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CGRP induces myofibroblast differentiation and the production of extracellular matrix in MRC5s via autocrine and paracrine signalings

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Öztay, Füsun

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There are contradictory views on which calcitonin gene-related peptide (CGRP) causes pulmonary fibrosis. Fibrotic potency of CGRP was tested and compared to that of transforming growth factor-beta (TGF-beta). Myofibroblast differentiation, cell proliferation, and activations of TGF-beta and Writ pathways were examined for 24, 48, and 72 h in A549 and MRC5 cell lines stimulated with CGRP and TGF-beta. CGRP-induced cell proliferation in MRC5s early on while cell proliferation in A549 occurred progressively. CGRP promoted fibroblast-myofibroblast differentiation by inducing the transcription of ACTA2, COL1A1, SMAD2/3, and SMAD4 genes, the production of collagen, fibronectin, alpha-smooth muscle actin, and activation of TGF-beta signaling starting from 24 h. Additionally, TGF-beta signaling induced by CGRP decreased the DKK1 level and activated the Wnt signaling in MRC5s. After CGRP stimulation, Wnt7a levels were increased from 24 to 72 h, while Wnt5a levels were elevated at 72 h in MRC5s. CGRP did not induce epithelial-mesenchymal transition in A549s, unlike TGF-beta. A comparison of fibrotic potency of CGRP and TGF-beta showed that TGF-beta is a powerful profibrotic molecule and induces earlier myofibroblast differentiation. Even so, CGRP promotes myofibroblast differentiation and extra-cellular matrix production by inducing Smad-dependent-TGF-beta and Wnt signalings via autocrine and paracrine signalings in MRC5s.

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Wiley

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Biochemistry, Molecular biology, Toxicology

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Journal of Biochemical and Molecular Toxicology

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10.1002/jbt.23204

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