Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice
Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice
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DOI：
10.1038/sj.gt.3301540
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发表时间：
2001-10-01
期刊：
影响因子：
5.1
通讯作者：
Ishigatubo, Y
中科院分区：
文献类型：
--
作者：
Hashiba, T;Suzuki, M;Ishigatubo, Y
血红素加氧酶-1 (HO-1) 是一种诱导型热休克蛋白，可调节血红素代谢形成胆红素、铁蛋白和一氧化碳。基于 HO-1 通过调节凋亡细胞死亡或细胞因子表达参与炎症消退的最新证据，本研究检验了外源 HO-1 基因转移的过度表达是否对 A 型流感病毒引起的急性肺损伤小鼠模型具有治疗作用。我们在此证明HO-1 cDNA的转移导致(1)抑制病理变化和肺内出血； (2)提高动物的生存率； (3)肺部炎症细胞减少。 TUNEL分析显示HO-1基因转移减少了DNA损伤的呼吸道上皮细胞的数量，caspase测定表明HO-1通过caspase-8介导的途径抑制肺损伤。这些发现表明 HO-1 基因转移治疗临床常见病原体引起的肺损伤的可行性。由于氧化应激和肺损伤与许多肺部疾病有关，例如多种微生物引起的肺炎和肺纤维化，HO-1可能在针对包括急性肺炎和肺纤维化在内的肺部疾病的治疗中具有更广泛的临床应用价值。
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 gone therapy targeting lung disorders including acute pneumonia and pulmonary fibrosis.