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

Abstract

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 proteincoupled 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 2/2 ) 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 (a-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor-b (TGF-b), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA 2 attenuated the LPA-induced expression of TGF-b1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of FN, a-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knockdown of LPA 2 with small interfering RNA also mitigated the TGF-b1-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.

The Rho Kinases: Critical Mediators of Multiple Profibrotic Processes and Rational Targets for New Therapies for Pulmonary Fibrosis

“…Bleomycininduced pulmonary fibrosis is the most widely studied mouse model of pulmonary fibrosis (Moore et al, 2013) and may also develop in humans treated with bleomycin for a variety of cancers. Mice genetically deficient for LPA 1 or LPA 2 are significantly protected from fibrosis and mortality in this model (Tager et al, 2008;Huang et al, 2013). We also found that LPA 1 was highly expressed by fibroblasts recovered from BAL fluid of persons with IPF, and inhibition of LPA 1 markedly reduced fibroblast responses to the chemotactic activity present in their BAL fluid (Tager et al, 2008), demonstrating the potential relevance of LPA 1 to human pulmonary fibrosis.…”

“…LPA signaling through two of its receptors, LPA 1 and LPA 2 , is shown be required for the development of pulmonary fibrosis in mouse models (Tager et al, 2008;Huang et al, 2013). We found that LPA levels are increased in the bronchoalveolar lavage (BAL) fluid acquired from persons with IPF compared with healthy controls.…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…The subsequent cell growth can result in the pathogenic fi broblast proliferation seen in fi brosis. Lpar2 may also be involved in pulmonary fi brosis, as knockout mice demonstrated protection against bleomycin-induced lung injury, fi brosis, and death (248). In addition, LPA and ATX levels not by 16:0 LPA or 18:0 LPA (223).…”

The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

“…In light of the poor prognosis and lack of available antiinflammatory therapies, there is a pressing need for alternative approaches including evaluation of new targets and pathways in animal models of fibrosis. Accordingly, two bioactive lipids, lysophosphatidic acid and sphingosine-1-phosphate, and enzymes involved in their metabolism have been implicated in regulating the development of pulmonary fibrosis (7)(8)(9)(10)(11).…”