Lysophosphatidic acid receptor-2 deficiency confers protection against bleomycin-induced lung injury and fibrosis in mice.

TitleLysophosphatidic acid receptor-2 deficiency confers protection against bleomycin-induced lung injury and fibrosis in mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsHuang LShuang, Fu P, Patel P, Harijith A, Sun T, Zhao Y, Garcia JGN, Chun J, Natarajan V
JournalAm J Respir Cell Mol Biol
Volume49
Issue6
Pagination912-22
Date Published2013 Dec
ISSN Number1535-4989
KeywordsActins, Animals, Apoptosis, Bleomycin, Cell Differentiation, Collagen, Disease Models, Animal, Fibroblasts, Fibronectins, Gene Knockdown Techniques, Humans, Idiopathic Pulmonary Fibrosis, Lung Injury, Male, MAP Kinase Signaling System, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Receptors, Lysophosphatidic Acid, Transforming Growth Factor beta
Abstract

<p>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 LPA2 in pulmonary fibrogenesis. In the present study, we found 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), α-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-β1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the 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 knockdown of LPA2 with small interfering RNA also mitigated the TGF-β1-induced differentiation of lung fibroblasts. In addition, 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.</p>

DOI10.1165/rcmb.2013-0070OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID23808384
PubMed Central IDPMC3931116
Grant ListHL 091916 / HL / NHLBI NIH HHS / United States
HL P01 98050 / HL / NHLBI NIH HHS / United States
P01 58064 / / PHS HHS / United States
R01 HL091916 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States