PGI synthase overexpression protects against bleomycin-induced mortality and is associated with increased Nqo 1 expression

Weisong Zhou; Dustin R Dowell; Mark W Geraci; Timothy S Blackwell; Robert D Collins; Vasiliy V Polosukhin; William E Lawson; Pingsheng Wu; Thomas Sussan; Shyam Biswal; Kasia Goleniewska; Jamye O'Neal; Dawn C Newcomb; Shinji Toki; Jason D Morrow; R Stokes Peebles Jr

doi:10.1152/ajplung.00224.2010

PGI synthase overexpression protects against bleomycin-induced mortality and is associated with increased Nqo 1 expression

Am J Physiol Lung Cell Mol Physiol. 2011 Oct;301(4):L615-22. doi: 10.1152/ajplung.00224.2010. Epub 2011 Jul 15.

Authors

Weisong Zhou¹, Dustin R Dowell, Mark W Geraci, Timothy S Blackwell, Robert D Collins, Vasiliy V Polosukhin, William E Lawson, Pingsheng Wu, Thomas Sussan, Shyam Biswal, Kasia Goleniewska, Jamye O'Neal, Dawn C Newcomb, Shinji Toki, Jason D Morrow, R Stokes Peebles Jr

Affiliation

¹ Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA. weisong.zhou@vanderbilt.edu

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.

MeSH terms

Acute Lung Injury / chemically induced
Acute Lung Injury / genetics*
Acute Lung Injury / metabolism
Acute Lung Injury / mortality
Acute Lung Injury / prevention & control*
Animals
Apoptosis / genetics
Bleomycin / adverse effects
Bronchoalveolar Lavage Fluid / chemistry
Epoprostenol* / biosynthesis
F2-Isoprostanes / analysis
F2-Isoprostanes / biosynthesis
Female
Gas Chromatography-Mass Spectrometry
Gene Expression
Humans
Immunohistochemistry
Lung / drug effects
Lung / metabolism*
Lung / pathology
Mice
Mice, Transgenic
NAD(P)H Dehydrogenase (Quinone)* / biosynthesis
NAD(P)H Dehydrogenase (Quinone)* / genetics
Polymerase Chain Reaction
Prostaglandin-Endoperoxide Synthases* / biosynthesis
Prostaglandin-Endoperoxide Synthases* / genetics
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism
Receptors, Epoprostenol / metabolism
Respiratory Function Tests
Respiratory Mucosa / drug effects
Respiratory Mucosa / metabolism*
Respiratory Mucosa / pathology
Signal Transduction*
Survival Rate

Substances

F2-Isoprostanes
Reactive Oxygen Species
Receptors, Epoprostenol
Bleomycin
Epoprostenol
Prostaglandin-Endoperoxide Synthases
NAD(P)H Dehydrogenase (Quinone)
Nqo1 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding