Division of Pulmonary Disease and Critical Care Medicine, University of Rochester Medical Center Rochester, Rochester, NY 14642, USA.
Department of Human Genetics, University of Utah Salt Lake City, Salt Lake City, UT 84112, USA.
Int J Mol Sci. 2022 Oct 8;23(19):11946. doi: 10.3390/ijms231911946.
Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, interstitial lung disease with a poor prognosis. Although specific anti-fibrotic medications are now available, the median survival time following diagnosis remains very low, and new therapies are urgently needed. To uncover novel therapeutic targets, we examined how biochemical properties of the fibrotic lung are different from the healthy lung. Previous work identified lactate as a metabolite that is upregulated in IPF lung tissue. Importantly, inhibition of the enzyme responsible for lactate production prevents fibrosis in vivo. Further studies revealed that fibrotic lesions of the lung experience a significant decline in tissue pH, likely due to the overproduction of lactate. It is not entirely clear how cells in the lung respond to changes in extracellular pH, but a family of proton sensing G-protein coupled receptors has been shown to be activated by reductions in extracellular pH. This work examines the expression profiles of proton sensing GPCRs in non-fibrotic and IPF-derived primary human lung fibroblasts. We identify TDAG8 as a proton sensing GPCR that is upregulated in IPF fibroblasts and that knockdown of TDAG8 dampens myofibroblast differentiation. To our surprise, BTB, a proposed positive allosteric modulator of TDAG8, inhibits myofibroblast differentiation. Our data suggest that BTB does not require TDAG8 to inhibit myofibroblast differentiation, but rather inhibits myofibroblast differentiation through suppression of RhoA mediated signaling. Our work highlights the therapeutic potential of BTB as an anti-fibrotic treatment and expands upon the importance of RhoA-mediated signaling pathways in the context of myofibroblast differentiation. Furthermore, this works also suggests that TDAG8 inhibition may have therapeutic relevance in the treatment of IPF.
特发性肺纤维化（IPF）是一种进行性、慢性、间质性肺疾病，预后不良。虽然现在有特定的抗纤维化药物，但诊断后的中位生存时间仍然很低，急需新的治疗方法。为了发现新的治疗靶点，我们研究了纤维化肺的生化特性与健康肺有何不同。以前的工作发现乳酸是 IPF 肺组织中上调的代谢物。重要的是，抑制负责乳酸生成的酶可防止体内纤维化。进一步的研究表明，肺纤维化病变的组织 pH 值显著下降，可能是由于乳酸的过度产生。尚不清楚肺细胞如何对细胞外 pH 值的变化做出反应，但已表明一组质子感应 G 蛋白偶联受体（GPCR）可被细胞外 pH 值降低激活。这项工作检查了非纤维化和 IPF 来源的原代人肺成纤维细胞中质子感应 GPCR 的表达谱。我们确定 TDAG8 是一种在 IPF 成纤维细胞中上调的质子感应 GPCR，并且 TDAG8 的敲低可抑制肌成纤维细胞分化。令我们惊讶的是，BTB，TDAG8 的一种拟议正变构调节剂，可抑制肌成纤维细胞分化。我们的数据表明，BTB 抑制肌成纤维细胞分化不需要 TDAG8，而是通过抑制 RhoA 介导的信号转导来抑制肌成纤维细胞分化。我们的工作强调了 BTB 作为抗纤维化治疗的治疗潜力，并扩展了 RhoA 介导的信号通路在肌成纤维细胞分化中的重要性。此外，这项工作还表明 TDAG8 抑制在治疗 IPF 方面可能具有治疗相关性。
