Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Laboratory Medicine, Department of Pathology, Division of Clinical Chemistry, Johns Hopkins University, Baltimore, MD 21287, USA.
Cells. 2022 Aug 16;11(16):2540. doi: 10.3390/cells11162540.
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis.
特发性肺纤维化 (IPF) 是一种以不可逆性肺瘢痕化为特征的疾病。其病理生理学尚未完全阐明，但工作假说假定上皮损伤和肌成纤维细胞分化的组合驱动进行性肺纤维化。我们之前的研究表明，细胞外 pH 值的降低会激活潜伏的 TGF-β1，而 TGF-β1 随后会自行激活，从而形成一个促进肌成纤维细胞分化的正反馈机制。鉴于细胞外 pH 值在肺纤维化进展中的重要作用，我们试图确定 pH 值是否独立于 TGF-β1 介导其他细胞表型。质子感应 G 蛋白偶联受体在酸性环境中被激活，但它们在纤维化中的作用尚未得到研究。在这里，我们报告卵巢癌 G 蛋白偶联受体 1 (OGR1 或 GPR68) 在促进和减轻肺纤维化方面具有双重作用。我们证明 OGR1 蛋白表达在 IPF 患者的肺组织中显著降低，并且 TGF-β1 降低了 OGR1 的表达。在成纤维细胞中，OGR1 抑制肌成纤维细胞分化，并且不促进炎症。然而，在上皮细胞中，OGR1 促进上皮细胞向间充质转化 (EMT) 和炎症。然后，我们证明细胞内定位和替代信号通路可能是 OGR1 在每种细胞类型中产生不同作用的原因。我们的研究结果表明，选择性靶向 OGR1 表达的策略可能代表一种治疗肺纤维化的新策略。
