Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice.
Heme oxygenase-1 (HO-1) is an inducible heat shock protein that regulates heme metabolism to form bilirubin, ferritin and carbon monoxide. Based on recent evidence that HO-1 is involved in the resolution of inflammation by modulating apoptotic cell death or cytokine expression, the present study examined whether overexpression of exogenous HO-1 gene transfer provides a therapeutic effect on a murine model of acute lung injury caused by the type A influenza virus. We demonstrate herein that the transfer of HO-1 cDNA resulted in (1) suppression of both pathological changes and intrapulmonary hemorrhage; (2) enhanced survival of animals; and (3) a decrease of inflammatory cells in the lung. TUNEL analysis revealed that HO-1 gene transfer reduced the number of respiratory epithelial cells with DNA damage, and caspase assay suggested that HO-1 suppressed lung injury via a caspase-8-mediated pathway. These findings suggest the feasibility of HO-1 gene transfer to treat lung injury induced by a pathogen commonly seen in the clinical setting. Since oxidative stress and lung injury are involved in many lung disorders, such as pneumonia induced by a variety of microorganisms and pulmonary fibrosis, HO-1 may be useful for wider clinical applications in gene therapy targeting lung disorders including acute pneumonia and pulmonary fibrosis.
Hashiba
T
T
First Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan.
Suzuki
M
M
Nagashima
Y
Y
Suzuki
S
S
Inoue
S
S
Tsuburai
T
T
Matsuse
T
T
Ishigatubo
Y
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D020287:In Situ Nick-End Labeling; D009980:Influenza A virus; D008168:Lung / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018384:Oxidative Stress
D008565:Membrane Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020169:Caspases