Macrophage Activation/Deactiviation in ALI

ALI 中的巨噬细胞激活/失活

• 批准号: 7108653
• 负责人: Theodore J. Standiford
• 金额: $ 27.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108653
• 关键词: adult respiratory distress syndrome; alveolar macrophages; biological signal transduction; clinical research; fluorimetry; genetic polymorphism; genetic susceptibility; human subject; inflammation; laboratory mouse; leukocyte activation /transformation; lung injury; macrophage activating factor; peroxisome proliferator activated receptor; receptor expression

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.

急性呼吸窘迫综合征（ARDS）是以肺功能亢进为特征的一种呼吸系统疾病。 炎症和肺泡-毛细血管膜损伤，这可能导致肺修复失调（纤维增生）和医院感染，特别是肺炎的发展。虽然在急性肺损伤（AL 1）中控制肺内炎症的机制仍不清楚，但据信肺泡巨噬细胞（AM）功能的失调在该疾病的发病机制中起重要作用。最近，过氧化物酶体增殖物激活受体-γ（PPAR-gamma），配体依赖性转录因子的核受体超家族的成员，已被证明下调来自单核细胞/巨噬细胞（包括AM）的炎性介质的表达。PPAR-gamma在调节AL 1中的肺部炎症中的作用尚未研究，并且是本申请的焦点。 该提议的中心假设是，AL 1中AM的活化状态受PPAR-gamma调节，PPAR-gamma起到抑制AL 1中AM炎症反应的程度的作用。此外，确定AL 1过程中AM的激活状态可作为该疾病后续临床结果的独立预测因子。 在本申请中，我们将采用实验室到床边的方法，利用动物模型和涉及患有ALI/ARDS的患者的人研究来解决以下具体目的：1）评估实验性鼠FITC诱导的AL 1期间AM中的PPAR-gamma的表达和调节; 2）确定PPAR-gamma在调节鼠FITC诱导的AL 1中的AM活化状态中的作用; 3）前瞻性地将PPAR-gamma表达/活性与ALI/ARDS患者的肺部炎症程度、内源性配体表达和临床结果相关联; 4）确定PPAR-gamma对ALI/ARDS患者的预后的贡献。 在ALI/ARDS患者中功能性AM表型改变;和5）确定PPAR-gamma多态性是否改变ALI/ARDS患者的疾病易感性和/或疾病的临床过程。在本申请中提出的研究的性能将提供对AL 1中肺部炎症的控制的重要见解，这可能导致评估和治疗这种毁灭性疾病的新方法。