Investigators in this Center Application have identified chronic alcohol abuse as a co-morbid variable that significantly increases the incidence and severity of the Acute Respiratory Distress Syndrome (ARDS). The overall theme of this Center application postulates that chronic ethanol ingestion enhances the risk of alveolar flooding in response to inflammatory mediators and activated neutrophils. This suggests a """"""""two-hit"""""""" model wherein chronic ethanol ingestion constitutes the first hit but does not generate pulmonary dysfunction. However, the first hit does predispose the lung to an enhanced response to the inflammatory mediators and activated neutrophils produced during sepsis. We postulate that one mechanism by which chronic ethanol ingestion predisposes the lung to endothelial barrier dysfunction involves ethanol-induced decreases in the availability of the antioxidant glutathione (GSH), particularly the mitochondrial pool in pulmonary microvascular endothelial cells (MVEC). When GSH availability decreases, the reactive oxygen species (ROS) generated during normal respiration and ethanol detoxification becomes amplified. With chronic exposure to ROS, the MVEC is altered and the basal expression of adhesion molecules are upregulated. During sepsis, the adhesion of the activated neutrophils and the microenvironment is potentiated. The ethanol-induced GSH depletion then amplifies the ROS produced resulting in mitochondrial dysfunction and decreased ATP generation. With limited ATP availability, the MVEC are more susceptible to cytotoxin- and neutrophil-induced apoptosis and necrosis. When MVEC death is enhanced, barrier dysfunction and neutrophil migration is potentiated. Furthermore, we propose that GSH precursors will attenuate this enhanced endothelial:neutrophil interaction and result in decreased sepsis-induced acute lung injury. Using a rat model of chronic ethanol ingestion, three Specific Aims will explore this hypothesis to determine: 1) if chronic ethanol ingestion potentiates inflammatory mediator-induced oxidative stress in MVEC, 2) if ethanol-induced chronic ROS up regulates MVEC adhesion factor expression and neutrophil transmigration during sepsis and 3) if intervention with GSH precursors will attenuate ethanol potentiation of adhesion factor expression and neutrophil transmigration during sepsis. This proposal will improve our understanding of the relationship between alcohol and lung injury and potentially identify strategies for ARDS prevention and treatment.
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