Pulmonary inflammation and emphysema - Role of the Cytokines IL-18 and IL-13
Pulmonary inflammation and emphysema - Role of the Cytokines IL-18 and IL-13
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DOI：
10.1164/rccm.200603-316oc
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发表时间：
2007-07-01
影响因子：
24.7
通讯作者：
Aizawa, Hisamichi
中科院分区：
文献类型：
--
作者：
Hoshino, Tomoaki;Kato, Seiya;Aizawa, Hisamichi
基本原理：慢性阻塞性肺疾病（COPD）被认为是一种炎症性细胞因子驱动的疾病，但尚未直接证明与特定细胞因子相关的因果关系。我们之前曾报道过促炎细胞因子IL-18的表达在小鼠肺部炎症和肺损伤的发病机制中很重要。我们的研究结果表明，IL-18在肺中的过量产生可以引起肺部疾病，如肺部炎症、肺纤维化和COPD。目的：我们分析IL-18在COPD发病机制中的作用。使用人表面活性蛋白C启动子驱动成熟小鼠IL-18 cDNA的表达，我们开发了两种不同系的转基因（Tg）小鼠，其在肺中组成性地或响应于多西环素而过量产生小鼠成熟IL-18。肺中IL-18的组成性过度产生导致IFN-γ、IL-5和IL-13的产生增加，以及慢性肺部炎症，出现CD 8（+）T细胞、巨噬细胞、中性粒细胞和嗜酸性粒细胞。在（超过15周龄）Tg小鼠中观察到肺容量增加、重度肺气肿变化、右心室扩张和轻度肺动脉高压。有趣的是，IL-13基因的破坏，而不是IFN-γ基因，防止肺气肿和肺部炎症在Tg小鼠。此外，当IL-18的生产诱导肺组织4周，通过使用强力霉素依赖性表面活性蛋白C的启动子，间质炎症induced.Conclusions：我们的研究结果表明，IL-18和IL-13可能有一个重要的作用，在COPD的发病机制。
Rationale: Chronic obstructive pulmonary disease (COPD) is believed to be an inflammatory cytokine-driven disease, but a causal basis that can be associated with a specific cytokine has not been directly demonstrated. We have previously reported that proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate that IL-18 overproduction in the lungs can induce lung diseases, such as pulmonary inflammation, lung fibrosis, and COPD.Objectives: We analyzed the role of IL-18 in the pathogenesis of COPD.Methods: Using the human surfactant protein C promoter to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic (Tg) mice that overproduced mouse mature IL-18 in the lungs either constitutively or in response to doxycycline.Measurements and Main Results: Constitutive overproduction of IL-18 in the lungs resulted in the increased production of IFN-gamma, IL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8(+) T cells, macrophages, neutrophils, and eosinophils. Increased lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in (more than 15-wk-old) Tg mice. Interestingly, disruption of the IL-13 gene, but not the IFN-gamma gene, prevented emphysema and pulmonary inflammation in Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent surfactant protein C promoter, interstitial inflammation was induced.Conclusions: Our results indicate that IL-18 and IL-13 may have an important role in the pathogenesis of COPD.