TRPing Up Fibrosis: A Novel Role for TRPA1 in Intestinal Myofibroblasts
Bibliographic record
Abstract
Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs), affecting 30%–50% of patients with Crohn’s disease (CD). It is thought to be a consequence of chronic inflammation, and intestinal fibrosis is characterized by myofibroblast accumulation, excessive deposition of extracellular matrix (ECM), and in some cases smooth muscle hypertrophy. The most severe phenotype, in which tissue remodeling leads to luminal narrowing, occurs in more than 30% of CD patients within 10 years of disease diagnosis,1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar with many of these patients requiring surgery and, ultimately, experiencing stricture recurrence. The introduction of agents that modulate inflammation has improved many aspects of IBD management; however, these therapies have done relatively little to reduce pathogenic tissue remodeling. Most strikingly, despite markedly improved mucosal healing in many patients, the frequency of fibrostenotic complications in CD has not decreased significantly. This is owing, in part, to limited understanding of the mechanisms that initiate and propagate intestinal fibrosis. Fibrosis occurs when repair responses fail to restore normal tissue architecture and, in part, reflects an imbalance between ECM production and degradation. In an otherwise healthy individual, intestinal injury (eg, after biopsy) and the resulting repair responses heal damaged tissues in a timely fashion. In this scenario, recruitment and activation of ECM-producing myofibroblasts are transient. After injury resolution, myofibroblasts undergo apoptosis and therefore cannot contribute to excessive ECM deposition. However, failure to heal damaged tissue and restore normal tissue structure leads to a chronic inflammatory response with enhanced recruitment of ECM-producing myofibroblasts that diverts resolution toward fibrosis.1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar From this model, it is apparent that targeting fibrogenic signaling within myofibroblasts might prove efficacious in treating inflammation-associated intestinal fibrosis. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Kurahara et al2Kurahara L.H. Hiraishi K. Hu Y. Koga K. Onitsuka M. Doi M. Aoyagi K. Takedatsu H. Kojima D. Fujihara Y. Jian Y. Inoue R. Activation of myofibroblast TRPA1 by steroids and pirfenidone ameliorates fibrosis in experimental Crohn's disease.Cell Mol Gastroenterol Hepatol. 2018; 5: 299-318Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar identified the transient receptor potential ankyrin 1 (TRPA1) channel as a novel antifibrotic target in intestinal myofibroblasts. Although other investigators have reported varying roles of TRPA1 in the regulation of intestinal inflammation,1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 3Engel M.A. Leffler A. Niedermirtl F. et al.TRPA1 and substance P mediate colitis in mice.Gastroenterology. 2011; 141: 1346-1358Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 4Kun J. Szitter I. Kemeny A. et al.Upregulation of the transient receptor potential ankyrin 1 ion channel in the inflamed human and mouse colon and its protective roles.PLoS One. 2014; 9: e108164Crossref PubMed Scopus (92) Google Scholar Kurahara et al2Kurahara L.H. Hiraishi K. Hu Y. Koga K. Onitsuka M. Doi M. Aoyagi K. Takedatsu H. Kojima D. Fujihara Y. Jian Y. Inoue R. Activation of myofibroblast TRPA1 by steroids and pirfenidone ameliorates fibrosis in experimental Crohn's disease.Cell Mol Gastroenterol Hepatol. 2018; 5: 299-318Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar showed that TRPA1 activation in myofibroblasts attenuates transforming growth factor β1–induced fibrogenic signaling. By using an in vivo colitis model, Kurahara et al2Kurahara L.H. Hiraishi K. Hu Y. Koga K. Onitsuka M. Doi M. Aoyagi K. Takedatsu H. Kojima D. Fujihara Y. Jian Y. Inoue R. Activation of myofibroblast TRPA1 by steroids and pirfenidone ameliorates fibrosis in experimental Crohn's disease.Cell Mol Gastroenterol Hepatol. 2018; 5: 299-318Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar showed that Trpa1 expression is increased in intestinal myofibroblasts within inflamed regions of wild-type mice, and that exaggerated tissue remodeling occurred in Trpa1-/- mice. Analysis of human CD tissues showed that TRPA1 was increased in fibrostenotic regions. Finally, Kurahara et al2Kurahara L.H. Hiraishi K. Hu Y. Koga K. Onitsuka M. Doi M. Aoyagi K. Takedatsu H. Kojima D. Fujihara Y. Jian Y. Inoue R. Activation of myofibroblast TRPA1 by steroids and pirfenidone ameliorates fibrosis in experimental Crohn's disease.Cell Mol Gastroenterol Hepatol. 2018; 5: 299-318Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar reported that pirfenidone, an antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis, selectively activates TRPA1 in intestinal myofibroblasts, and that this is associated with reduced transforming growth factor β1–induced fibrogenic signaling. To date, no agents for treating fibrosis and stricture formation in IBD have been evaluated in clinical trials. For new therapeutics to be conceived, there is a pressing need for greater understanding of the mechanisms that regulate the biology of the intestinal myofibroblast and fibrogenic signaling. The study by Kurahara et al2Kurahara L.H. Hiraishi K. Hu Y. Koga K. Onitsuka M. Doi M. Aoyagi K. Takedatsu H. Kojima D. Fujihara Y. Jian Y. Inoue R. Activation of myofibroblast TRPA1 by steroids and pirfenidone ameliorates fibrosis in experimental Crohn's disease.Cell Mol Gastroenterol Hepatol. 2018; 5: 299-318Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar makes an important contribution to this field and provides translational insight into the potential efficacy of pirfenidone and other TRPA1-activating agents for the treatment of intestinal fibrosis. Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's DiseaseCellular and Molecular Gastroenterology and HepatologyVol. 5Issue 3PreviewThe 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. Full-Text PDF Open Access
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".