Abstract
Studies have shown that burn patients who are intoxicated at the time of injury are more susceptible to infection and have a higher incidence of mortality. A major cause of death in burn and trauma patients regardless of their alcohol (EtOH) exposure is multiple organ dysfunction, which is driven in part by the systemic inflammatory response and activated neutrophils. Neutrophils are short lived and undergo apoptosis to maintain homeostasis and resolution of inflammation. A delay in apoptosis of neutrophils is one important mechanism which allows for their prolonged presence and the release of potentially harmful enzymes. The purpose of this study was to examine whether EtOH intoxication combined with burn injury influences neutrophil apoptosis and whether IL-18 plays any role in this setting. To accomplish this investigation, rats were gavaged with EtOH (3.2 g/kg) 4 h before being subjected to sham or burn injury of ~12.5% of the total body surface area, and then killed on d 1 after injury. Peripheral blood neutrophils were isolated and lysed. The lysates were analyzed for pro- and antiapoptotic proteins. We found that EtOH combined with burn injury prolonged neutrophil survival. This prolonged neutrophil survival was accompanied by a decrease in the levels of the neutrophil proapoptotic protein Bax, and an increase in antiapoptotic proteins Mcl-1 and Bcl-xl. Administration of IL-18 antibody following burn injury normalized the levels of Bax, Mcl-1 and Bcl-xl. The decrease in caspase-3 and DNA fragmentation observed following EtOH and burn injury was also normalized in rats treated with anti-IL-18 antibody. These findings suggest that IL-18 delays neutrophil apoptosis following EtOH and burn injury by modulating the pro- and antiapoptotic proteins.
Highlights
Major trauma remains a leading cause of death in humans of all ages
An ~50% decrease in Bax levels was observed in neutrophils from rats that received vehicle plus burn injury compared with sham animals gavaged with water
In the present study, we have shown that EtOH intoxication combined with burn injury decreases neutrophil apoptosis by modulating pro- and antiapoptotic proteins of the neutrophils
Summary
Major trauma remains a leading cause of death in humans of all ages. Approximately one million burn injuries are reported every year within the United States, and nearly half of them occur in individuals who are under the influence of alcohol/ethanol (EtOH) [1,2,3]. Chronic EtOH exposure sensitizes Kupffer cells, the resident macrophages in liver, to activation by lipopolysaccharide (LPS). This sensitization increases the production of proinflammatory mediators, such as tumor necrosis factor-α (TNF-α) and reactive oxygen species, that contribute to hepatocyte dysfunction and induction of apoptosis [14]. We found that EtOH intoxication combined with burn injury delays neutrophil apoptosis [11]. This effect was accompanied by marked neutrophil accumulation in intestinal tissue [15]. Antiapoptotic proteins Bcl-2 and Bcl-xl, from the Bcl-2 family, inhibit the release of cytochrome c from the mitochondria
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