The acute respiratory distress syndrome (ARDS) is a severe form of acute edematous lung injury that afflicts approximately 150,000 individuals per year in the United States. Despite three decades of research concerning ARDS, there are presently no effective therapies and the mortality from this syndrome remains unacceptably high at 40-60 percent. The ability of the lung to neutralize the harmful effects of oxygen radicals has been postulated to be a critical step in preventing the development and decreasing the severity of ARDS. Initially, we hypothesized that the presence of pre-existing co-morbid conditions, which independently reduce the anti-oxidant capacity of the lung, will result in an increased incidence and severity of ARDS in critically ill patients. We have previously reported that chronic alcohol abuse, without hepatic dysfunction, decreases pulmonary glutathione concentrations and alters surfactant function in both animals and humans, and increases the incidence and severity of ARDS in critically ill patients. Based on the profound effects of chronic hepatic dysfunction on systemic glutathione homeostasis, we hypothesize that cirrhosis secondary to chronic alcohol abuse will lead to a dramatic reduction in pulmonary glutathione reserve with subsequent impairment of surfactant function, thereby markedly increasing the risk of critically ill cirrhotic patients to develop ARDS. In this first part of this proposal, we will determine lung lavage glutathione concentrations and surfactant properties in control subjects and patients with clinically stable cirrhosis. In the second part of the proposal, we will examine how cirrhosis alters the pulmonary response to sepsis. Finally, we will further explore the epidemiological association between cirrhosis and ARDS using a large national database. The results of these studies will create a strong foundation of evidence supporting the potential use of glutathione replacement therapy to decrease lung injury in patients with cirrhosis secondary to alcohol abuse.
| Foreman, Marilyn G; Mannino, David M; Moss, Marc (2003) Cirrhosis as a risk factor for sepsis and death: analysis of the National Hospital Discharge Survey. Chest 124:1016-20 |
| Foreman, Marilyn G; Hoor, Terri Ten; Brown, Lou Ann S et al. (2002) Effects of chronic hepatic dysfunction on pulmonary glutathione homeostasis. Alcohol Clin Exp Res 26:1840-5 |
