Redundant Mechanisms of Multi-Organ Injury

Excessive and frequent alcohol consumption has increasingly been linked to alcohol-associated tissue injury and pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal and in vitro models has elucidated the salient mechanisms involved in alcohol-induced tissue and organ injury. In some cases, these pathophysiological mechanisms are shared across organ systems. The mechanisms implicated in alcohol-induced multiorgan injury are multifactorial and are frequently shared across organ systems, and depend on several factors, including genetics, sex, tissue and cell type, and patterns of alcohol use. The health care burden due to at-risk alcohol use is influenced not only by the well-recognized risk for the development of alcohol addiction and ALD but also by its effects on the development of organ injuries and diseases, including cardiovascular disease and diabetes, FAS, pancreatic disease, respiratory disease, and cancer. This conference focuses on recent advances in some of the most critical pathophysiological mechanisms of alcohol-induced organ injury. Key discussion topics include:

Tissue regeneration and repopulation by stem cells are essential for the maintenance of normal structure and physiology of organs, and alcohol perturbs these complex regenerative mechanisms.

Cell death and survival pathways are significantly altered by at-risk alcohol use and contribute to impaired immune responses and multiorgan injury.

The risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption. Among modifiable risk factors for cancer risk, following cigarette smoking and excess body weight (both strongly associated with alcohol use), alcohol consumption ranks third.

Among the oldest recognized pathophysiological consequences of at-risk alcohol use are impaired host immune defense mechanisms. Alcohol decreases host immune response to infections and increases morbidity and mortality from viral and bacterial infections, including pneumonia.

The gut microbiome plays a critical role in endocrine and neurological functions. It preserves barrier integrity, limiting pathogen dissemination; promotes maturation; maintains and stimulates host defense; contributes to amino acid and vitamin synthesis; and is involved in toxin and drug metabolism and macromolecule catabolism.

Alcohol dysregulates multiple mechanisms involved in energy metabolism homeostasis at the cellular and whole-body levels. Mitochondrial dysfunction contributes to alcohol-mediated pathophysiology in mitochondria-rich tissues.

Alcohol metabolism and elimination through various pathways generate toxic by-products that, in turn, can promote tissue and cell injury.

Alcohol dysregulates matrisome proteins in multiple organs, favoring a profibrotic phenotype predisposing to fibrosis. Several studies demonstrate that extracellular matrix (ECM) remodeling is one of the major mechanisms underlying the development of ALD.