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Investigation on atrial natriuretic peptide as an endogenous antipyretic

心房钠尿肽作为内源性解热药的研究

基本信息

批准号：
17590204
负责人：
WATANABE Tatsuo
金额：
$ 2.24万
依托单位：
Tottori University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590204/
关键词：
ANP LPS IL-1 fever rat NF-κB AP-1 microglial cell NO 形態変化脾臓脳アンギオテンシンII

项目摘要

We investigated whether natriuretic peptide (NP) acts as an endogenous antipyretic inside and/or outside the blood-brain barrier in rats made febrile by intravenous (i.v.) injection of bacterial endotoxin (lipopolysaccharide ; LPS). LPS induced a triphasic fever, the second phase of which was significantly enhanced by an i.v. injection of the NP-receptor antagonist HS-142-1. In contrast., the same antagonist (i.v.) had no effect on the fever induced by i.v. injection of interleukin-β (IL-1β). An i.v. administration of HS-142-1 enhanced the LPS (i.v.)-induced IL-1β response in the rat spleen. An i.v. treatment with atrial NP (ANP) significantly attenuated the second phase of the LPS-induced fever. Intracerebroventricular (i.c.v.) injection of the above NP-receptor antagonist resulted in an augmentation of the third phase of the fever induced by i.v. administration of LPS, the same phase that, was attenuated by ANP given i.c.v. When given i.c.v., the antagonist had no effect on the fever … More induced by i.v. IL-1β. On the other hand, we used primary cultures of rat brain macrophage-like cells (i.e., microglial cells) to investigate whether ANP binding to its receptors inhibits LPS-induced microglial activation via effects on the activation of the proinflammatory transcription factors NF-κB and AP-1. UPS-stimulated microglial cells showed increases in nitrite and IL-1 concentrations, and in the expression of IL-1 mRNA, as well as a morphological change from an amoeboid shape to a multipolar rod shape. These effects were all significantly inhibited by treatment with ANP. The inhibition by ANP of the LPS-induced nitrite response was abrogated by HS-142-1. NF-κB and AP-1 activities were enhanced in LPS-stimulated microglial cells, and these enhancements were significantly suppressed by ANP. Collectively, these results suggest that the production of pyrogenic cytokines may be inhibited by NP acting inside and outside the blood-brain barrier, leading to an inhibition of the fever in rats. Less

我们研究了是否利钠肽（NP）作为一种内源性解热剂的内部和/或外部的血脑屏障在大鼠发热静脉注射（i. v.）注射细菌内毒素（脂多糖; LPS）。LPS诱导的三相发热，其中第二阶段是显着增强静脉注射的NP-受体拮抗剂HS-142-1。相反，相同的拮抗剂（i. v.）对静脉注射白细胞介素-β（IL-1β）引起的发热无影响。静脉内施用HS-142-1增强了LPS（静脉内）-诱导大鼠脾脏中的IL-1β反应。静脉注射心房NP（ANP）治疗显着衰减LPS引起的发热的第二阶段。脑室内（i. c. v.）注射上述NP-受体拮抗剂导致由静脉内给予LPS诱导的发热的第三阶段增强，该阶段与静脉内给予ANP减弱的阶段相同。当静脉内给予时，拮抗剂对发热无影响 ...更多信息 i. v. IL-1β诱导。另一方面，我们使用大鼠脑巨噬细胞样细胞的原代培养物（即，小胶质细胞）以研究ANP与其受体结合是否通过影响促炎性转录因子NF-κB和AP-1的活化来抑制LPS诱导的小胶质细胞活化。UPS刺激的小胶质细胞显示亚硝酸盐和IL-1浓度增加，IL-1 mRNA的表达，以及从阿米巴形状到多极杆形状的形态变化。这些作用均被ANP显著抑制。ANP对LPS诱导的亚硝酸盐反应的抑制被HS-142-1消除。LPS刺激的小胶质细胞NF-κB和AP-1活性增强，ANP可显著抑制这种增强。总的来说，这些结果表明，热原性细胞因子的产生可能被抑制NP作用于血脑屏障内外，从而抑制大鼠的发热。少