PDF(Pubmed)
Abstract：
Lung parenchymal hypoxia has emerged as a cardinal feature of idiopathic pulmonary fibrosis (IPF). Hypoxia promotes cancer cell invasion and metastasis through signaling that is dependent upon the lysophosphatidic acid (LPA) receptor, LPA1 (LPAR1). Abundant data indicate that LPA1-dependent signaling also enhances lung fibrogenesis in IPF. We recently reported that fibroblasts isolated from the lungs of individuals with IPF have an increased capacity to form subcellular matrix-degradative structures known as invadosomes, an event that correlates with the degree of lung fibrosis. We therefore hypothesized that hypoxia promotes invadosome formation in lung fibroblasts through LPA1-dependent signaling. Here, it is demonstrated that invadosome formation by fibroblasts from the lungs of individuals with advanced IPF is inhibited by both the tyrosine receptor kinase inhibitor nintedanib and inhibition of LPA1. In addition, exposure of normal human lung fibroblasts to either hypoxia or LPA increased their ability to form invadosomes. Mechanistically, the hypoxia-induced invadosome formation by lung fibroblasts was found to involve LPA1 and PDGFR-Akt signaling. We concluded that hypoxia increases the formation of invadosomes in lung fibroblasts through the LPA1 and PDGFR-Akt signaling axis, which represents a potential target for suppressing lung fibrosis.
摘要：
肺实质缺氧已成为特发性肺纤维化（IPF）的主要特征。缺氧通过依赖于溶血磷脂酸（LPA）受体的信号促进癌细胞的侵袭和转移，LPA1(LPAR1)。大量数据表明LPA1依赖性信号传导也增强IPF中的肺纤维化发生。我们最近报道，从患有IPF的个体的肺中分离的成纤维细胞具有增加的形成亚细胞基质降解结构的能力，称为invadosome。与肺纤维化程度相关的事件。因此，我们假设缺氧通过LPA1依赖性信号传导促进肺成纤维细胞中的侵袭小体形成。这里,已证明，酪氨酸受体激酶抑制剂nintedanib和LPA1的抑制作用都抑制了晚期IPF患者肺成纤维细胞的嵌入体形成。此外,暴露于缺氧或LPA的正常人肺成纤维细胞增加了它们形成包裹体的能力。机械上,研究发现,低氧诱导的肺成纤维细胞侵入体形成涉及LPA1和PDGFR-Akt信号传导.我们得出结论，缺氧通过LPA1和PDGFR-Akt信号轴增加了肺成纤维细胞中侵入体的形成，这代表了抑制肺纤维化的潜在目标。
