Macrophage Activation/Deactiviation in ALI

急性呼吸窘迫综合征(ARDS)的特征是肺功能旺盛 炎症和对肺泡毛细血管膜的损伤，可导致失调的肺修复(纤维增殖)和医院感染的发展，特别是肺炎。虽然控制急性肺损伤(ALL)肺内炎症的机制尚不清楚，但肺泡巨噬细胞(AM)功能失调被认为在该病的发病机制中起着重要作用。最近，作为配体依赖转录因子核受体超家族的一员，过氧化物酶体增殖物激活受体-γ(PPAR-Gamma)被证明能够下调包括AM在内的单核/巨噬细胞的炎症介质的表达。PPAR-γ在调节ALL肺部炎症中的作用尚未被研究，这是本应用的重点。 这一建议的中心假设是ALL中AM的激活状态受PPAR-γ调节，其功能是抑制ALL中AM炎症反应的幅度。此外，在ALL病程中确定AM的激活状态可作为该疾病后续临床结局的独立预测因子。 在这项应用中，我们将使用床旁动物模型和涉及ALI/ARDS患者的人类研究来解决以下特定目标：1)评估实验性FITC诱导的ALL小鼠AM中PPAR-γ的表达和调节；2)确定PPAR-Gamma在调节FITC诱导的ALL小鼠AM激活状态中的作用；3)前瞻性地将PPAR-Gamma的表达/活性与ALI/ARDS患者的肺部炎症程度、内源性配体的表达以及临床结果相关联；4)确定PPAR-Gamma在ALI/ARDS患者中对AM激活状态的调节作用 ALI/ARDS患者的功能性AM表型改变；以及5)确定PPAR-γ基因多态性是否改变ALI/ARDS患者的疾病易感性和/或临床病程。在这项申请中提出的研究将为控制肺部炎症提供重要的见解，这可能导致评估和治疗这种毁灭性疾病的新方法。

The Acute Respiratory Distress Syndrome (ARDS) is characterized by exuberant pulmonary inflammation and injury to the alveolar-capillary membrane, which can result in dysregulated lung repair (fibroproliferation) and the development of nosocomial infection, particularly pneumonia. While mechanisms that control intrapulmonary inflammation in acute lung injury (ALl) remain unclear, dysregulation of alveolar macrophage (AM) function is believed to play an important role in the pathogenesis of this disease. Recently, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, has been shown to down-regulate the expression of inflammatory mediators from monocytes/macrophages, including AM. The role of PPAR-gamma in regulating pulmonary inflammation in ALl has not been investigated, and is the focus of this application. The central hypothesis of this proposal is that the activation state of AM in ALl is regulated by PPAR-gamma, which functions to dampen the magnitude of AM inflammatory responses in ALl. Furthermore, determining the activation state of AM during the course of ALl may serve as an independent predictor of subsequent clinical outcomes in this disease. In this application, we will employ a bench-to-bedside approach utilizing both animal models and human studies involving patients with ALI/ARDS to address the following Specific Aims: 1) to assess the expression and regulation of PPAR-gamma in AM during experimental murine FITC-induced ALl; 2) to determine the role of PPAR-gamma in regulating AM activation state in murine FITC-induced ALl; 3) to prospectively correlate PPAR-gamma expression/activity with the magnitude of pulmonary inflammation, the expression of endogenous ligands, and clinical outcomes in patients with ALI/ARDS; 4) to determine the contribution of PPAR-gamma to functional AM phenotypic changes in patients with ALI/ARDS; and 5) to determine whether PPAR-gamma polymorphisms alter disease susceptibility and/or the clinical course of disease in patients with ALI/ARDS. The performance of studies proposed in this application will provide important insights into the control of pulmonary inflammation in ALl, which may lead to novel approaches to both the assessment and treatment of this devastating disease.