SURGERY AND IV NUTRITION MODULATE MACROPHAGE FUNCTION

手术和静脉营养调节巨噬细胞功能

• 批准号: 2685042
• 负责人: W SCOTT HELTON
• 金额: $ 10.87万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2685042
• 关键词: alveolar macrophages; cytokine; dietary lipid; disease /disorder proneness /risk; immunocytochemistry; injury /disease stressor; laboratory rat; macrophage; multiple organ failure; neuroendocrine system; nutrition related tag; parenteral feedings; postoperative complications; superoxides; surgery; wound infection

The long term objectives of this application are to improve host defense in critically ill surgical patients as a means for preventing or attenuating the deleterious consequences of infection during intravenous feeding (TPN). TPN is immunosuppressive and predisposes to hospital acquired infection by unclear mechanisms. Infection in TPN-fed patients results in an altered neuroendocrine and catabolic response which may contribute to multiple organ failure and increased mortality during surgical critical illness. The roles that the macrophage (Mphi) sympathetic and hypothalamic- pituitary-adrenal axis play in mediating these pathophysiologic events during TPN are incompletely understood. Studies are proposed to investigate the hypothesis that TPN activates the sympathoadrenal, sympathetic nervous and hypothalamic pituitary -adrenal axis play in mediating these pathophysiologic events during TPN are incompletely understood. Studies are proposed to investigate the hypothesis that TPN activates the sympathoadrenal, sympathetic nervous and hypothalamic pituitary adrenal axis and impairs Mphi function. Mphis will be isolated from the mesenteric lymph nodes, peritoneal cavity, lung, and spleen and their function studied. Mphi functions to be studied include: 1) ability to kill bacteria, 2) production of superoxide anion; and 3) basal and lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor (TNF), Prostaglandin E2 (PGE2), and procoagulant activity (PCA). Immunohistochemistry will be used to count the number of Mphis in the gut wall. Quantitative northern assays of Mphi TNF and PCA mRNA will be performed on unsolicited mphis from the peritoneal cavity, lung, spleen and mesenteric lymph nodes and used as an indirect marker of Mphi activation and exposure to LPS. Mphi fatty acid composition will be measured and correlated with specific functions and alterations in cytokine responses to LPS. Mesenteric lymph nodes will be cultured for bacteria. Sympathoadrenal and sympathetic nervous activity will be assessed by measuring urinary catecholamine excretion and tissue norepinephrine content and turnover respectively. Activation of the hypothalamic-pituitary- adrenal axis will be indirectly assessed by measuring serum corticosterone. Mphi functions and bacterial translocation to mesenteric lymph nodes will be correlated with plasma corticosterone, urinary catecholamine excretion, tissue norepinephrine content and tissue norepinephrine turnover. Studies will investigate several mechanisms of TPN-induced stress a d macrophage dysfunction and include: oral antibiotic gut decontamination, intravenous polymixin B, partial duodenal nutrition, ingestion of a non digestible non-nutritious meal, chewing on a metal spoon, and anatomic sympathectomy. It is hypothesized that all of these interventions will improve Mphi function decrease bacterial translocation to MLN, and attenuate sympathetic, sympathoadrenal, and hypothalamic-pituitary adrenal activation during TPN. Fundamental knowledge of the physiologic effects of TPN on Mphi function and the neuroendocrine system are potentially useful in the development of therapies for the prevention of sepsis and multiple organ failure in TPN-fed critically ill surgical patients.

该应用程序的长期目标是提高宿主的防御能力 作为预防或减轻危重手术患者的手段 静脉喂养（TPN）期间感染的有害后果。 TPN 具有免疫抑制作用，容易发生医院获得性感染 机制不明确。 TPN 喂养患者的感染会导致 神经内分泌和分解代谢反应可能导致多种 外科危重疾病期间的器官衰竭和死亡率增加。 巨噬细胞 (Mphi) 交感神经和下丘脑的作用 垂体-肾上腺轴在介导这些病理生理事件中发挥作用 TPN 期间的情况尚不完全理解。 拟议的研究旨在调查 TPN 激活的假设 交感肾上腺、交感神经和下丘脑垂体-肾上腺 TPN 期间轴在介导这些病理生理事件中的作用是 不完全理解。 拟议的研究旨在调查 TPN 激活的假设 交感肾上腺、交感神经和下丘脑垂体肾上腺 轴并损害 Mphi 功能。 Mphis 将从肠系膜中分离出来 淋巴结、腹膜腔、肺和脾及其功能 研究过。 Mphi要研究的功能包括：1）杀伤能力 细菌，2）产生超氧阴离子； 3) 基础和 脂多糖（LPS）刺激肿瘤坏死因子（TNF）的释放， 前列腺素 E2 (PGE2) 和促凝血活性 (PCA)。 免疫组织化学将用于计算肠道中 Mphi 的数量 墙。 Mphi TNF 和 PCA mRNA 的定量 Northern 测定将 对来自腹膜腔、肺、脾和未经请求的 mphis 进行 肠系膜淋巴结并用作 Mphi 激活的间接标志物 和暴露于脂多糖（LPS）。 将测量 Mphi 脂肪酸组成并 与细胞因子反应的特定功能和变化相关 脂多糖。 将培养肠系膜淋巴结的细菌。 交感肾上腺和交感神经活动将通过以下方式评估 测量尿儿茶酚胺排泄量和组织去甲肾上腺素含量 和营业额分别。 激活下丘脑-垂体- 通过测量血清皮质酮来间接评估肾上腺轴。 Mphi 功能和细菌易位至肠系膜淋巴结将 与血浆皮质酮、尿儿茶酚胺排泄相关， 组织去甲肾上腺素含量和组织去甲肾上腺素周转率。 研究将调查 TPN 引起的应激的几种机制 巨噬细胞功能障碍包括：口服抗生素肠道净化， 静脉注射多粘菌素 B、部分十二指肠营养、摄入非 易消化的非营养餐，咀嚼金属勺子，以及解剖学 交感神经切除术。 假设所有这些干预措施都将 改善 Mphi 功能，减少细菌易位至 MLN，以及 减弱交感神经、交感肾上腺和下丘脑-垂体肾上腺 TPN 期间激活。 生理效应的基础知识 TPN 对 Mphi 功能和神经内分泌系统有潜在用途 开发预防败血症和多发性硬化症的疗法 TPN 喂养的危重手术患者出现器官衰竭。