Persistent hypoxia promotes myofibroblast differentiation via GPR-81 and differential regulation of LDH isoenzymes in normal and idiopathic pulmonary fibrosis fibroblasts.
Persistent hypoxia promotes myofibroblast differentiation via GPR-81 and differential regulation of LDH isoenzymes in normal and idiopathic pulmonary fibrosis fibroblasts.
复制标题
DOI：
10.14814/phy2.15759
复制
发表时间：
2023-09
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
--
作者：
缺氧，一种氧气供应不足的状态，促进细胞乳酸的产生。特发性肺纤维化（IPF）是一种以过度瘢痕形成为特征的疾病，其患者肺部乳酸水平升高，乳酸与肺纤维化的病理生物学有关。然而，缺氧和乳酸对成纤维细胞表型影响的机制尚不清楚。我们将正常和IPF肺成纤维细胞暴露于持续缺氧中，发现IPF成纤维细胞乳酸生成的增加是由FoxM1依赖性乳酸脱氢酶A （LDHA）的增加和LDHB的降低驱动的，而这在正常肺成纤维细胞中没有观察到。重要的是，缺氧降低了正常成纤维细胞中α‐平滑肌肌动蛋白（α‐SMA）的表达，但对IPF成纤维细胞中这一分化标志物没有显著影响。缺氧条件下用TGF‐β处理对照和IPF成纤维细胞没有显著改变LDHA或LDHB的表达。令人惊讶的是，乳酸直接诱导正常的成纤维细胞分化，而不是缺氧条件下的IPF成纤维细胞。此外，虽然GPR - 81（一种结合细胞外乳酸的G蛋白偶联受体）的表达在正常和IPF成纤维细胞中均因缺氧而增加，但其抑制或沉默仅抑制正常成纤维细胞中乳酸介导的分化。这些研究表明，缺氧对正常和纤维化成纤维细胞的影响不同，通过调节LDHA/LDHB比例促进IPF成纤维细胞乳酸生成的增加，并通过GPR‐81促进正常肺成纤维细胞对乳酸的反应。这支持了一种新的范式，即乳酸盐可能在缺氧微环境中作为旁分泌细胞间信号。
Hypoxia, a state of insufficient oxygen availability, promotes cellular lactate production. Lactate levels are increased in lungs from patients with idiopathic pulmonary fibrosis (IPF), a disease characterized by excessive scar formation, and lactate is implicated in the pathobiology of lung fibrosis. However, the mechanisms underlying the effects of hypoxia and lactate on fibroblast phenotype are poorly understood. We exposed normal and IPF lung fibroblasts to persistent hypoxia and found that increased lactate generation by IPF fibroblasts was driven by the FoxM1‐dependent increase of lactate dehydrogenase A (LDHA) coupled with decreased LDHB that was not observed in normal lung fibroblasts. Importantly, hypoxia reduced α‐smooth muscle actin (α‐SMA) expression in normal fibroblasts but had no significant impact on this marker of differentiation in IPF fibroblasts. Treatment of control and IPF fibroblasts with TGF‐β under hypoxic conditions did not significantly change LDHA or LDHB expression. Surprisingly, lactate directly induced the differentiation of normal, but not IPF fibroblasts under hypoxic conditions. Moreover, while expression of GPR‐81, a G‐protein‐coupled receptor that binds extracellular lactate, was increased by hypoxia in both normal and IPF fibroblasts, its inhibition or silencing only suppressed lactate‐mediated differentiation in normal fibroblasts. These studies show that hypoxia differentially affects normal and fibrotic fibroblasts, promoting increased lactate generation by IPF fibroblasts through regulation of the LDHA/LDHB ratio and promoting normal lung fibroblast responsiveness to lactate through GPR‐81. This supports a novel paradigm in which lactate may serve as a paracrine intercellular signal in oxygen‐deficient microenvironments.
登录
查看更多内容
影响因子：
--
作者：
Arora R;Schmitt D;Karanam B;Tan M;Yates C;Dean-Colomb W
通讯作者：
Dean-Colomb W
影响因子：
4.8
作者：
Guzy, Robert D.;Li, Ling;Ornitz, David M.
通讯作者：
Ornitz, David M.
安罗替尼抑制肌成纤维细胞中 PFKFB3 驱动的糖酵解以逆转肺纤维化
影响因子：
5.6
作者：
Chen W;Zhang J;Zhong W;Liu Y;Lu Y;Zeng Z;Huang H;Wan X;Meng X;Zou F;Cai S;Dong H
通讯作者：
Dong H
针对特发性肺纤维化疗法的GPCR信号传导。
影响因子：
13.8
作者：
Haak AJ;Ducharme MT;Diaz Espinosa AM;Tschumperlin DJ
通讯作者：
Tschumperlin DJ
影响因子：
3.9
作者：
Devic S
通讯作者：
Devic S