| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2006: ¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 2005: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Research Abstract |
Rationale : COPD is thought 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 proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate 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 : Utilizing the human surfactant protein C promoter SP-C to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic mice that overproduced mouse mature IL-18 in the lungs either constitutively or in response to doxycycline.
Results : Constitutive overproduction of IL-18 in the lungs resulted in the increased production of IFN-γIL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8P^<+P> T cells, macrophages, neutrophils, and eosinophils. Enlarged lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in aged Tg mice. Interestingly, disruption of the IL-13 gene but not the IFN-□ gene prevented emphysema and pulmonary inflammation in aged Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent SP-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.
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