasuaki Nagami, et al.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: in press
  • Peer Reviewed
• [Presentation] 食道潰瘍治癒及び瘢痕狭窄に対するNLRP3インフラマソームを介したピルフェニドンの効果 (2022)
  • Author(s): 平野慎二、東森啓、永見康明、灘谷祐二、大谷恒史 、渡辺俊雄 、藤原靖弘
  • Organizer: GIweek2022 (潰瘍学会)
• [Presentation] The effect of Pirfenidone for esophageal stricture after circumferential esophageal endoscopic submucosal dissection in a porcine model (2020)
  • Author(s): Shinji Hirano, Yasuaki Nagami, Taishi Sakai, Yuki Kakiya, Kojiro Tanoue, Kappei Hayashi, Masafumi Yamamura, Akinari Sawada, Hirotsugu Maruyama, Masaki Ominami, Shusei Fukunaga, Yuji Nadatani, Koji Otani, Shuhei Hosomi, Fumio Tanaka, Noriko Kamata, Koichi Taira, Tetsuya Tanigawa, Toshio Watanabe and Yasuhiro Fujiwara
  • Organizer: 第99回日本消化器内視鏡学会総会
• [Presentation] THE EFFECT OF PIRFENIDONE FOR ESOPHAGEAL STRICTURE AFTER CIRCUMFERENTIAL ESOPHAGEAL ENDOSCOPIC SUBMUCOSAL DISSECTION IN A PORCINE MODEL (2020)
  • Author(s): Shinji Hirano, Yasuaki Nagami, Taishi Sakai, Yuki Kakiya, Kojiro Tanoue, Kappei Hayashi, Masafumi Yamamura, Akinari Sawada, Hirotsugu Maruyama, Masaki Ominami, Shusei Fukunaga, Yuji Nadatani, Koji Otani, Shuhei Hosomi, Fumio Tanaka, Noriko Kamata, Koichi Taira, Tetsuya Tanigawa, Toshio Watanabe and Yasuhiro Fujiwara
  • Organizer: DDW2020
  • Int'l Joint Research
• [Presentation] THE EFFECT OF PIRFENIDONE FOR ESOPHAGEAL STRICTURE AFTER CIRCUMFEREENTIAL ESOPHAGEAL ENDOSCOPIC SUBMUCOSAL DISSECTION IN A PORCINE MODEL (2020)
  • Author(s): Shinji Hirano, Yasuaki Nagami
  • Organizer: DDW2020
  • Int'l Joint Research