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

A Randomized Trial of GM-CSF in Patients with ALI; Robert Paine, III, PI.

Despite significant progress in intensive care unit care and ventilator management, respiratory failure due to ALI and ARDS remains a major health problem, with unacceptably high mortality despite enormous expenditure of health care resources. Survivors face long term consequences for quality of life. New therapies are needed both to improve early survival and to decrease long term sequelae of this syndrome. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a naturally occurring cytokine that is present in the normal lung, with important roles in pulmonary homeostasis. GM-CSF is essential for normal maturation and function of alveolar macrophages, resident inflammatory cells that are responsible for initial defense against pneumonia. Alveolar epithelial cells line the gas exchange surface of the lung. Injury and delayed repair of damage to this epithelium is an important mechanism of acute lung injury and subsequent abnormal healing, leading to pulmonary fibrosis. GM-CSF has potent effects on alveolar epithelial cells, promoting proliferation and limiting epithelial cell death. Thus, GM-CSF has a distinctive combination of activities making it an excellent candidate for a therapeutic intervention in ALI/ARDS. Preliminary studies for this project demonstrate that GM-CSF can protect experimental animals against acute lung injury, can decrease susceptibility to pneumonia, and is protective against pulmonary fibrosis following acute lung injury. There is extensive experience with the administration of recombinant human GM-CSF to human patients; this biological is approved by the FDA has been well-tolerated in trials involving critically ill patients. This project is based on the hypothesis that administration of GM-CSF will improve clinical outcomes for patients with ALI/ARDS. A randomized, placebo-controlled trial of GM-CSF is being performed to determine whether treatment with GM-CSF for 14 days will shorten the duration of mechanical ventilation for patients with ALI/ARDS, allowing patients to breath without ventilator support earlier in their course. Additional endpoints to be evaluated include effects on the incidence of newly acquired pneumonia in the ICU, mortality, and parameters of alveolar macrophage and alveolar epithelial cell function. Finally, quality of life and incidence of pulmonary fibrosis after 6 months will be assessed in survivors. Patients enrolled in this study will receive mechanical ventilation according to a standardized protocol. Periodically, they will have blood drawn and undergo bronchoscopy for studies to evaluate in more detail the mechanisms of GM-CSF effects. When completed, these Specific Aims will determine whether treatment with recombinant GM-CSF will improve outcome in these critically ill patients, and will determine through which of several potential mechanisms GM-CSF is acting.

PROJECT ABSTRACTS

Despite significant progress in intensive care unit care and ventilator management, respiratory failure due to acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) remains a major health problem, with approximately >30% mortality despite enormous expenditure of health care resources. Survivors face long term consequences for quality of life. New therapies are needed both to improve early survival and to decrease long term sequelae of this syndrome. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a multifunctional cytokine that is present in the normal lung, with important roles in pulmonary homeostasis. GM-CSF has a distinctive combination of activities making it an ideal candidate for a therapeutic intervention in ALI/ARDS. It is essential for normal maturation of alveolar macrophages and has potent effects on alveolar epithelial cells, promoting proliferation and limiting epithelial cell death. Preliminary studies for this application demonstrate that GM-CSF can protect mice against acute lung injury, can decrease susceptibility to pneumonia, and is protective against pulmonary fibrosis following acute lung injury. There is extensive experience with the administration of recombinant human GM-CSF to human patients; this biological is approved by the FDA has been well-tolerated in trials involving critically ill patients. This proposal is based on the hypothesis that administration of GM-CSF will improve clinical outcomes for patients with ALI/ARDS. A randomized, placebo-controlled trial of GM-CSF (250 mcg/M2/day x 14 days) will be performed with 5 Specific Aims. These Aims will determine the effect of treatment with GM-CSF on: 1) days free of mechanical ventilation (days 1-28) (the primary endpoint of this study), mortality, ICU stay, and incidence of ventilator-associated pneumonia; 2) physiologic variables associated with respiratory failure; 3) parameters of alveolar epithelial dysfunction; 4) alveolar macrophage function for host defense in the context of ARDS; 5) quality of life and progression to fibrosis in survivors of ARDS. For each patient enrolled, clinical parameters (both acute and late) and serial bronchoalveolar lavage specimens will be collected. When completed, these Specific Aims will determine whether treatment with recombinant GM-CSF will improve outcome in these critically ill patients, and will determine through which of four potential mechanisms GM-CSF is acting.