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
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
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DOI：
10.1089/104303401750195926
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发表时间：
2001-05-20
影响因子：
4.2
通讯作者：
Ishigatsubo, Y
中科院分区：
文献类型：
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作者：
Inoue, S;Suzuki, M;Ishigatsubo, Y
采用血红素加氧酶1（HO-1）腺病毒直接肺内接种的方法，对吸入性病原体所致的急性肺损伤进行了模型基因治疗。数据表明，Ad.HO-1给药与氯化血红素对内源性HO-1基因表达的药理学上调一样有效，以减轻雾化脂多糖（LPS）暴露后肺的嗜酸性炎症。有趣的是，免疫组织化学分析显示HO-1基因不仅转移到气道上皮，而且转移到肺泡巨噬细胞（AM）。此外，外源性HO-1在巨噬细胞中的过表达提供了高水平的内源性白细胞介素10（IL-10）从巨噬细胞产生，并且使用IL-10敲除小鼠的另外的实验证明，巨噬细胞中IL-10的增加对于LPS暴露后肺中嗜酸性细胞迁移的解决是关键的。这些结果表明，AM不仅是有效的基因转移到呼吸道上皮细胞的障碍，但也代表了逻辑的目标，广告介导的，直接的，在体内的基因治疗策略，在人类炎症性疾病。
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.