Lysophosphatidic Acid Receptor-2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice
Lysophosphatidic Acid Receptor-2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice
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DOI：
10.1165/rcmb.2013-0070oc
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发表时间：
2013-12-01
影响因子：
6.4
通讯作者：
Natarajan, Viswanathan
中科院分区：
文献类型：
--
作者：
Huang, Long Shuang;Fu, Panfeng;Natarajan, Viswanathan
特发性肺纤维化是一种以肺泡上皮细胞损伤、成纤维细胞/肌成纤维细胞积聚和细胞外基质蛋白沉积为特征的破坏性疾病。溶血磷脂酸（LPA）通过其G蛋白偶联受体信号传导对其多种生物学功能至关重要。近年来，LPA和LPA受体1与肺纤维化有关。然而，其他LPA受体在纤维化中的作用尚不清楚。在这里，我们使用博莱霉素诱导的肺纤维化模型来研究LPA(2)在肺纤维化中的作用。在本研究中，我们发现与野生型对照小鼠相比，LPA(2)敲除（Lpar2(-/-)）小鼠对博莱霉素诱导的肺损伤、纤维化和死亡率具有保护作用。此外，LPA(2)缺乏减弱了博莱霉素诱导的肺组织中纤维连接蛋白（FN）、a-平滑肌肌动蛋白（α - sma）和胶原蛋白的表达，以及支气管肺泡灌洗液中IL-6、转化生长因子- β (tgf - β)和总蛋白的水平。在人肺成纤维细胞中，LPA(2)的下调减弱了LPA诱导的tgf - β 1的表达和肺成纤维细胞向肌成纤维细胞的分化，导致FN、α - sma和胶原的表达降低，以及细胞外调节激酶1/2、Akt、Smad3和p38丝裂原活化蛋白激酶的活化降低。此外，用小干扰RNA敲低LPA(2)也减轻了tgf - β 1诱导的肺成纤维细胞分化。此外，LPA(2)缺乏显著减弱了博莱霉素诱导的小鼠肺肺泡和支气管上皮细胞的凋亡。总之，我们的数据表明，LPA(2)的下调减轻了博莱霉素诱导的肺损伤和肺纤维化，这可能与LPA诱导的TGF-b表达和成纤维细胞的激活和分化的抑制有关。
Idiopathic pulmonary fibrosis is a devastating disease characterized by alveolar epithelial cell injury, the accumulation of fibroblasts/myofibroblasts, and the deposition of extracellular matrix proteins. Lysophosphatidic acid (LPA) signaling through its G protein-coupled receptors is critical for its various biological functions. Recently, LPA and LPA receptor 1 were implicated in lung fibrogenesis. However, the role of other LPA receptors in fibrosis remains unclear. Here, we use a bleomycin-induced pulmonary fibrosis model to investigate the roles of LPA(2) in pulmonary fibrogenesis. In the present study, we found that LPA(2) knockout (Lpar2(-/-)) mice were protected against bleomycin-induced lung injury, fibrosis, and mortality, compared with wild-type control mice. Furthermore, LPA(2) deficiency attenuated the bleomycin-induced expression of fibronectin (FN), a-smooth muscle actin (alpha-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor-beta (TGF-beta), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA(2) attenuated the LPA-induced expression of TGF-beta 1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of FN, alpha-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knockdownof LPA(2) with small interfering RNA also mitigated the TGF-beta 1-induced differentiation of lung fibroblasts. In addition, LPA(2) deficiency significantly attenuated the bleomycin-induced apoptosis of alveolar and bronchial epithelial cells in the mouse lung. Together, our data indicate that the knockdown of LPA(2) attenuated bleomycin-induced lung injury and pulmonary fibrosis, and this may be related to an inhibition of the LPA-induced expression of TGF-b and the activation and differentiation of fibroblasts.