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激素，在营养不良的能量中减少，已知的是调节先天免疫反应。我们观察到，通过遗传手段或禁食导致瘦素缺陷的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。体内外源性给予瘦素缺乏和禁食的小鼠在体内和体外重建抗菌宿主防御终点。我们的总体假设是，瘦素在体内和体外调节AM和PMN效应功能、PMN募集、细胞因子和白三烯的合成，以对抗肺炎链球菌的先天免疫反应。为了验证这一假设，我们将探索以下目标：1)通过使用药物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宿主防御肺炎链球菌中的作用；2)确定肺炎链球菌肺炎过程中瘦素产生的动力学和细胞来源，以及肺中瘦素活性的靶细胞；3)利用瘦素受体转基因小鼠的细胞，在体外检测不同的瘦素受体信号通路在AM和PMN抗肺炎链霉菌作用中的作用；4)研究肺炎链球菌给药后不同时间点给予瘦素对WT小鼠细菌清除、存活的影响，以及AM和PMN效应功能的机制。这些研究将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，并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 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.