| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Recent evidence suggests that alveolar cell death is involved in the pathogenesis of COPD. Geranylgeranylacetone (GGA), an acyclic polyisoprennoid compound formulated with a retinoid skeleton, is a safe and inexpensive orally-active antiulcer drug that has been used clinically in Japan since 1984 and has recently been shown to induce heat shock protein (HSP)-70 and to protect gastric mucosal cells and hepatocytes against both apoptosis and necrosis induced by acid, oxidants, ethanol, and other insults. We studied the protective effects of GGA on alveolar cell death and emphysema. Human normal alveolar epithelial cells and human normal lung microvascular endothelial cells were employed to study the cytoprotective effect of GGA. Animal models of emphysema induced by SU5416 (VEGF receptor2 kinase inhibitor) injection or chronic cigarette smoking were used to study the in vivo effect of GGA. Pretreatment with GGA for 6 hours protected alveolar epithelial and endothelial cell death against cigarette smoke extracts, hydrogen peroxide, growth factor (e.g., VEGF, EGF) deprivation, and anoikis, which are thought to mediate cell death in pulmonary emphysema. The cytoprotective effect of GGA was associated with induction of HSPs. In vivo experiments with rats and guinea pigs showed that treatment with GGA prevented emphysema induced by SU5416 or chronic cigarette smoking. Furthermore, GGA prevented alveolar cell death but not alveolar inflammation. In conclusion, we found that GGA protected alveolar epithelial and endothelial cell death and emphysema. Cytoprotection of alveolar cells by the heat shock protein inducer, which is already available in clinical settings, may open an avenue to a new strategy in treating COPD.
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