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 receptor1were implicatedinlungfibrogenesis. However, the role of other LPA receptors in fibrosis remains unclear. Here, we use a bleomycin-induced pulmonary fibrosis model to investigate the rolesof LPA₂ in pulmonaryfibrogenesis.In the present study,wefound that LPA₂ knockout (Lpar2^-/-) mice were protected against bleomycin-induced lung injury, fibrosis, and mortality, compared with wild-type control mice. Furthermore, LPA₂ deficiency attenuated the bleomycin-induced expression of fibronectin (FN), a-smooth muscle actin (α-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor-β (TGF-β), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA₂ attenuated the LPA-induced expression of TGF-β1andthe differentiationoflungfibroblaststomyofibroblasts, resultinginthe decreased expression of FN, α-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knock down of LPA₂withsmallinterfering RNA alsomitigated the TGF-β1-induced differentiationoflung fibroblasts.Inaddition, LPA₂ 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 LPA₂ attenuated bleomycin-induced lung injury and pulmonary fibrosis, and this may be related to an inhibition of the LPA-induced expression of TGF-β and the activation and differentiation of fibroblasts.