ETOH Abuse

Ingested ethanol (EtOH) rapidly enters the bloodstream and freely enters various tissue compartments. Chronic ethanol ingestion and metabolism can lead to an altered cellular redox state due to increased production of reactive oxygen species (ROS) by Kupffer cells (KC) and translocation of bacteria and endotoxin (lipopolysaccharide, LPS). LPS signalling through Toll-like receptor 4 (TLR4) leads to the release of pro-inflammatory cytokines (tumour-necrosis factor- (TNF-) and interleukin-1 (IL-1)) and chemokines (IL-8 and monocyte chemoattractant protein-1). These events are thought to be crucial in the development of chronic liver disease. Local production of TNF- can also induce the local production of the suppressor of cytokine signalling 3 (SOCS3), which can inhibit STAT (signal transducers and activators of transcription) signalling and so lead to the resistance of alcoholic liver disease patients to type-I interferons. Ethanol also results in the loss of splenic and circulating T and B cells, partly through apoptosis. In the lung compartment, ethanol suppresses the production of pro-inflammatory cytokines by the alveolar macrophages (AM) and of IL-17 by T cells in lung tissue or bronchiole-associated lymphoid tissue (BALT), which results in a diminished cytokine/chemokine cascade and hence defective polymorphonuclear leukocyte (PMN) recruitment and host defence. NF-B, nuclear factor-B.