28. Ketotifen Inhibits Dermal Fibroblast Responses To The Pro-fibrotic Effects Of TGF-beta
Bibliographic record
Abstract
Purpose: During tissue repair, dermal fibroblasts become activated, begin to differentiate, and synthesize extracellular matrix (ECM) proteins to restore tissue integrity. Transforming growth factor (TGF)-beta is a major regulator in tissue repair and fibrosis, activating fibroblasts and eliciting many tissue repair processes. These include increases in alpha-smooth muscle actin (SMA), fibroblast differentiation into myofibroblasts, and increased collagen deposition. Dysregulated TGF-beta signaling has been implicated in scarring, chronic wounds, and other fibrotic conditions. Previously, the clinically-approved mast cell (MC) stabilizing agent ketotifen has been reported to decrease fibrous band thickness and myofibroblast numbers in the skin through MC-associated mechanisms of action. Our research examined the direct effects of ketotifen on human dermal fibroblasts. Methods: Human dermal fibroblasts (HDFs) were activated with recombinant TGF-beta [10ng/mL] for 48 hours to induce a pro-repair phenotype. Ketotifen [25uM] was added to fibroblasts 24 hours after TGF-beta activation. Untreated and ketotifen treatment-only groups served as controls. Gene expression and protein analyses were performed through qPCR, immunofluorescence, and western blotting. Fibroblast-populated collagen lattices were generated for functional assessments of contraction. Bleomycin-induced skin fibrosis was produced in mice. Ketotifen-supplemented or regular water was provided during bleomycin treatment. Skin collagen density was determined, after 21 days, using Masson’s Trichrome histological staining. Results: TGF-beta-activated HDFs treated with ketotifen showed significant decreases in cytoskeletal and contractility-associated genes ACTA2 (alpha-SMA), CNN1 (calponin 1), and TAGLN (transgelin) compared to TGF-beta-treated controls. Significantly reduced alpha-SMA protein expression was observed with ketotifen treatment in TGF-beta-activated HDFs, indicating impaired differentiation into myofibroblasts. Ketotifen increased phosphorylation of Yes-associated protein (YAP1) and decreased total transcriptional co-activator with PDZ-binding motif (TAZ) protein, suggesting impairment of transcriptional co-regulators involved in cytoskeletal-associated changes. Ketotifen also reduced phosphorylation of protein kinase B (AKT) in activated HDFs. Collagen lattice contraction was decreased with ketotifen treatment, further corroborating decreased contractility of activated HDFs given ketotifen. Using a murine model of skin fibrosis, ketotifen reduced dermal collagen density compared to controls. Conclusion: Previously, anti-fibrotic effects of ketotifen have been attributed to effects on MC stabilization. Here we show that ketotifen directly influences activated dermal fibroblasts by inhibiting differentiation and function through impairment of cytoskeletal and contractility-associated mechanisms in vitro and impairs collagen deposition in vivo. These results demonstrate a previously unknown mechanism and effect of a clinically-approved MC stabilizer in fibrotic settings.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| 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".