Regulation of Pulmonary Host Defense by Leptin

瘦素对肺宿主防御的调节

• 批准号: 7030058
• 负责人: PETER MANCUSO
• 金额: $ 36.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030058
• 关键词: Streptococcus pneumoniae; alveolar macrophages; bacterial pneumonia; bactericidal immunity; bioenergetics; cytokine receptors; genetically modified animals; hormone regulation /control mechanism; hormone therapy; immune response; immunosuppression; laboratory mouse; leptin; malnutrition; neutrophil; nutrition related tag; phagocytosis

DESCRIPTION (provided by applicant): Streptococcus pneumoniae is the most common cause of community-acquired pneumonia accounting for 40,000 deaths/year in the US. Individuals who are most susceptible to pneumococcal pneumonia include those who are energy malnourished as a secondary consequence of chronic diseases such as cancer, emphysema, and AIDS. The mechanisms responsible for impaired innate immunity against bacterial infections arising from energy malnutrition are poorly understood. Leptin is a hormone produced by adipose tissue that is reduced in the energy malnourished and is known to regulate innate immune responses. We have observed that mice rendered leptin-deficient by genetic means or by fasting are more susceptible to bacterial pneumonia and alveolar macrophages (AMs) and neutrophils (PMNs) obtained from these animals exhibit defects in phagocytosis and killing of bacteria in vitro. The exogenous administration of leptin in vivo to leptin-deficient and fasted mice reconstitutes antibacterial host defense endpoints in vivo and in vitro. Our global hypothesis is that leptin regulates AM and PMN effector functions, PMN recruitment, and cytokine and leukotriene synthesis in the innate immune response against S. pneumoniae in vivo and in vitro. To test this hypothesis we will explore the following aims: 1) Assess the role of endogenous leptin in pulmonary host defense against S. pneumoniae by blocking leptin receptor signaling in vivo using a pharmacologic agent and leptin receptor transgenic mice; 2) Determine the kinetics and cellular sources of leptin produced during the course of pneumococcal pneumonia and the target cells in the lung for leptin activity; 3) Examine the effect of distinct leptin receptor signaling pathways in AM and PMN effector functions against S. pneumoniae in vitro using cells from leptin receptor transgenic mice; and 4) Determine the effects of leptin administered at different time points following S. pneumoniae administration on bacterial clearance, survival, and mechanisms of AM and PMN effector functions in WT mice. These studies will provide novel insights into the mechanisms by which leptin regulates innate immune responses against bacterial pathogens and will test the use of exogenous leptin as an adjunctive therapeutic agent in the treatment of pneumococcal pneumonia.

描述（由申请人提供）：肺炎链球菌是社区获得性肺炎的最常见原因，在美国，每年40,000例死亡。最容易受到肺炎球菌肺炎的个体包括那些能量营养不良的人，因为癌症，肺气肿和艾滋病等慢性疾病的次要后果。对能量营养不良引起的细菌感染的造成的造成的先天免疫力受损的机制知之甚少。瘦素是由脂肪组织产生的激素，在营养不良的能量中降低，已知可以调节先天免疫反应。我们已经观察到，通过遗传手段或禁食使细菌性肺炎和肺泡巨噬细胞（AMS）和嗜中性粒细胞（PMN）更容易受到细菌性肺炎和肺泡（PMN）的影响，从这些动物中获得的细菌缺陷在吞噬和杀害细菌中杀死了细菌在VITRO中表现出缺陷。瘦素在体内的外源给予瘦素缺乏和禁食的小鼠在体内和体外重构抗菌宿主防御终点。我们的全球假设是，瘦素调节AM和PMN效应子功能，PMN募集以及在体内和体外针对肺炎链球菌的先天免疫反应中的细胞因子和白三烯合成。为了检验该假设，我们将探讨以下目的：1）通过使用药理学剂和瘦素受体转基因小鼠在体内阻断瘦素受体信号传导，评估内源性瘦素在肺宿主防御肺炎链球菌中的作用； 2）确定在肺炎球菌性肺炎和肺中的靶细胞中产生的瘦素的动力学和细胞来源； 3）使用瘦素受体转基因小鼠的细胞在体外对AM和PMN效应子功能中不同的瘦素受体信号通路的作用； 4）确定肺炎链球菌施用后在不同时间点施用的瘦素对WT小鼠中AM和PMN效应子功能的细菌清除，生存和机制的影响。这些研究将提供有关瘦素调节对细菌病原体的先天免疫反应的机制的新见解，并将测试外源瘦素作为辅助治疗剂在治疗肺炎肺炎治疗中的使用。