Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-β
Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-β
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DOI：
10.1164/rccm.201201-0084oc
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发表时间：
2012-10-15
影响因子：
24.7
通讯作者：
Sime, Patricia J.
中科院分区：
文献类型：
--
作者：
Kottmann, Robert Matthew;Kulkarni, Ajit A.;Sime, Patricia J.
特发性肺纤维化(IPF)是一种复杂的疾病，其发病机制尚不清楚。目的：探讨乳酸对肺成纤维细胞分化和肺纤维化的影响。方法：应用代谢组学方法检测IPF患者肺组织中乳酸和乳酸脱氢酶-5(LDH5)过表达对成肌细胞分化和转化生长因子-β(TGF-β)活性的影响。IPF肺组织乳酸和LDH5水平明显高于对照组。生理浓度乳酸通过激活转化生长因子-β诱导肌成纤维细胞分化。转化生长因子β通过缺氧诱导因子1α(HIF1α)诱导LDH5的表达。重要的是，HIF1α和LDH5在人肺成纤维细胞中的过表达诱导肌成纤维细胞分化，并与低剂量的转化生长因子-β协同诱导分化。此外，HIF1α和LDH5的抑制抑制了转化生长因子-β诱导的肌成纤维细胞分化。结论：我们通过对转化生长因子-β的pH依赖性激活，确认代谢产物乳酸是肌成纤维细胞分化的重要介质。我们认为，肺和其他组织的代谢环境是肌成纤维细胞分化的重要驱动力，并可能是纤维性疾病的开始和进展。
Rationale Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF.Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis.Methods: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-beta activation in vitro.Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; alpha-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-beta. TGF-beta induced expression of LDH5 via hypoxia-inducible factor 1 alpha (HIF1 alpha). Importantly, overexpression of both HIF1 alpha and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-beta to induce differentiation. Furthermore, inhibition of both HIF1 alpha and LDH5 inhibited TGF-beta-induced myofibroblast differentiation.Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pH-dependent activation of TGF-beta. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.