The Adult Respiratory Distress Syndrome (ARDS) continues to be a major cause of morbidity and mortality in the United States and its most common cause is sepsis syndrome. There is reason to believe that tumor necrosis factor alpha (TNFalpha) and other cytokines are directly involved in oxidant stress. Depletion of glutathione in these closely related syndromes may be a fundamental process in their development. TNFalpha has been implicated as a major mediator of lung injury following sepsis and anti-TNF has been successful in preventing pathophysiologic changes and death in animal models of bacterial and endotoxemia shock. In the current studies, we propose to use an ovine polyclonal Fab purified antibody to TNF to study patients with early ARDS who will be randomized to receive either placebo or glutathione therapy in order to increase glutathione concentrations in red cells, plasma and alveolar lining fluid in order to increase glutathione reserve and hence resistance to oxidant stress. Employing both trials as tools, we will explore the relevance of TNFalpha and glutathione to other specimens from patients enrolled in these studies, we will examine the development of lung inflammation in sepsis and its progress and resolution in ARDS. In addition to the biochemical parameters, the results of these studies will be used to determine the feasibility of using these approaches in the therapy of sepsis and ARDS.
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