Regulation of Pulmonary Host Defense by Leptin

瘦素对肺宿主防御的调节

• 批准号: 7163692
• 负责人: PETER MANCUSO
• 金额: $ 34.19万
• 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/7163692
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adipose tissue; Alveolar; Alveolar Macrophages; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Pneumonia; Cells; Cessation of life; Chronic Disease; Communities; Defect; Development; End Point; Energy Intake; Exhibits; Fasting; Genetic; Goals; Hormones; Host Defense; Immune response; Immunity; Impairment; In Vitro; Individual; Infection; Kinetics; Leptin; Leptin deficiency; Leukotrienes; Lung; Malignant Neoplasms; Malnutrition; Mus; Mutant Strains Mice; Natural Immunity; Phagocytosis; Pneumococcal Pneumonia; Pneumonia; Production; Pulmonary Emphysema; Receptor Signaling; Regulation; Role; Signal Pathway; Source; Streptococcus pneumoniae; Testing; Therapeutic Agents; Time; Transgenic Mice; Upper respiratory tract; Wild Type Mouse; cytokine; in vivo; insight; killings; leptin receptor; macrophage; mortality; neutrophil; novel; pathogen; peripheral blood; reconstitution; response

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（由申请方提供）：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例死亡。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一种激素，其在能量营养不良时减少，并且已知其调节先天免疫反应。我们已经观察到，通过遗传手段或禁食使瘦素缺乏的小鼠对细菌性肺炎更敏感，并且从这些动物获得的肺泡巨噬细胞（AM）和中性粒细胞（PMN）在体外吞噬和杀死细菌方面表现出缺陷。瘦素缺乏和禁食小鼠体内外源性瘦素给药重建体内和体外抗菌宿主防御终点。我们的总体假设是，瘦素调节AM和PMN效应器功能，PMN募集，细胞因子和白三烯合成的先天性免疫反应对S。pneumoniae在体内和体外。为了验证这一假设，我们将探讨以下目的：1）评估内源性瘦素在肺宿主防御S。通过使用药理学试剂和瘦素受体转基因小鼠在体内阻断瘦素受体信号传导来治疗肺炎链球菌感染; 2）确定肺炎球菌肺炎过程中产生的瘦素的动力学和细胞来源以及肺中瘦素活性的靶细胞; 3）检查不同的瘦素受体信号传导途径在AM和PMN效应器功能中对S.使用来自瘦素受体转基因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。在WT小鼠中，研究了肺炎链球菌给药对细菌清除、存活和AM和PMN效应子功能的机制的影响。这些研究将提供新的见解瘦素调节先天性免疫反应对细菌病原体的机制，并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。