| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
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.
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