title: Microsomal prostaglandin E synthase-1 deficiency exacerbates pulmonary fibrosis induced by bleomycin in mice.
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.
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Peking University, Beijing 100034, China. weibo-0@126.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.affiliation: No.3 Outpatient Department, No.58 Anli Road, Chaoyang District, Beijing 100021, China. philk_515@163.com.
authors.forename: Linhong
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Peking University, Beijing 100034, China. shelley007810626@hotmail.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Peking University, Beijing 100034, China. wangyanhua3826@163.com.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Peking University, Beijing 100034, China. queen-rui@163.com.
authors.forename: Cairui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Peking University, Beijing 100034, China. klmytchristy@163.com.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chai
authors.affiliation: Department of Urology, Peking University First Hospital & the Institute of Urology, Peking University, Beijing 100034, China. xiefengjoy@126.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Xie
authors.affiliation: Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, FuWai Hospital & Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China. suming28@163.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Su
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Peking University, Beijing 100034, China. youngbear@126.com.
authors.forename: Fangrui
authors.initials: F
authors.lastname: Ding
authors.affiliation: Department of Urology, Peking University First Hospital & the Institute of Urology, Peking University, Beijing 100034, China. soloriver@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, 38 Xueyuan Road, Beijing 100191, China. yangj@hsc.pku.edu.cn.
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China. youfeiguan@szu.edu.cn.
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Peking University, Beijing 100034, China. lxm2128@163.com.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000199:Actins; D047428:Protein Kinase Inhibitors; C545651:Ptger4 protein, mouse; D034741:RNA, Small Interfering; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D001761:Bleomycin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
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