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Alkaline phosphatases as a self-defense in the lung and intestine.

碱性磷酸酶作为肺和肠的自卫作用。

基本信息

批准号：
16590469
负责人：
KOYAMA Iwao
金额：
$ 1.79万
依托单位：
Saitama Medical University College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Physiological substrates for alkaline phosphatases (APs) in the organism remain unclear. Lipopolysaccharide (LPS), an endotoxin, elicits a fulminant inflammatory response by the toxic moiety of lipid A. Lipid A contains two phosphonyl groups that are looked upon its biological action. We previously found that intestinal-type APs (IAPs) reduced the toxicity of LPS. After the oral administration to rats, the LPS content in serum increased within 2hr and then decreased. In contrast, when L-phenylalanine as an inhibitor of IAP was co-administered with LPS, the LPS content rapidly increased within 1 hr and the area under the concentration-time curve of serum LPS was augmented to approx. 2-fold, suggesting that the action of APs in gastrointestinal tract was to reduced serum LPS content. We also found that lung APs detoxified LPS administered by intratracheal instillation.In this study, the further investigation of IAP function was proceeded in IAP-deficient mice (-/-). AP activities in the serum and the intestine from (-/-) mice were very low, although AP activity in kidney was significantly high. When LPS was orally administered to mice, the serum content of LPS in (-/-) mice was augmented up to 2.5-fold in comparison with wild-type mice. The level of IL-6, determined by Western blot analysis, was also enhanced in intestine from (-/-) mice challenged with LPS. Numbers of neutrophils in blood circulation also increased to 2-fold in (-/-) mice challenged with LPS. These results strongly suggest that the IAPs reduce the toxicity of LPS in gastrointestinal tract, as a host defense factor against LPS.

生物体中碱性磷酸酶（AP）的生理底物仍不清楚。脂多糖（LPS）是一种内毒素，通过脂质A的毒性部分引发爆发性炎症反应。脂质A含有两个膦酰基基团，这被认为是其生物学作用。我们以前发现，尿道型AP（IAP）降低LPS的毒性。灌胃给药后，大鼠血清中LPS含量在2 h内升高，然后下降。与此相反，当L-苯丙氨酸作为IAP的抑制剂与LPS共同给药时，LPS含量在1小时内迅速增加，血清LPS浓度-时间曲线下面积增加至约100 μ g/ml。2倍，提示AP在胃肠道的作用是降低血清LPS含量。本研究在IAP缺陷小鼠（-/-）中进一步研究了IAP的功能。（-/-）小鼠血清和小肠中AP活性很低，而肾脏中AP活性显著升高。当LPS经口给予小鼠时，与野生型小鼠相比，（-/-）小鼠中LPS的血清含量增加至2.5倍。免疫印迹分析表明，LPS刺激后（-/-）小鼠肠道IL-6水平明显升高。在LPS激发的（-/-）小鼠中，血液循环中的中性粒细胞数量也增加至2倍。这些结果强烈地表明，IAPs作为宿主对LPS的防御因子，降低了LPS在胃肠道中的毒性。