Prostaglandin E<sub>2</sub> inhibits profibrotic function of human pulmonary fibroblasts by disrupting Ca<sup>2+</sup> signaling
Bibliographic record
Abstract
We have shown that calcium (Ca 2+ ) oscillations in human pulmonary fibroblasts (HPFs) contribute to profibrotic effects of transforming growth factor-β (TGF-β) and that disruption of these oscillations blunts features of pulmonary fibrosis. Prostaglandin E 2 (PGE 2 ) exerts antifibrotic effects in the lung, but the mechanisms for this action are not well defined. We thus sought to explore interactions between PGE 2 and the profibrotic agent TGF-β in pulmonary fibroblasts (PFs) isolated from patients with or without idiopathic pulmonary fibrosis (IPF). PGE 2 inhibited TGF-β-promoted [Ca 2+ ] oscillations and prevented the activation of Akt and Ca 2+ /calmodulin-dependent protein kinase-II (CaMK-II) but did not prevent activation of Smad-2 or ERK. PGE 2 also eliminated TGF-β-stimulated expression of collagen A1, fibronectin, and α-smooth muscle actin and reduced stress fiber formation in the HPFs. RNA sequencing revealed that HPFs preferentially express EP 2 receptors relative to other prostanoid receptor subtypes: EP 2 expression is ~10-fold higher than that of EP 4 receptors; EP 1 and EP 3 receptors are barely detectable; and EP 2 -receptor expression is ~3.5-fold lower in PFs from IPF patients than in normal HPFs. The inhibitory effects of PGE 2 on synthetic function and stress fiber formation were blocked by selective EP 2 or EP 4 antagonists and mimicked by selective EP 2 or EP 4 agonists, the phosphodiesterase inhibitor isobutylmethylxanthine and forskolin, all of which elevate cellular cAMP concentrations. We conclude that PGE 2 , likely predominantly via EP 2 receptors, interferes with Ca 2+ signaling, CaMK-II activation, and Akt activation in IPF-HPFs and HPFs treated with TGF-β. Moreover, a decreased expression of EP 2 receptors in pulmonary fibroblasts from IPF patients may contribute to the pathophysiology of this disease.
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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 | 0.000 |
| 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 | 0.000 | 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".