title: Prostaglandin E(2) protects human lung fibroblasts from cigarette smoke extract-induced apoptosis via EP(2) receptor activation.
abstract: Prostaglandin E(2) (PGE(2)) has been shown to have a strong cytoprotective effect, inhibiting apoptosis. In the present study, we evaluated whether PGE(2) has a protective effect on cigarette smoke extract (CSE)-induced apoptosis in human lung fibroblasts. Apoptosis was assessed by various methods, including DNA content analysis. CSE (15%-20%) led to apoptosis and induced imbalance in favor of pro- over anti-apoptotic protein expression and activated caspases. PGE(2) blocked CSE-induced apoptosis and modulated the balance of pro- and anti-apoptotic proteins and decreased the activation of caspases. This anti-apoptotic effect was mediated via EP(2) receptor activation as the EP(2) agonist butaprost mimicked PGE(2) activity and siRNA for the EP(2) receptor blocked it. An adenylyl cyclase inhibitor was found to abolish the PGE(2)-mediated cytoprotective effect. Correspondingly, c-AMP analogs blocked CSE-induced apoptosis. Consistently, the protein kinase A (PKA) inhibitor KT-5720 abolished PGE(2)-mediated protection. PGE(2) and butaprost phosphorylated Bad and KT-5720 blocked phosphorylation. These results suggest that PGE(2) inhibits CSE-induced apoptosis via EP(2) receptor activation and activation of PKA, which leads to an alteration in the balance between pro- and anti-apoptotic factors. Through such a mechanism, PGE(2) may alter survival of cells in the smoke-exposed lungs, thus affecting the pathogenesis of cigarette smoke-induced disease.
authors.affiliation: University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Sugiura
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Togo
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.forename: Shin
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kamio
authors.forename: Xing Qi
authors.initials: XQ
authors.lastname: Wang
authors.forename: Li Jun
authors.initials: LJ
authors.lastname: Mao
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D013876:Thiophenes / Q000494:pharmacology; D014026:Nicotiana; D014230:Triazoles / Q000494:pharmacology
chemical_list: C092396:17-phenyltrinorprostaglandin E2; D000067956:Adenylyl Cyclase Inhibitors; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C508711:L-161982; C545644:PTGER2 protein, human; D011758:Pyrroles; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012906:Smoke; D013876:Thiophenes; D014230:Triazoles; D016048:Dideoxyadenosine; C016767:sulprostone; C057416:KT 5720; C021008:2',5'-dideoxyadenosine; D017868:Cyclic AMP-Dependent Protein Kinases; D020169:Caspases; D000262:Adenylyl Cyclases; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone