Regulation of Pulmonary Host Defense by Leptin

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，在美国每年导致40，000人死亡。 最易感染肺炎球菌性肺炎的个体包括那些因慢性疾病（如癌症、肺气肿和艾滋病）而继发能量营养不良的人。 对能量营养不良引起的对细菌感染的先天免疫受损的机制知之甚少。 瘦素是由脂肪组织产生的激素，其在营养不良的能量中减少，并且已知其调节先天免疫反应。 我们已经观察到，瘦素缺乏的小鼠更容易感染细菌性肺炎，并且从这些动物中获得的肺泡巨噬细胞（AM）和中性粒细胞（PMN）在体外吞噬和杀死细菌方面表现出缺陷。 外源性瘦素在体内和体外瘦素缺乏的动物重建体内和体外抗菌宿主防御终点。 我们假设瘦素调节肺泡巨噬细胞效应子功能，中性粒细胞募集，细胞因子和白三烯合成的先天性免疫反应，对肺炎链球菌在体内和体外。 为了验证这一假设，我们将探讨以下目标：1）评估内源性瘦素在S.通过使用药理学拮抗剂和瘦素受体转基因小鼠体内阻断瘦素受体信号转导来对抗肺炎链球菌的攻击; 2）确定肺炎球菌肺炎过程中瘦素产生的动力学和细胞来源以及其作用的肺中的靶细胞; 3）检查不同的瘦素受体信号转导途径在AM和PMN吞噬和杀死S.使用来自瘦素受体信号传导突变小鼠的细胞在体外测定肺炎链球菌感染后不同时间点施用的瘦素的作用; pneumoniae给药对正常小鼠中细菌清除、存活以及AM和PMN吞噬和杀伤机制的影响。 这些研究将首次定义细菌性肺炎背景下瘦素的产生和反应，并为瘦素调节针对细菌病原体的先天免疫反应的机制提供新的见解。 他们还将测试使用外源性瘦素作为治疗肺炎球菌性肺炎的一种预防性治疗剂。

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 hormone produced by adipose tissue that is reduced in the energy malnourished and is known to regulate innate immune responses. We have observed that leptin-deficient mice 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 and in vitro to leptin-deficient animals reconstitutes antibacterial host defense endpoints in vivo and in vitro. We hypothesize that leptin regulates alveolar macrophage effector functions, neutrophil recruitment, and cytokine and leukotriene synthesis in the innate immune response against Streptococcus pneumoniae in vivo and in vitro. To test this hypothesis we will explore the following aims: 1) Assess the role of endogenous leptin in survival, bacterial clearance, and cellular recruitment following S. pneumoniae challenge by blocking leptin receptor signaling in vivo using a pharmacologic antagonist and leptin receptor transgenic mice; 2) Determine the kinetics and cellular sources of leptin production during the course of pneumococcal pneumonia and the target cells in the lung for its action; 3) Examine the importance of distinct leptin receptor signaling pathways in AM and PMN phagocytosis and killing of S. pneumoniae in vitro using cells from leptin receptor signaling mutant mice; and 4) Determine the effects of leptin administered at different time points following S. pneumoniae administration on bacterial clearance, survival, and AM and PMN mechanisms of phagocytosis and killing in normal mice. These studies will, for the first time, define leptin production and responses in the context of bacterial pneumonia and provide novel insights into the mechanisms by which leptin regulates innate immune responses against bacterial pathogens. They will also test the use of exogenous leptin as an adjunctive therapeutic agent in the treatment of pneumococcal pneumonia.