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

生物体中碱性磷酸酶(AP)的生理底物尚不清楚。脂多糖是一种内毒素，通过脂类A的毒性部分引起暴发性炎症反应，脂类A含有两个膦酰基，被认为具有生物学作用。我们先前发现，肠型AP(IAP)可降低内毒素的毒性。大鼠灌胃给药后，血清中内毒素含量在2小时内先升高后下降。而当L-苯丙氨酸与内毒素合用时，内毒素含量在1小时内迅速升高，血清内毒素浓度-时间曲线下面积增大至约50%。2倍，提示胃肠道AP的作用是降低血清中的内毒素含量。在本研究中，我们对IAP缺陷小鼠(-/-)的IAP功能进行了进一步的研究。(-/-)小鼠血清和肠道中的AP活性很低，而肾脏中的AP活性明显较高。小鼠口服内毒素后，(-/-)小鼠血清中的内毒素含量比野生型小鼠高2.5倍。免疫印迹分析表明，(-/-)小鼠肠道中IL-6水平也明显升高。血液循环中的中性粒细胞数量在(-/-)小鼠中也增加了2倍。这些结果有力地表明，IAP作为一种宿主防御因子，降低了内毒素在胃肠道中的毒性。

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.