PPARGamma in Sepsis-Induced Immunosuppression

描述（由申请人提供）： 脓毒症患者极易发生院内感染， 感染，特别是肺部的细菌感染。虽然确切的 导致脓毒症介导的免疫抑制的机制仍然存在 目前尚不清楚，单核细胞/巨噬细胞功能失调被认为是 在这些现象中扮演重要角色。最近，过氧化物酶体增殖物激活 受体-γ（PPARy），核受体超家族的成员 配体依赖性转录因子，已被证明可以抑制 单核细胞/巨噬细胞和其他细胞的炎症介质表达 白细胞群这一提议的假设是，脓毒症诱导 免疫抑制部分由PPARy介导。此外，我们假设 抑制这种配体依赖性转录因子 脓毒症引起的肺泡巨噬细胞功能的变化，导致增强 肺抗菌宿主防御。 盲肠结扎和穿刺的小鼠模型（导致腹部 脓毒症）将用于评估以下具体目的：I） 确定在肺中的时间过程和PPARy表达的幅度， 小鼠腹腔脓毒症的演变; II）确定功能性 PPARy激活对原代小鼠效应细胞功能影响 肺泡巨噬细胞或鼠肺泡巨噬细胞系; III）至 鉴定在细胞增殖过程中调节PPARy表达的内源性信号， 小鼠腹部脓毒症的演变;和IV）确定 PPARy对脓毒症所致肺泡巨噬细胞损伤抑制作用 体外功能和体内对肺炎假单胞菌的易感性。 所概述的研究的表现将有助于定义PPARy作为一种 介导脓毒症诱导的肺泡巨噬细胞功能障碍，并可能导致 用于治疗患者的新疗法的开发 败血症

DESCRIPTION (provided by applicant): Patients with sepsis are highly susceptible to the development of nosocomial infection, particularly bacterial infection of the lung. While the exact mechanism(s) that contribute to sepsis-mediated immunosuppression remains unclear, dysregulation of monocyte/macrophage function is believed to play an important role in these phenomena. Recently, peroxisome proliferator-activated receptor-gamma (PPARy), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, has been shown to inhibit the expression of inflammatory mediators from monocytes/macrophages and other leukocyte populations. The hypothesis of this proposal is that sepsis induced immunosuppression is mediated, in part, by PPARy. Furthermore, we postulate that inhibition of this ligand dependent transcription factor will reverse sepsis-induced changes in alveolar macrophage function, resulting in augmented lung antibacterial host defense. A murine model of cecal ligation and puncture (resulting in an abdominal sepsis syndrome) will be utilized to assess the following Specific Aims: I) to determine the time course and magnitude of PPARy expression in lung during the evolution of murine abdominal sepsis; II) to determine the functional significance of PPARy activation on effector cell functions of primary murine alveolar macrophages or murine alveolar macrophage cell lines; III) to identify the endogenous signals that regulate PPARy expression during the evolution of murine abdominal sepsis; and IV) to determine the effect of inhibition of PPARy on sepsis- induced alterations in alveolar macrophage function ex-vivo and susceptibility to Pseudomonas pneumonia in-vivo. Performance of the studies outlined will help define the role of PPARy as a mediator of sepsis-induced alveolar macrophage dysfunction, and may lead to the development of novel therapies to be employed in the treatment of patients with sepsis.