PPARGamma in Sepsis-Induced Immunosuppression

描述(由申请人提供)： 脓毒症患者极易发生医院感染 感染，尤指肺部的细菌感染。而完全相同的 脓毒症介导的免疫抑制的机制(S)仍然存在 不清楚的，单核/巨噬细胞功能失调被认为在 在这些现象中扮演着重要的角色。最近，过氧化物酶体增殖物激活的 核受体超家族成员受体-γ(PPARy) 配体依赖的转录因子，已被证明能抑制 单核/巨噬细胞等炎症介质的表达 白细胞群。这项提议的假设是败血症导致 免疫抑制部分是由PPARy介导的。此外，我们假设 对这种配体依赖的转录因子的抑制将逆转 脓毒症引起的肺泡巨噬细胞功能的改变，导致 肺抗菌宿主防御。 盲肠结扎和穿孔的小鼠模型(导致腹部 将用来评估以下具体目标：i) 测定肺组织中PPARy表达的时程和强度 小鼠腹部脓毒症的演变；II)确定功能性 PPARy激活对原代小鼠效应细胞功能的影响 肺泡巨噬细胞或小鼠肺泡巨噬细胞系； 确定调控PPARy表达的内源信号 小鼠腹腔脓毒症的演变；以及IV)以确定 PPARy对脓毒症诱导的肺泡巨噬细胞改变的抑制作用 体外功能和体内对肺炎假单胞菌的敏感性。 所述研究的执行情况将有助于确定PPARy作为 脓毒症诱导的肺泡巨噬细胞功能障碍的介质，并可能导致 用于患者治疗的新疗法的发展 患有败血症。

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.