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Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease

BACKGROUND & AIMS: The transient receptor potential ankyrin 1 (TRPA1) channel is highly expressed in the intestinal lamina propria, but its contribution to gut physiology/pathophysiology is unclear. Here, we evaluated the function of myofibroblast TRPA1 channels in intestinal remodeling. METHODS...

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Autores principales: Kurahara, Lin Hai, Hiraishi, Keizo, Hu, Yaopeng, Koga, Kaori, Onitsuka, Miki, Doi, Mayumi, Aoyagi, Kunihiko, Takedatsu, Hidetoshi, Kojima, Daibo, Fujihara, Yoshitaka, Jian, Yuwen, Inoue, Ryuji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852292/
https://www.ncbi.nlm.nih.gov/pubmed/29552620
http://dx.doi.org/10.1016/j.jcmgh.2017.12.005
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author Kurahara, Lin Hai
Hiraishi, Keizo
Hu, Yaopeng
Koga, Kaori
Onitsuka, Miki
Doi, Mayumi
Aoyagi, Kunihiko
Takedatsu, Hidetoshi
Kojima, Daibo
Fujihara, Yoshitaka
Jian, Yuwen
Inoue, Ryuji
author_facet Kurahara, Lin Hai
Hiraishi, Keizo
Hu, Yaopeng
Koga, Kaori
Onitsuka, Miki
Doi, Mayumi
Aoyagi, Kunihiko
Takedatsu, Hidetoshi
Kojima, Daibo
Fujihara, Yoshitaka
Jian, Yuwen
Inoue, Ryuji
author_sort Kurahara, Lin Hai
collection PubMed
description BACKGROUND & AIMS: The transient receptor potential ankyrin 1 (TRPA1) channel is highly expressed in the intestinal lamina propria, but its contribution to gut physiology/pathophysiology is unclear. Here, we evaluated the function of myofibroblast TRPA1 channels in intestinal remodeling. METHODS: An intestinal myofibroblast cell line (InMyoFibs) was stimulated by transforming growth factor-β1 to induce in vitro fibrosis. Trpa1 knockout mice were generated using the Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. A murine chronic colitis model was established by weekly intrarectal trinitrobenzene sulfonic acid (TNBS) administration. Samples from the intestines of Crohn’s disease (CD) patients were used for pathologic staining and quantitative analyses. RESULTS: In InMyoFibs, TRPA1 showed the highest expression among TRP family members. In TNBS chronic colitis model mice, the extents of inflammation and fibrotic changes were more prominent in TRPA1(-/-) knockout than in wild-type mice. One-week enema administration of prednisolone suppressed fibrotic lesions in wild-type mice, but not in TRPA1 knockout mice. Steroids and pirfenidone induced Ca(2+) influx in InMyoFibs, which was antagonized by the selective TRPA1 channel blocker HC-030031. Steroids and pirfenidone counteracted transforming growth factor-β1–induced expression of heat shock protein 47, type 1 collagen, and α-smooth muscle actin, and reduced Smad-2 phosphorylation and myocardin expression in InMyoFibs. In stenotic intestinal regions of CD patients, TRPA1 expression was increased significantly. TRPA1/heat shock protein 47 double-positive cells accumulated in the stenotic intestinal regions of both CD patients and TNBS-treated mice. CONCLUSIONS: TRPA1, in addition to its anti-inflammatory actions, may protect against intestinal fibrosis, thus being a novel therapeutic target for highly incurable inflammatory/fibrotic disorders.
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spelling pubmed-58522922018-03-16 Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease Kurahara, Lin Hai Hiraishi, Keizo Hu, Yaopeng Koga, Kaori Onitsuka, Miki Doi, Mayumi Aoyagi, Kunihiko Takedatsu, Hidetoshi Kojima, Daibo Fujihara, Yoshitaka Jian, Yuwen Inoue, Ryuji Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: The transient receptor potential ankyrin 1 (TRPA1) channel is highly expressed in the intestinal lamina propria, but its contribution to gut physiology/pathophysiology is unclear. Here, we evaluated the function of myofibroblast TRPA1 channels in intestinal remodeling. METHODS: An intestinal myofibroblast cell line (InMyoFibs) was stimulated by transforming growth factor-β1 to induce in vitro fibrosis. Trpa1 knockout mice were generated using the Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. A murine chronic colitis model was established by weekly intrarectal trinitrobenzene sulfonic acid (TNBS) administration. Samples from the intestines of Crohn’s disease (CD) patients were used for pathologic staining and quantitative analyses. RESULTS: In InMyoFibs, TRPA1 showed the highest expression among TRP family members. In TNBS chronic colitis model mice, the extents of inflammation and fibrotic changes were more prominent in TRPA1(-/-) knockout than in wild-type mice. One-week enema administration of prednisolone suppressed fibrotic lesions in wild-type mice, but not in TRPA1 knockout mice. Steroids and pirfenidone induced Ca(2+) influx in InMyoFibs, which was antagonized by the selective TRPA1 channel blocker HC-030031. Steroids and pirfenidone counteracted transforming growth factor-β1–induced expression of heat shock protein 47, type 1 collagen, and α-smooth muscle actin, and reduced Smad-2 phosphorylation and myocardin expression in InMyoFibs. In stenotic intestinal regions of CD patients, TRPA1 expression was increased significantly. TRPA1/heat shock protein 47 double-positive cells accumulated in the stenotic intestinal regions of both CD patients and TNBS-treated mice. CONCLUSIONS: TRPA1, in addition to its anti-inflammatory actions, may protect against intestinal fibrosis, thus being a novel therapeutic target for highly incurable inflammatory/fibrotic disorders. Elsevier 2017-12-21 /pmc/articles/PMC5852292/ /pubmed/29552620 http://dx.doi.org/10.1016/j.jcmgh.2017.12.005 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Kurahara, Lin Hai
Hiraishi, Keizo
Hu, Yaopeng
Koga, Kaori
Onitsuka, Miki
Doi, Mayumi
Aoyagi, Kunihiko
Takedatsu, Hidetoshi
Kojima, Daibo
Fujihara, Yoshitaka
Jian, Yuwen
Inoue, Ryuji
Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease
title Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease
title_full Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease
title_fullStr Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease
title_full_unstemmed Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease
title_short Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease
title_sort activation of myofibroblast trpa1 by steroids and pirfenidone ameliorates fibrosis in experimental crohn's disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852292/
https://www.ncbi.nlm.nih.gov/pubmed/29552620
http://dx.doi.org/10.1016/j.jcmgh.2017.12.005
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