Programs and cores

Project 1 : Dynamic Effects of Chemokines on Systemic Inflammation

Project 2: Macrophage Activation /Deactivation in ALI

Project 3: Alveolar Mesenchymal Cells in Acute Lung Injury

Project 4: A Randomized Trial of GM-CSF in Patients with ALI

Core A: Clinical Core

Administrative Core

Macrophage Activation/Deactivation in ALI; Theodore J. Standiford, PI.

A hallmark of ALI/ARDS is 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 the exact mechanism(s) that control intraalveolar inflammation in acute lung injury (ALI) remains unclear, dysregulation of alveolar macrophage function is believed to play a central role in disease pathogenesis. Recently, peroxisome proliferator-activated receptor-gamma (PPAR- g ), 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. The studies in Project 2 have focused on PPAR- g because preliminary data have identified this transcription factor as a critical regulator of alveolar macrophage effector cell function and alveolar macrophage-mediated inflammation in ALI. The hypothesis of Project 2 is that the activation state of alveolar macrophages in ALI is regulated by PPAR- g , which functions to dampen the magnitude of alveolar macrophage inflammatory responses in ALI. Furthermore, it is postulated that determining the activation state of alveolar macrophages during the course of ALI may serve as an independent predictor of subsequent clinical outcomes in this disease. In Aims 1 and 2 of this project, an animal model of FITC-induced lung injury will be utilized to assess the expression, regulation, and function of PPAR- g in experimental lung injury. In studies using samples collected from patients with ALI/ARDS, PPAR- g expression/activity in alveolar macrophages will be correlated with the magnitude of pulmonary inflammation, the expression of endogenous ligands, and clinical outcomes in these patients. Additionally, the contribution of PPAR- g to functional alveolar macrophage phenotypic changes will be determined using inhibitor experiments. In final studies, we will determine if specific loss of function polymorphisms in PPAR- g alter disease susceptibility and/or clinical course of disease in patients with ALI/ARDS. Collectively, the studies proposed in Project 2 will provide novel insights into the role of PPAR- g in regulating alveolar macrophage inflammatory responses that are critical to the pathogenesis of ALI.

PROJECT ABSTRACTS

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 (ALI) 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- g ), 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- g in regulating pulmonary inflammation in ALI 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 ALI is regulated by PPAR- g , which functions to dampen the magnitude of AM inflammatory responses in ALI. Furthermore, determining the activation state of AM during the course of ALI 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- g in AM during experimental murine FITC-induced ALI; 2) to determine the role of PPAR- g in regulating AM activation state in murine FITC-induced ALI; 3) to prospectively correlate PPAR- g 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- g to functional AM phenotypic changes in patients with ALI/ARDS; and 5) to determine whether PPAR- g 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 ALI, which may lead to novel approaches to both the assessment and treatment of this devastating disease.