Lysophosphatidic Acid Receptor-2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

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.