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

生物体内碱性磷酸酶（APs）的生理底物尚不清楚。脂多糖（LPS）是一种内毒素，通过脂质a的毒性部分引起暴发性炎症反应。脂质a含有两个膦基，它们被认为是其生物作用。我们之前发现肠型APs （IAPs）降低了LPS的毒性。大鼠口服后，血清LPS含量在2hr内先升高后降低。而作为IAP抑制剂的l -苯丙氨酸与LPS共给药时，LPS含量在1小时内迅速升高，血清LPS浓度-时间曲线下面积增大至约。2倍，提示APs在胃肠道中的作用是降低血清LPS含量。我们还发现肺APs通过气管内滴注可以解毒LPS。本研究对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AP活性极低，而肾脏中AP活性显著升高。当给小鼠口服LPS时，（-/-）小鼠血清中LPS的含量比野生型小鼠增加了2.5倍。Western blot分析显示，LPS刺激（-/-）小鼠的肠道中IL-6水平也有所提高。在LPS刺激的（-/-）小鼠中，血液循环中的中性粒细胞数量也增加到2倍。这些结果强烈提示IAPs降低了LPS在胃肠道中的毒性，作为宿主对LPS的防御因子。

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.