Abstract: Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2), plays an important role in a variety of diseases. So far, the role of mPGES-1 in idiopathic pulmonary fibrosis (IPF) remained unknown. The current study aimed to investigate the role of mPGES-1 in pulmonary fibrosis induced by bleomycin in mice. We found that mPGES-1 deficient (mPGES-1−/−) mice exhibited more severe fibrotic lesions with a decrease in PGE2 content in lungs after bleomycin treatment when compared with wild type (mPGES-1+/+) mice. The mPGES-1 expression levels and PGE2 content were also decreased in bleomycin-treated mPGES-1+/+ mice compared to saline-treated mPGES-1+/+ mice. Moreover, in both mPGES-1−/− and mPGES-1+/+ mice, bleomycin treatment reduced the expression levels of E prostanoid receptor 2 (EP2) and EP4 receptor in lungs, whereas had little effect on EP1 and EP3. In cultured human lung fibroblast cells (MRC-5), siRNA-mediated knockdown of mPGES-1 augmented transforming growth factor-β1 (TGF-β1)-induced α-smooth muscle actin (α-SMA) protein expression, and the increase was reversed by treatment of PGE2, selective EP2 agonist and focal adhesion kinase (FAK) inhibitor. In conclusion, these findings revealed mPGES-1 exerts an essential effect against pulmonary fibrogenesis via EP2-mediated signaling transduction, and activation of mPGES-1-PGE2-EP2-FAK signaling pathway may represent a new therapeutic strategy for treatment of IPF patients.
Keywords: microsomal prostaglandin E synthase-1; idiopathic pulmonary fibrosis; prostaglandin E2; E prostanoid receptor 2; focal adhesion kinase
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Wei, B.; Cai, L.; Sun, D.; Wang, Y.; Wang, C.; Chai, X.; Xie, F.; Su, M.; Ding, F.; Liu, J.; Yang, J.; Guan, Y.; Liu, X. Microsomal Prostaglandin E Synthase-1 Deficiency Exacerbates Pulmonary Fibrosis Induced by Bleomycin in Mice. Molecules 2014, 19, 4967-4985.
Wei B, Cai L, Sun D, Wang Y, Wang C, Chai X, Xie F, Su M, Ding F, Liu J, Yang J, Guan Y, Liu X. Microsomal Prostaglandin E Synthase-1 Deficiency Exacerbates Pulmonary Fibrosis Induced by Bleomycin in Mice. Molecules. 2014; 19(4):4967-4985.
Wei, Bo; Cai, Linhong; Sun, Dan; Wang, Yanhua; Wang, Cairui; Chai, Xiaoyu; Xie, Feng; Su, Ming; Ding, Fangrui; Liu, Jie; Yang, Jichun; Guan, Youfei; Liu, Xinmin. 2014. "Microsomal Prostaglandin E Synthase-1 Deficiency Exacerbates Pulmonary Fibrosis Induced by Bleomycin in Mice." Molecules 19, no. 4: 4967-4985.