Abstract
Sepsis is a major cause of mortality worldwide. Acute or chonic ethanol exposure typically suppresses innate immunity and inflammation and increases the risk of mortality in patients with sepsis. The study described here was designed to address the mechanism(s) by which acute ethanol exposure alters the course of sepsis. Ethanol administered to mice shortly before Escherichia coli (injected ip to produce sepsis) decreased production of proinflammatory cytokines and chemokines for several hours. Bacteria in the peritoneal cavity decreased over time in control mice and were mostly cleared by 21 h, but in ethanol-treated mice, bacteria increased over time to more than 2 × 10(8) at 21 h. Killing of bacteria in macrophages and neutrophils was apparently compromised by ethanol, as the percentage of these cells that had cleared phagocytosed bacteria increased over time in control mice but not in ethanol-treated mice. The roles of TLR4, MyD88, and myeloperoxidase (MPO) were evaluated using mutant or knockout mice, and these experiments indicated that mice with hyporesponsive TLR4 survived better than those with normal TLR4. Lack of MyD88 or MPO did not significantly alter survival in the presence or absence of ethanol. Ethanol decreased survival in all groups. This indicates that the antimicrobial activities induced though TLR4 are dispensable for survival but contribute to lethality late in the course of sepsis. Thus, the effects of ethanol responsible for lethal outcome in sepsis are not dependent on inhibition of TLR4 signaling, as we and others had previously suspected.