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

Leo E. Otterbein, Jay K. Kolls, Lin L. Mantell, Julia L. Cook, Jawed Alam, Augustine M.K. Choi

Research output: Contribution to journalArticle

454 Scopus citations

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 AdS-HO-1 were generated by homologous recombination. Intratracheal administration of AdS-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-βGal, a recombinant adenovirus expressing Escherichia coli β- 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- βGal. 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.

Original languageEnglish (US)
Pages (from-to)1047-1054
Number of pages8
JournalJournal of Clinical Investigation
Volume103
Issue number7
DOIs
StatePublished - Apr 1999

ASJC Scopus subject areas

  • Medicine(all)

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