Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis.
Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis.
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特发性肺纤维化（IPF）是一种以不可逆的肺瘢痕形成为特征的疾病。病理生理学尚未完全了解，但工作假设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。我们之前证明，细胞外pH值的降低激活了潜伏的TGF-β1，然后TGF-β1驱动其自身的激活，从而产生了一种前馈机制，促进了肌成纤维细胞的分化。鉴于细胞外pH在肺纤维化进展中的重要作用，我们试图确定pH是否介导不依赖于TGF-β1的其他细胞表型。质子敏感G蛋白偶联受体被酸性环境激活，但它们在纤维化中的作用尚未研究。在这里，我们报告卵巢癌G蛋白偶联受体1（OGR 1或GPR 68）在促进和减轻肺纤维化方面具有双重作用。我们证实，IPF患者肺组织中OGR 1蛋白表达显著降低，TGF-β1可降低OGR 1表达。在成纤维细胞中，OGR 1抑制肌成纤维细胞分化，不会导致炎症。然而，在上皮细胞中，OGR 1促进上皮向间质转化（EMT）和炎症。然后，我们证明，亚细胞定位和替代信号通路可能是负责OGR 1在每种细胞类型的差异效应。我们的研究结果表明，选择性靶向OGR 1表达的策略可能是肺纤维化的一种新的治疗策略。
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.
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影响因子：
4.9
作者：
de Vallière C;Wang Y;Eloranta JJ;Vidal S;Clay I;Spalinger MR;Tcymbarevich I;Terhalle A;Ludwig MG;Suply T;Fried M;Kullak-Ublick GA;Frey-Wagner I;Scharl M;Seuwen K;Wagner CA;Rogler G
通讯作者：
Rogler G
影响因子：
3.7
作者：
Li H;Wang D;Singh LS;Berk M;Tan H;Zhao Z;Steinmetz R;Kirmani K;Wei G;Xu Y
通讯作者：
Xu Y
DOI：
10.1097/00005373-198310000-00001
发表时间：
1983-01-01
影响因子：
--
作者：
BAUR, PS;PARKS, DH
通讯作者：
PARKS, DH
影响因子：
--
作者：
Li J;Guo B;Wang J;Cheng X;Xu Y;Sang J
通讯作者：
Sang J
影响因子：
3.9
作者：
Gauldie, J.;Bonniaud, P.;Kolb, M.
通讯作者：
Kolb, M.