Transfer of heme oxygenase 1 cDNA by a replication-deficient adenovirus enhances interleukin 10 production from alveolar macrophages that attenuates lipopolysaccharide-induced acute lung injury in mice.
By using a direct, intratracheal inoculation of an adenovirus encoding heme oxygenase 1 (Ad.HO-1), model gene therapy for acute lung injury induced by inhaled pathogen was performed. Data demonstrated that Ad.HO-1 administration is as effective as the pharmacologic upregulation of the endogenous HO-1 gene expression by hemin to attenuate neutrophilic inflammations of the lung after aerosolized lipopolysaccharide (LPS) exposure. Interestingly, immunohistochemical analysis revealed that the HO-1 gene was transferred not only to the airway epithelium, but to the alveolar macrophages (AMs). Moreover, overexpression of exogenous HO-1 in the macrophages provided a high level of endogenous interleukin 10 (IL-10) production from the macrophages, and additional experiments using IL-10 knockout mice demonstrated that the increase in IL-10 in the macrophages was critical for the resolution of neutrophilic migration in the lung after LPS exposure. These results suggest that AMs not only are barriers for efficient gene transfer to the respiratory epithelium, but also represent logical targets for Ad-mediated, direct, in vivo gene therapy strategies for inflammatory disorders in humans.
Inoue
S
S
First Department of Internal Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama, Kanagawa, 236-0004, Japan.
Suzuki
M
M
Nagashima
Y
Y
Suzuki
S
S
Hashiba
T
T
Tsuburai
T
T
Ikehara
K
K
Matsuse
T
T
Ishigatsubo
Y
Y
D000256:Adenoviridae / Q000235:genetics*; D000336:Aerosols; D000818:Animals; D018893:Bronchoalveolar Lavage; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics*; D016209:Interleukin-8 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D055370:Lung Injury; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000096:biosynthesis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000336:Aerosols; D018076:DNA, Complementary; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D006861:Hydrogen Peroxide; D009195:Peroxidase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse