title: PGI synthase overexpression protects against bleomycin-induced mortality and is associated with increased Nqo 1 expression.
abstract: The mortality rate for acute lung injury (ALI) is reported to be between 35-40%, and there are very few treatment strategies that improve the death rate from this condition. Previous studies have suggested that signaling through the prostaglandin (PG) I(2) receptor may protect against bleomycin-induced ALI in mice. We found that mice that overexpress PGI synthase (PGIS) in the airway epithelium were significantly protected against bleomycin-induced mortality and had reduced parenchymal consolidation, apoptosis of lung tissue, and generation of F(2)-isoprostanes compared with littermate wild-type controls. In addition, we show for the first time in both in vivo and in vitro experiments that PGI(2) induced the expression of NADP (H): quinoneoxidoreductase 1 (Nqo 1), an enzyme that prevents the generation of reactive oxygen species. PGI(2) induction of Nqo 1 provides a possible novel mechanism by which this prostanoid protects against bleomycin-induced mortality and identifies a potential therapeutic target for human ALI.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA. weisong.zhou@vanderbilt.edu
authors.forename: Weisong
authors.initials: W
authors.lastname: Zhou
authors.forename: Dustin R
authors.initials: DR
authors.lastname: Dowell
authors.forename: Mark W
authors.initials: MW
authors.lastname: Geraci
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Wu
authors.forename: Thomas
authors.initials: T
authors.lastname: Sussan
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.forename: Jamye
authors.initials: J
authors.lastname: O'Neal
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.forename: Shinji
authors.initials: S
authors.lastname: Toki
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D011464:Epoprostenol / Q000096:biosynthesis; D028441:F2-Isoprostanes / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000378:metabolism; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D028441:F2-Isoprostanes; D017382:Reactive Oxygen Species; D044006:Receptors, Epoprostenol; D001761:Bleomycin; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse