PLATELET ACTIVATING FACTOR AND THROMBOXANES IN LIVER

血小板活化因子(PAF)和血栓素A2(TXA2)是有效的 急性过敏和炎症反应的脂类化学介体。 最近，我们观察到AGEPC(合成聚酰胺)和U-46619(一种TXAS) 模拟专家对灌流液中糖原分解的强大刺激作用 通过一种间接机制引起的大鼠肝脏的收缩 脉管系统。急性期肝血管收缩。 过敏反应和PAF和TXA2是由炎症细胞产生的 并活在免疫挑战中。因此，PAF和TXA2可能会发挥作用 在调节肝脏血流和供血方面具有潜在的重要作用 在病理生理状态下，肝外组织中含有葡萄糖。 这项研究的主要目的是阐明PAF的ROE和 血栓素A2对肝脏血流动力学和体内糖原分解的影响 深入了解这些脂质介体在心脏疾病中作用的分子基础 肝内皮细胞和库普弗细胞，它们通过 肝窦。在体内的实验将表征的影响 从肝脏测定中探讨硒对肝脏血流动力学的影响 门脉压力、肝门脉和肝动脉血流。同时进行 将进行测量以评估肝糖原分解和 在这些实验条件下的血糖浓度。 最后，我们将评估PAF和TXA2作为血管紧张素转换酶调节因子的作用。 肝脏病理生理过程中血流动力学和糖原分解的变化 情况。确定所涉及的肝脏受体的实验 对这些脂质激动剂的血流动力学反应将在 灌流肝脏、肝内皮细胞和枯否细胞。放射性配体 PAF-ad-TXA2受体与PAF-ad-TXA2受体的结合及其机制 将探索内皮细胞和库普弗细胞中的信号转导。 我们的初步实验表明，这些受体与 枯否细胞胞浆游离钙浓度([Ca~(2+)]_i)的变化 细胞和AGEPC受体对磷脂酰肌醇特异性的刺激 磷脂酶C这些脂质激动剂对[Ca~(2+)]i的影响将是 以Fura-2负载细胞的数字图像分析为特征 对磷脂酶C激活和产生的影响的比较 钙离子调节第二信使。蛋白激酶C和鸟嘌呤的作用 受体介导的生物信号转导中的核苷酸调节蛋白将 探索过了。将在效力的等级顺序之间建立相关性 肝血管收缩的激动剂和拮抗剂，受体结合， [CA2=]I和磷脂酶C这项拟议的研究将提供新的 PAF和TXA2在肝脏和肝脏中作用机制的研究 希望这将有助于更准确地了解他们的 在其他非肝细胞和组织中的作用。

Platelet activating factor (PAF) and thromboxane A2 (TxA2) are potent lipid chemical mediators of acute allergic and inflammatory responses. Recently, we observed that AGEPC (synthetic PAF) and U-46619 (a TxAs analog expert powerful stimulatory effects on glycogenolysis in perfused rat livers by an indirect mechanism involving constriction of the hepatic vasculature. Constriction of the hepatic vasculature occurs during acute allergic reactions and PAF and TxA2 are produced by inflammatory cells and live during immune challenge. Thus, PAF and TxA2 may play a potentially important role in regulating hepatic blood flow and supplying extrahepatic tissues with glucose during pathophysiological states. The major objectives of this study are to elucidate the roe of PAF and TxA2 on hepatic hemodynamics and glycogenolysis in vivo and to provide insight into the molecular basis of action of these lipid mediators in hepatic endothelial and Kupffer cells, which regulate flow through the hepatic sinusoids. Experiments in vivo will characterize the effects of the se mediators on hepatic hemodynamics by measurements of hepatic portal pressure and hepatic portal and arterial flows. Simultaneous measurements will be performed to evaluate hepatic glycogenolysis and blood glucose concentrations under these experimental conditions. finally, we will assess the role of PAF and TxA2 as mediators of hemodynamic and glycogenolytic changes in liver during pathophysiologic situations. Experiments to characterize the hepatic receptors involved in hemodynamic responses to these lipid agonists will be performed in perfused livers and hepatic endothelial and Kupffer cells. Radioligand binding to PAF ad TxA2 receptors and mechanisms involved in receptor signal transduction in endothelial and Kupffer cells will be explored. Our preliminary experiments suggest these receptors are coupled to changes in cytosolic free calcium concentrations ([Ca2+]i) in Kupffer cells and, with AGEPC receptors, stimulation of phosphoinositide-specific phospholipase C. Effects of these lipid agonists on [Ca2+]i will be characterized by digital image analysis of Fura 2-loaded cells and compared to effects on activation of phospholipase C and production of Ca2+-regulating second messengers. Roles of protein kinase C and guanine nucleotide regulatory proteins in receptor-mediated biosignalling will be explored. Correlations will be made between rank order of potencies of agonists and antagonists on hepatic vasoconstriction, receptor binding, [Ca2=]i and phospholipase C. The proposed study will provide new insights into the mechanisms of action of PAF and TxA2 in liver and hopefully will contribute to a more precise understanding of their actions in other non-hepatic cells and tissues.