Regulation of the intestinal smooth muscle cell phenotype by the antifibrotic drug nintedanib
Bibliographic record
Abstract
The phenotype of the intestinal smooth muscle cell (ISMC) is typically contractile and non- proliferative, but this can be modulated to allow for proliferation as a wound repair mechanism. While phenotypic modulation of ISMC is normal, chronic inflammation causes excessive proliferation of ISMC, which can contribute to the pathophysiology of inflammatory bowel diseases (IBD). Particularly, in Crohn’s disease (CD), as a consequence of ISMC hyperplasia and extracellular matrix (ECM) collagen deposition, intestinal strictures may arise, ultimately leading to obstruction. Since there are minimal effective treatment options for intestinal strictures, we explored the effects of a multimodal tyrosine kinase inhibitor, nintedanib (NIND), which was recently approved for idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung condition resembling CD. High-passage adult rat ISMC were used in vitro as a model system to study the growth and phenotypic changes that occur in the inflamed intestine. NIND successfully suppressed growth of ISMC but was ineffective against intestinal epithelial cells (IEC), showing selectivity towards cells of the mesenchymal origin. Interestingly, NIND showed protracted inhibition of growth, and pretreated cells grew at a slower rate after subculturing, suggesting heritable effects. Additionally, NIND induced collagen secretion in ISMC, showing that its multimodal capabilities can contribute to wound repair. Further, NIND treatment upregulated smooth muscle contractile marker expression in high-passage ISMC. Finally, and importantly, we showed that the proinflammatory cytokines, IL1β/TNFα, stimulate cytokine production in ISMC, causing a positive feedback loop, and this can be controlled with NIND treatment. Overall, these findings provide evidence that NIND controls the phenotype of ISMC, and because these changes are heritable, the effects of NIND may be associated with epigenetic changes. The effect of NIND on ISMC elucidates its role as a therapy for intestinal strictures, through restoring contractility, and improving intestinal motility.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".