Recent epidemiological studies demonstrated that chronic alcohol abuse increases the morbidity and mortality from acute respiratory distress syndrome (ARDS). In clinical specimens, we demonstrated that chronic alcohol abuse was associated with a dramatic decrease in the antioxidant glutathione (GSH) in the fluid lining the alveolar epithelium. In an animal model, we demonstrated that chronic ETOH ingestion specifically decreased GSH in the alveolar epithelial type II (AT2) cell, a pulmonary cell critical in maintenance of pulmonary function and repair of acute lung injury. This ETOH-induced decrease in GSH of the AT2 cell then potentiated the effects of cytotosin-induced apoptosis and necrosis. In hepatocytes, the central feature of ETOH- induced hepatocyte toxicity is inhibited GSH transport from the cytoplasmic pool to the mitochondrial pool resulting in increased mitochondrial reactive oxygen species (ROS) generation and compromised mitochondrial functional integrity. We propose a similar paradigm for the ling, i.e. that the central feature of chronic ETOH toxicity to the AT2 cell is inhibition of mitochondrial GSH transport. However, it is the up regulation of mitochondrial ROS generation that sensitizes the cell to cytotoxins. The led to the following hypothesis: as mitochondrial GSH decreases with extended ETOH ingestion 1) mitochondrial ROS generation is initiated and 2) the subsequent mitochondrial ROS generation sensitizes the AT2 cell to the cytotoxins up regulated during sepsis, the major risk factor for ARDS. Such a scenario suggest a two hit model and provides a mechanism by which chronic ETOH alone does not alter pulmonary function but potentiates sepsis-induced acute lung injury. As the mitochondrial GSH availability decreases during ETOH ingestion, the ROS generated during respiration and during ETOH metabolism to acetaldehyde will accumulate and result in mitochondrial ROS generation (Aim 1). With increased mitochondrial ROS generation, mitochondrial function becomes compromised and sensitizes the AT2 cell to the cytotoxic agents up regulated during sepsis (Aim 2). If the mitochondrial ROS generation is secondary to mitochondrial GSH availability, then maintenance or restoration of the mitochondrial GSH pool should block ETOH-induced mitochondrial ROS generation. Inhibition of ETOH-induced ROS generation should then normalize mitochondrial function and desensitize the ETOH-exposed AT2 cells to cytotoxic agents.
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