A211 ANTIFIBROTIC ACTIVITY OF NOVEL TYROSINE KINASE INHIBITORS IN VITRO
Bibliographic record
Abstract
Abstract Background Chronic inflammation in inflammatory bowel disease (IBD) causes structural alterations of the intestine. In Crohn’s disease, this can lead to stricture formation, arising from unclear interactions among local inflammatory cells, cytokines, and mesenchymal intestinal cells. Specifically, proliferation of smooth muscle and increased deposition of collagen-rich extracellular matrix leads to fibrosis and obstructive wall thickening. Since there are minimal treatment options, we explored the effects of two multimodal tyrosine kinase inhibitors, nintedanib and pirfenidone, which were recently approved for idiopathic pulmonary fibrosis (IPF), a chronic lung condition resembling Crohn’s disease. Aims To understand the basic pharmacology of two novel anti-fibrotic tyrosine kinase inhibitors and their effects on cell proliferation and collagen deposition. Methods In vitro model systems of adult rat colonic circular smooth muscle cells (CSMS), rat IEC-18 intestinal epithelial cells or mouse 3T3 were assessed for response to serum or the mesenchymal growth factor PDGF-BB, evaluating growth responses by proliferation assay, and type I collagen expression by immunocytochemistry and western blotting. Programmed cell death was detected by ICC and western blotting for caspase-dependent apoptotic markers. Results Both 3T3 fibroblasts and rat ISMC showed concentration-dependent proliferation in response to serum or PDGF application. Nintedanib reduced this response to baseline at EC100 of 2.3 ± 0.7 (n=5) µM, and EC50 of 0.3 ± 0.1 (n=6) µM without cytotoxicity, while pirfenidone was ineffective at levels ≤ 5mM. Nintedanib (10 µM) was ineffective against serum-induced growth of rat IEC-18 cells while blocking growth of rat CSMC or mouse 3T3 fibroblasts in parallel assays, suggesting a selective effect on mesenchymal cell types. In nintedanib-treated cultures, nuclear staining showed concentration-dependent reduction of mitotic figures with proportional appearance of nuclear fragmentation, typical of apoptosis. Western blotting for collagen I identified at 125kD band for both CSMC and 3T3 cells and suggested down-regulation with both nintedanib and pirfenidone. Conclusions Novel anti-fibrotic therapies for chronic idiopathic pulmonary disease display distinctive effects on ISMC proliferation and extracellular matrix production. These address molecular mechanisms of fibrosis that are in common with IBD, and so the translation of therapeutic approaches may be a promising treatment option. Detecting specific mechanisms of action of nintedanib, such as apoptosis, leads to better targets for therapeutic options. Funding Agencies NSERC
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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) | 0.001 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".