| Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
The mechanism of alcoholic liver disease has been largely investigated in parenchymal hepatocyte. However, little is known about the mechanisms underlying the protection of sinusoidal endothelial cells (SECs) against ethanol-induced injury. Recently, sphingosine 1-phosphate (S1P), a serum-borne bioactive lipid released from activated platelets, has been reported to regulate diverse biological processes, such as cell proliferation, migration, wound healing and inhibition of apoptosis. To test whether S1P may affect biological function of SECs in ethanol-induced liver injury, we examined the effect of extracellular S1P on SECs in primary culture.
Our results show that S1P protects SECs against ethanol-induced injury in primary culture of rat liver, and that the protective effect of S1P may be mediated by activation of Ca^<2+>-sensitive eNOS and subsequent NO formation. This is consistent with previous report that NO generated by eNOS is important for protection of apoptosis in several cell types, and further supported by our present finding that inhibition of calmodulin, a Ca^<2+> binding protein, attenuates S1P-induced eNOS activity in SECs. S1P also ameliorated the decreased DNA synthesis of cells caused by ethanol. We thus propose that S1P, which is possibly released from activated platelets in response to ethanol consumption, could contribute to sinusoidal protection and remodeling in alcoholic liver injury.
Although further research is required to elucidate the molecular interaction between Ca^<2+>, CaM and eNOS activity, our results suggest a possible mechanism for the regulation of ethanol-induced apoptosis in SECs by S1P. Physiological importance of S1P is uncertain. However, our findings may lead to a better understanding of S1P as a target for novel therapeutic strategies in alcoholic liver injury.
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