PROTECTIVE EFFECT OF SPHINGOSINE 1-PHOSPHATE ON LIVER SINUSOIDAL ENDOTHELIAL CELLS AGAINST ETHANOL-INDUCED APOPTOSIS

1-磷酸鞘氨醇对肝窦内皮细胞乙醇诱导的细胞凋亡的保护作用

• 批准号: 15590689
• 负责人: KITAMURA Tsuneo
• 金额: $ 1.54万
• 依托单位: JUNTENDO UNWARILY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590689/
• 关键词: Alcoholic Liver Injury; Liver Sinusoidal Endothelial Cells; Syhingosine 1-Phosphate; Apoptosis; Calcium; Nitric Oxide; eNOS; 細胞内カルシウム

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.

酒精性肝病的发病机制在实质肝细胞中得到了广泛的研究。然而，关于窦状内皮细胞（SECs）抵抗乙醇诱导损伤的保护机制知之甚少。最近，鞘氨醇-磷酸（S1P）是一种从活化血小板中释放的血清性生物活性脂质，被报道调节多种生物过程，如细胞增殖、迁移、伤口愈合和抑制细胞凋亡。为了验证S1P是否会影响乙醇肝损伤中SECs的生物学功能，我们在原代培养中检测了细胞外S1P对SECs的影响。我们的研究结果表明，S1P可以保护大鼠肝脏原代培养的SECs免受乙醇诱导的损伤，并且S1P的保护作用可能是通过激活Ca^<2+>敏感的eNOS和随后的NO形成来介导的。这与之前的报道一致，即eNOS产生的NO对几种细胞类型的凋亡具有重要的保护作用，并且进一步支持了我们目前的发现，即抑制钙调素（Ca^<2+>结合蛋白）可以减弱s1p诱导的SECs中eNOS的活性。S1P还能改善乙醇引起的细胞DNA合成下降。因此，我们认为S1P可能在酒精消耗时从活化的血小板中释放出来，可能有助于酒精性肝损伤的正弦保护和重塑。虽然Ca^<2+>、CaM和eNOS活性之间的分子相互作用还需要进一步的研究，但我们的研究结果提示了S1P调控乙醇诱导的SECs凋亡的可能机制。S1P的生理重要性尚不确定。然而，我们的发现可能有助于更好地理解S1P作为酒精性肝损伤新治疗策略的靶点。

项目成果

Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of PPAR{gamma}, Pioglitazone.

PPAR{γ} 激动剂吡格列酮预防大鼠乙醇诱导的肝损伤。

• 发表时间: 2003
• 期刊: J Pharmacol Exp Ther 306
• 作者: Enomoto N;Takei Y;Hirose M;Konno A;Shibuya T;Matsuyama S;Suzuki S;Ikejima K;Kitamura T;Sato N
• 通讯作者: Sato N

Burn injury sensitizes rat Kupffer cells via mechanisms dependent on gut-derived endotoxin

• DOI: 10.1007/s00535-004-1468-9
• 发表时间: 2004-12-01
• 期刊: JOURNAL OF GASTROENTEROLOGY
• 影响因子: 6.3
• 作者: Enomoto, N;Takei, Y;Sato, N
• 通讯作者: Sato, N

The phosphodiesterase III inhibitor olprinone decreases sensitivit y of rat Kupffer cells to endotoxin.

磷酸二酯酶 III 抑制剂 olprinone 可降低大鼠 Kupffer 细胞对内毒素的敏感性。

• 发表时间: 2004
• 期刊: Alcohol Clin Exp Res 28
• 作者: Enomoto N;Takei Y;Hirose M;Ikejima K;Kitamura T;Sato N.
• 通讯作者: Sato N.

The phosphodiesterase III inhibitor olprinone decreases sensitivity of rat Kupffer cells to endotoxin

磷酸二酯酶 III 抑制剂奥普林酮降低大鼠 Kupffer 细胞对内毒素的敏感性

• 发表时间: 2004
• 期刊: Alcohol Clin Exp Res 28
• 作者: Nobuyuki Enmoto;et al.
• 通讯作者: et al.

Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of PPAR {gamma}, Pioglitazone.

PPAR {gamma} 激动剂吡格列酮预防大鼠乙醇诱导的肝损伤。

• 发表时间: 2003
• 期刊: Pharmacol Exp Ther 306
• 作者: Enomoto N;Takei Y;Hirose M;Konno A;Shibuya T;Matsuyama S;Suzuki S;Ikejima K;Kitamura T;Sato N.
• 通讯作者: Sato N.