Antioxidant Replacement Therapy in Patients With Alcohol Abuse

Alcohol is one of the most commonly abused drugs in the world. Up to 40% of medical and
surgical patients have alcohol related problems, and alcohol use accounts for more than 10%
of U.S. health care costs. In the intensive care unit (ICU), patients with a history of
alcohol abuse are common where their rates of mortality and ICU-related morbidity are
significantly higher when compared to patients without a history of alcohol abuse. Though
ICU patients are a heterogeneous group, Acute Respiratory Distress Syndrome (ARDS), a
devastating form of acute lung injury, is one of the more frequent diagnoses among these
critically ill patients.

In 1996, we made the novel observation that a prior history of chronic alcohol abuse is
associated with an increased incidence and severity of ARDS in critically ill patients. In
our epidemiological studies of over 570 critically ill patients, 50% of all patients with
ARDS have a significant history of chronic alcohol abuse. Since ARDS affects approximately
150,000 patients per year in the United States, and mortality is 40-50% even in previously
healthy individuals, alcohol-related ARDS is an enormous national health care problem. We
estimate that between 15,000 and 25,000 deaths per year in the United States are associated
with alcohol-related ARDS, a number consistent with or even exceeding the number of deaths
due to many other alcohol-related diseases such as cirrhosis of the liver and
alcohol-related traffic accidents. Further investigations of the association between chronic
alcohol abuse and ARDS are needed to develop therapies that improve morbidity and mortality
in this important patient population.

The clinical syndrome of ARDS is defined as refractory hypoxemia with bilateral infiltrates
on chest radiograph in the absence of left atrial hypertension. Pathophysiologically, ARDS
is characterized by diffuse alveolar damage, increased pulmonary alveolar-capillary
permeability, and the subsequent accumulation of extravascular lung water. In animal models
of chronic alcohol abuse, we showed that chronic ethanol ingestion causes chronic oxidative
stress, depletes lung glutathione, impairs alveolar-capillary barrier function, and
exaggerates endotoxin-mediated acute lung injury. Ethanol-mediated disruption of the
alveolar-capillary barrier, and the associated susceptibility to acute edematous injury, is
modified by glutathione (GSH) replacement therapy in animal models.

Responding to NIH emphasis on studies of the mechanisms of disease and evaluation of
therapies in human subjects, our group has initiated translational studies that expand our
basic observations of the effects of chronic alcohol abuse on ARDS to the clinical setting.
We recently reported that lung epithelial lining fluid from individuals with a prior history
of chronic alcohol abuse is deficient in GSH, an essential antioxidant. The translational
experiments outlined in this proposal will identify alterations in the structure and
function of the lung in individuals with a history of chronic alcohol abuse and test a novel
medical therapy that may ultimately decrease the morbidity and mortality for 50,000-75,000
ARDS patients with a prior history of chronic alcohol abuse per year in the United States.

We propose the following hypothesis that antioxidant deficiency is a cause of abnormal
alveolar-capillary barrier function in individuals with a history of chronic alcohol abuse,
and oral anti-oxidant replacement therapy will correct the abnormality.

If this hypothesis can be confirmed, this work would pave the way for testing antioxidant
replacement as prophylaxis against acute lung injury in alcoholic patients at risk for the
development of ARDS.

Specific Aim: To determine the safety and efficacy of in vivo antioxidant replacement
therapy on alveolar-capillary barrier function in individuals with a history of chronic
alcohol abuse.