Project 3's long term goal is to develop new interventions that can favorably change the oxidant-antioxidant imbalance in subgroups of patients at risk for ARDS and characterized by high oxidant stress in order to prevent ARDS from occurring and, if it does occur in these patients, to reduce its severity and associated morbidity and mortality. Project 3 has the following four Specific Aims: 1. To test the hypothesis that elevated levels of selected biomarkers of oxidant stress are risk factors for the development of acute lung injury (ALI) or ARDS after trauma or sepsis, two nested case-control studies will be conducted within prospective cohorts of patients with trauma or sepsis. Levels of three biomarkers, serum protein 3-nitrotyrosine and carbonyls, and a urinary isoprostane (IPF2 alpha-I), will be related to the subsequent occurrence of ALI or ARDS in a multivariate statistical model. Controls will be selected from the same target population and control samples for biomarker analysis will be matched with cases on the basis of being from the same time after onset of trauma or sepsis. 2. To test the hypothesis that elevations in selected biomarkers of oxidant stress coincide with the onset of ALI/ARDS after major trauma or severe sepsis, two nested case-control studies will be conducted within the same cohorts described in Specific Aim 1. Levels of the same biomarkers (as listed above) from the first 48 hours after the onset of ALI or ARDS in cases will be compared with those obtained from matched controls. 3. To test the hypothesis that elevated levels of biomarkers of oxidant stress at the onset of ARDS due to trauma or sepsis are risk factors for prolonged respiratory failure, organ system failure and mortality, the same biomarkers listed in Specific Aim 1 at the onset of ARDS in patients due to trauma or sepsis will be compared (by multivariate statistical methods) with three outcomes (all at 28 days after onset of ARDS): 1. ventilator-free days, 2. organ failure free days and 3. mortality. 4. To test the hypothesis that administering a systemic anti-oxidant decreases the levels of biomarkers of oxidant stress in patients with ARDS due to trauma or sepsis, a randomized, double-blinded, placebo controlled study will be conducted to assess the effects of dl-alpha-tocopherol on the biomarkers in Specific Aim 1 in early ARDS due to trauma or sepsis.
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