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

被引：445

作者：

Otterbein, LE

Kolls, JK

Mantell, LL

Cook, JL

Alam, J

Choi, AMK

机构：

[1] Yale Univ, Sch Med, Pulm & Crit Care Med Sect, New Haven, CT 06520 USA

[2] Johns Hopkins Med Inst, Baltimore, MD 21205 USA

[3] Louisiana State Univ, Gene Therapy Program, New Orleans, LA 70112 USA

[4] Louisiana State Univ, Dept Med, New Orleans, LA 70112 USA

[5] Louisiana State Univ, Dept Pediat, New Orleans, LA 70112 USA

[6] SUNY Stony Brook, Sch Med, Mineola, NY 11501 USA

[7] Winthrop Univ Hosp, Dept Cardiovasc Thorac Surg, CardioPulm Res Inst, Mineola, NY 11501 USA

[8] Louisiana State Univ, Med Ctr, Dept Mol Genet, Alton Ochsner Med Fdn, New Orleans, LA 70121 USA

[9] Louisiana State Univ, Med Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70121 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 1999年 / 103卷 / 07期

关键词：

D O I：

10.1172/JCI5342

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Heme oxygenase-l (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 HB-l 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-l could confer protection against hyperoxia-induced lune injury. Rats receiving Ad5-HO-1, but not AdV-beta Gal, a recombinant adenovirus expressing Escherichia coli beta-galactosidase, before exposure to hyperoxia (>99% O-2) 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-beta Gal. 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.

引用

页码：1047 / 1054

页数：8

共 36 条

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