Regulation of Pulmonary Host Defense by Leptin

描述(申请人提供)：肺炎链球菌是社区获得性肺炎最常见的原因，在美国每年有40,000人死亡。最容易感染肺炎球菌肺炎的人包括那些因癌症、肺气肿和艾滋病等慢性疾病而导致的能量营养不良的人。对于能量营养不良引起的细菌感染的先天免疫力受损的机制，人们知之甚少。瘦素是一种由脂肪组织产生的荷尔蒙，在营养不良的能量中减少，并被认为调节先天免疫反应。我们观察到瘦素缺陷小鼠更容易患细菌性肺炎，从这些动物获得的肺泡巨噬细胞(AM)和中性粒细胞(PMN)在体外显示出吞噬和杀灭细菌的缺陷。瘦素在体内和体外对瘦素缺陷动物的外源性给药重建了体内和体外的抗菌宿主防御终点。我们假设瘦素在体内和体外调节肺泡巨噬细胞效应器功能、中性粒细胞募集、细胞因子和白三烯合成，以对抗肺炎链球菌的天然免疫反应。为了验证这一假说，我们将探索以下目标：1)通过使用药物拮抗剂和瘦素受体转基因小鼠在体内阻断瘦素受体信号，评估内源性瘦素在肺炎链球菌攻击后存活、细菌清除和细胞募集中的作用；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及其作用的靶细胞；3)利用瘦素受体信号突变小鼠的细胞，检测不同的瘦素受体信号通路在AM和PMN体外吞噬和杀伤肺炎链球菌的重要性；4)观察肺炎链球菌给药后不同时间点给予瘦素对正常小鼠细菌清除、存活及AM和PMN吞噬和杀伤机制的影响。这些研究将首次在细菌性肺炎的背景下定义瘦素的产生和反应，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。他们还将测试外源性瘦素作为辅助治疗剂在肺炎球菌肺炎治疗中的使用。

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.