Pharmacological activation of dopamine receptor D1 attenuates TGF-β-induced epithelial-mesenchymal transition in A549 and BEAS-2B cells.

Aberrant epithelial remodeling is implicated in idiopathic pulmonary fibrosis, and TGF-β-induced epithelial-mesenchymal transition (EMT)-like changes provide an in vitro model for studying this process. This study investigated whether pharmacological stimulation of dopamine receptor D1 (DRD1) attenuates TGF-β-induced EMT-related changes in A549 and BEAS-2B cells. GEO transcriptomic analysis was performed using GSE277168 to explore TGF-β-associated transcriptional changes in A549 cells. A549 and BEAS-2B cells were stimulated with TGF-β to establish an in vitro EMT model. Dopamine analogues, DRD1 agonists, and the DRD1 antagonist SCH23390 were used to evaluate the role of DRD1. Cell viability, EMT marker expression, intracellular cAMP levels, PKA phosphorylation, migration, and adhesion were assessed. Bioinformatic analysis showed that TGF-β treatment induced EMT-, extracellular matrix-, and cAMP/PKA-related transcriptional alterations. In vitro, TGF-β reduced E-cadherin and increased Vimentin, ZEB1, and Snail1 expression. Treatment with DRD1 agonists partially attenuated these marker changes, was associated with restoration of intracellular cAMP levels and PKA phosphorylation, reduced cell migration, and increased cell adhesion. The DRD1 antagonist SCH23390 weakened the effects of DOPA treatment. In these pulmonary epithelial cell-line models, DRD1 agonist treatment attenuated TGF-β-induced EMT-related changes and was associated with restoration of cAMP/PKA signaling. These in vitro findings identify DRD1 signaling as a candidate mechanism for further preclinical study; confirmation in primary cells, epithelial-fibroblast systems, and animal models is required before therapeutic relevance to pulmonary fibrosis can be inferred.