Inhibition of TGFβ-induced Fibroblast to Myofibroblast Transition by Conditioned Medium From Human Rhinovirus-infected Airway Epithelial Cells is Mediated by Prostaglandin E2
Bibliographic record
Abstract
Abstract Background Airway remodeling, including increased deposition of extracellular matrix proteins, is a hallmark of asthma. Myofibroblasts, derived via fibroblast to myofibroblast transition (FMT), play an important role in this increased deposition of matrix proteins. Expression of transforming growth factor β1 (TGFβ1) is increased in asthmatic airways and is known to induce FMT, as assessed by increased expression of α-smooth muscle actin (α-SMA). Because human rhinovirus (HRV) infections of airway epithelial cells have been linked to the generation of mediators involved in airway remodeling, we tested the hypothesis that conditioned medium from HRV-infected human airway epithelial cells from healthy normal subjects would enhance FMT, either alone or in combination with TGFβ1. Methods FMT was assessed by measuring α-SMA expression in human airway fibroblasts, both by western blotting and by immunohistochemistry. Statistical analysis was performed using ANOVA and Holm-Sidak or Bonferonni post hoc tests. Results Our data showed that conditioned medium from HRV infected epithelial cells significantly inhibited TGFβ1-induced expression of α-SMA in fibroblasts when compared to conditioned medium from uninfected epithelial cells. Treatment of epithelial cells with the nonselective cyclooxygenase inhibitor, diclofenac, during HRV infection significantly reversed the inhibitory effects of conditioned medium on TGFβ1-induced expression of α-SMA. This led us to hypothesize that HRV-infected epithelial cells release PGE2 that acts on EP receptors to suppress TGFβ1-induced expression of α-SMA in fibroblasts. We confirmed that HRV-infection of airway epithelial cells upregulated PGE2 release, and that exposure of fibroblasts to PGE2 significantly inhibited TGFβ1-induced expression of α-SMA in fibroblasts. Finally, studies using selective agonists and antagonists demonstrated that PGE2 inhibited TGFβ1-induced expression of α-SMA in fibroblasts via effects at the EP2 receptor. Conclusions Thus, using cells derived from healthy normal subjects we demonstrate that HRV infection of airway epithelial cells induces release of PGE2 that acts on EP2 receptors on fibroblasts to suppress TGFβ1-induced FMT. Additional studies are needed to determine if a different pattern of response is seen using cells from asthmatic subjects to determine if the inhibitory role of PGE2 on FMT in normal cells helps prevent airway remodeling in normal subjects.
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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) | 0.001 | 0.001 |
| 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) | 0.002 | 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".