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PMID: 10194478 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury.

The Journal of clinical investigation ·Vol. 103 ·No. 7 ·1999-04-00 ·Pages 1047-54

Otterbein LE, Kolls JK, Mantell LL, Cook JL, Alam J, Choi AM

Abstract

Heme oxygenase-1 (HO-1) confers protection against a variety of oxidant-induced cell and tissue injury. In this study, we examined whether exogenous administration of HO-1 by gene transfer could also confer protection. We first demonstrated the feasibility of overexpressing HO-1 in the lung by gene transfer. A fragment of the rat HO-1 cDNA clone containing the entire coding region was cloned into plasmid pAC-CMVpLpA, and recombinant adenoviruses containing the rat HO-1 cDNA fragment Ad5-HO-1 were generated by homologous recombination. Intratracheal administration of Ad5-HO-1 resulted in a time-dependent increase in expression of HO-1 mRNA and protein in the rat lungs. Increased HO-1 protein expression was detected diffusely in the bronchiolar epithelium of rats receiving Ad5-HO-1, as assessed by immunohistochemical studies. We then examined whether ectopic expression of HO-1 could confer protection against hyperoxia-induced lung injury. Rats receiving Ad5-HO-1, but not AdV-betaGal, a recombinant adenovirus expressing Escherichia coli beta-galactosidase, before exposure to hyperoxia (>99% O2) exhibited marked reduction in lung injury, as assessed by volume of pleural effusion and histological analyses (significant reduction of edema, hemorrhage, and inflammation). In addition, rats receiving Ad5-HO-1 also exhibited increased survivability against hyperoxic stress when compared with rats receiving AdV-betaGal. Expression of the antioxidant enzymes manganese superoxide dismutase (Mn-SOD) and copper-zinc superoxide dismutase (CuZn-SOD) and of L-ferritin and H-ferritin was not affected by Ad5-HO-1 administration. Furthermore, rats treated with Ad5-HO-1 exhibited attenuation of hyperoxia-induced neutrophil inflammation and apoptosis. Taken together, these data suggest the feasibility of high-level HO-1 expression in the rat lung by gene delivery. To our knowledge, we have demonstrated for the first time that HO-1 can provide protection against hyperoxia-induced lung injury in vivo by modulation of neutrophil inflammation and lung apoptosis.

MeSH Terms
Adenoviridae/genetics Animals Apoptosis/genetics Bronchoalveolar Lavage Fluid/cytology Gene Expression Regulation, Enzymologic/genetics Gene Transfer Techniques Heme Oxygenase (Decyclizing)/genetics,pharmacology Heme Oxygenase-1 Hyperoxia/physiopathology Immunohistochemistry Lung/metabolism,physiopathology Oxidative Stress Oxygen/toxicity Pleural Effusion/pathology RNA, Messenger/metabolism Rats Rats, Sprague-Dawley Superoxide Dismutase/genetics
Chemicals
RNA, Messenger Heme Oxygenase (Decyclizing) Heme Oxygenase-1 Superoxide Dismutase Oxygen
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Otterbein L E
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06250, USA.
Kolls J K
Mantell L L
Cook J L
Alam J
Choi A M
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI5342
Published
1999-04-00
Pages
1047-54
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC408257
Subset
IM
Grants
NIAAA NIH HHS · R29 AA010384 · United States
NHLBI NIH HHS · R01 HL060234 · United States
NHLBI NIH HHS · R01 HL-55330 · United States
NHLBI NIH HHS · R01 HL055330 · United States
NIAID NIH HHS · R01 AI-42365 · United States
NHLBI NIH HHS · R01 HL-60234 · United States
External Links
PubMed source DOI: 10.1172/JCI5342 PMC Full Text View journal details
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