Dose-Dependent Effect of Ethanol on Hepatic Oxidative Stress and Interleukin-6 Production After Burn Injury in the Mouse Alessandra Colantoni, Lisa A. Duffner, Nicola De Maria, Christine V. Fontanilla, Kelly A. N. Messingham, David H. Van Thiel, and Elizabeth J. Kovacs Background: Burned patients with detectable blood alcohol levels (BAL) show an elevated mortality rate. Interleukin (IL)-6 and reactive oxygen species (ROS) production is stimulated independently by alcohol and burn injury. The aim of the study was to determine whether increasing levels of alcohol differentially enhance the hepatic production of IL-6 and ROS after burn in a murine model of dorsal scald injury. Groups of mice received either saline or alcohol intraperitoneally to reach a BAL of 100 mg/dl or 300 mg/dl at the time of burn (15% total body surface scald) or sham injury. Results: Burn injury alone resulted in a low mortality rate at 24 hr after injury as did the burn group with a BAL of 100 mg/dl (15%), whereas 57% of the mice burned with a BAL of 300 mg/dl did not survive (p = 0.02). Twenty-four hours after burn or sham injury, IL-6 levels were measured by enzyme-linked immu- nosorbent assay in serum and liver. In the saline-treated group, IL-6 circulating and hepatic levels rose after burn injury (p  0.03). Circulating IL-6 levels in sham mice increased 1.5-fold in the group with a BAL of 100 mg/dl and 3-fold in those with a BAL of 300 mg/ml (p = 0.005 versus burn-injured, saline-treated). IL-6 hepatic production after burn injury was higher in the mice with a BAL of 300 mg/dl than in those with a BAL of 100 mg/dl and the saline-treated group (p = 0.001). Among the burned mice, alcohol exposure increased hepatic ROS production, measured by lipid peroxidation and protein oxidation, in a dose- dependent manner. Conclusions: Alcohol enhances in a dose-dependent manner the hepatic production of IL-6 induced by burn injury through the modulation of oxidative stress. The increased mortality rate of mice exposed to alcohol and burn injury may be due to the adverse effect on immune function induced by IL-6 elevation. Key Words: Alcohol, Burn, Liver, Interleukin-6, Lipid Peroxidation. A PERCENTAGE RANGING from 30 to 55 of the subjects admitted to the hospital for trauma have detectable blood alcohol levels (BAL) (Carrigan et al., 2000; Thal et al., 1985). Approximately half of the patients with thermal injury have a BAL ranging from 50 mg/dl, below the legal limit of 80 to 100 mg/dl, to 320 mg/dl, a BAL seen in subjects with severe ethanol intoxication (Haum et al., 1995). Alcohol intake identifies a patient population at high risk for death within the first 48 hr after thermal injury (Raff et al., 1996). Moreover, among these patients, the length of hospital stay is greater and the development of fatal infections and other complications is more frequent than that of burned subjects without alcohol in their blood (McGill et al., 1995). Inflammatory mediators play a major role in the systemic response to burn injury. Cytokines are important modula- tors of the physiological and pathological events that follow burn injury, and an increase in their blood levels has been documented. In particular, the circulating levels of inter- leukin (IL)-6 are elevated in thermally injured subjects (Ueyama e al, 1992; Yeh et al., 1999). IL-6 stimulates the acute phase response and is responsible for initiating the cascade of proinflammatory mediator production (Maher, 1999). Nevertheless, the elevation of IL-6 circulating levels induced by burn injury has been implicated in the patho- genesis of immunosuppression after injury (Faunce et al., 1998a; Gregory et al., 2000). In humans, as well as in animal models of injury, elevated blood IL-6 is associated with high mortality rates. A series of studies report a significant difference in serum IL-6 values on admission (within the first 13 hr posttrauma) between patients who survived or died as a result of burn injury (Drost et al., 1993; Gueug- niaud et al., 1997; Yeh et al., 1999). Among survivors, the increment and the peak of IL-6 at 6 hr after burn injury is less prominent than in nonsurvivors (Ueyama et al., 1992). From the Division of Gastroenterology and Hepatology (A.C., N.D.M., D.H.V.T.), Department of Medicine, and Cell Biology Neurobiology and Anatomy (L.A.D., C.V.F., K.A.N.M., E.J.K.), Immunology and Aging Pro- gram, Loyola University Chicago, Maywood, Illinois. Received for publication March 6, 2000; accepted June 28, 2000. Supported by Grants AA11134 and AA12034 from the National Institutes of Health. Reprint requests: Alessandra Colantoni, MD, Gastroenterology and Hepa- tology, Loyola University Medical Center, 2160 South First Ave., Building 114 Room 48, Maywood, IL 60153; Fax: 708-216-0423; E-mail: acolan@lumc.edu Copyright © 2000 by the Research Society on Alcoholism. 0145-6008/00/2409-1443$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 24, No. 9 September 2000 Alcohol Clin Exp Res, Vol 24, No 9, 2000: pp 1443–1448 1443