title: The protective effect of overexpression of extracellular superoxide dismutase on nitric oxide bioavailability in the lung after exposure to hyperoxia stress.
abstract: The objective of this study was to determine whether overexpression of human extracellular superoxide dismutase (hEC-SOD) can preserve nitric oxide (NO) bioavailability. In vitro studies examined the transient expression of hEC-SOD in mouse epithelial (C10) cells and its effect on extracellular accumulation of NO, intracellular cyclic guanosine monophosphate (cGMP), and nuclear factor kappa B (NF-κB) activation under normal and oxidative stress conditions. In vivo, newborn rabbits were treated with a plasmid containing hEC-SOD cDNA or vehicle plasmid alone, followed by exposure to hyperoxia (Fio₂ = 95% for 7 days). A third group was raised under normoxic conditions. cGMP and NF-κB activation were studied. There was significantly higher NO accumulation in cells expressing hEC-SOD exposed to oxidative stress compared with nontransfected cells. Accumulation of cGMP was significantly higher in cells expressing hEC-SOD. Oxidative stress induced NF-κB activation, which was abrogated by hEC-SOD expression. In vivo, there was significantly higher cGMP accumulation in transfected neonatal rabbit lung tissue at 3 and 7 days of hyperoxic exposure. Immunostaining for NF-κB, showed a marked increase in NF-κB concentration in nontreated neonatal rabbit lung tissue compared to transfected neonatal lung with hEC-SOD and the control air group. These results show that transient EC-SOD overexpression maintains NO bioavailability, which directly leads to maintenance of cGMP activity and reduction of NF-κB activation under oxidative stress.
authors.affiliation: Division of Neonatal-Perinatal Medicine, Schneider Children's Hospital and Center for Heart and Lung Research, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA. mahmed2@nshs.edu
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Ahmed
authors.forename: Champa
authors.initials: C
authors.lastname: Codipilly
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.forename: Richard L
authors.initials: RL
authors.lastname: Auten
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001682:Biological Availability; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D018496:Hyperoxia / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D055370:Lung Injury / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D011817:Rabbits; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D009569:Nitric Oxide; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; D006152:Cyclic GMP