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• W2912352885 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." @default.
• W2912352885 created "2019-02-21" @default.
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• W2912352885 date "2019-05-01" @default.
• W2912352885 modified "2023-10-16" @default.
• W2912352885 title "Prostaglandin E₂ inhibits profibrotic function of human pulmonary fibroblasts by disrupting Ca²⁺ signaling" @default.
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• W2912352885 doi "https://doi.org/10.1152/ajplung.00403.2018" @default.
• W2912352885 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6589580" @default.
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