New Search

Name:	Lou Ann S. Brown
Position:	Professor of Pediatrics
Degree:	Ph.D., St. Louis University, 1980
Programs:	NHS, Full Member MSP, Full Member
Phone:	404 727-5739
Address:	Room 170, 2040 Ridgewood Drive, 2172/003/1AA
Email:	lbrow03@emory.edu
Research Descriptions:
Short:	Impact of alcoholism (adult and fetal) on pulmonary oxidant injury.
Long:	Recently, a history of chronic alcohol abuse has been shown to be the first co-morbid variable that significantly increases the incidence and severity of Acute Respiratory Distress Syndrome (ARDS). Despite modest decreases in the plasma glutathione of non-cirrhotic patients, decreased availability for pulmonary transport resulted in an 80% decrease in glutathione in the fluid lining the alveolar surface. In an ethanol-fed rat model, chronic ethanol ingestion increased susceptibility sepsis-induced acute lung injury. Although many different cell types are likely altered by chronic ethanol exposure, we initially focused on the type II cell because of the many different roles this cell type plays in pulmonary function and repair. The glutathione pool in type II cells was decreased by 60% after 16 weeks of ethanol ingestion. Although the cytosolic glutathione pool was decreased during ethanol ingestion, the mitochondrial glutathione pool was dramatically decreased as a result of ethanol inhibition of mitochondrial glutathione uptake. Decreased mitochondrial glutathione then resulted in increased mitochondrial production of reactive oxygen species, particularly when sepsis was superimposed on ethanol ingestion. Increased mitochondrial reactive oxygen species generation then resulted in mitochondrial dysfunction, sensitization of the cell to the cytotoxins up regulated during sepsis and increased apoptosis and necrosis. The role of mitochondrial glutathione in this process was supported by the differential capacities of glutathione precursors to restore the mitochondrial glutathione pool and decrease the risk of sepsis-induced reactive oxygen species generation and type II cell apoptosis and necrosis. The alteration of mitochondrial ATP generation by chronic ethanol exposure is currently under intense study. Another hallmark of ARDS is excessive alveolar matrix deposition and turnover. Since ethanol-induced glutathione depletion altered homeostasis of the hepatic basement membrane, we proposed that a similar paradigm occurred in the lung. After chronic ethanol ingestion, type II cells generated an extracellular matrix with altered composition and decreased susceptibility against proteases. When acute endotoxemia was superimposed on chronic ethanol ingestion, there was increased matrix metalloproteinase activity and basement membrane fragments in the lavage fluid. Furthermore, the extracellular matrix generated by type II cells isolated from ethanol-fed rats promoted fibroblast adherence and activation. One mechanism by which the extracellular matrix generated by ethanol-exposed type II cells promoted fibroblast adherence and activation was through the production of fibronectin. Thus, the ethanol induced type II cells to produce excessive matrix proteins as well as produce a matrix that potentiated the release of fibrotic proteins from fibroblasts. The capacity of glutathione precursors to maintain extracellular matrix homeostasis during ethanol ingestion suggests that glutathione availability is an important modulator of these events. These studies have also been extended to determine if chronic alcohol exposure in utero increases the risk of acute lung injury when superimposed on a second insult such as sepsis, mechanical ventilation or oxygen therapy. Using a preterm guinea pig model, we have shown that chronic ethanol exposure resulted in decreased glutathione availability in the fluid lining the lung and the type II cell. Such dramatic decreases in these important glutathione pools were associated with increased risk of pulmonary oxidative injury during oxygen therapy. In addition to altered glutathione homeostasis, chronic ethanol exposure in utero resulted in decreased surfactant synthesis, decreased surfactant secretion and decreased lung volume. The capacity of glutathione precursors to prevent these effects on the surfactant homeostasis suggested that glutathione availability was an important component of the ethanol-induced toxicity.