Abstract
Acute lung injury (ALI) is a life threatening condition associated with hypoxemia, diffuse alveolar damage, inflammation, and loss of lung function. Lipopolysaccharide (LPS; endotoxin) from the outer membrane of Gram-negative bacteria is a major virulence factor involved in the development of ALI. The depletion of glutathione (GSH), an essential intra- and extra-cellular protective antioxidant, by LPS is an important event that contributes to the elevation in reactive oxygen species. Whether restoring GSH homeostasis can effectively ameliorate mitochondrial dysfunction and cellular apoptosis in ALI is unknown and therefore, was the focus of this study. In peripheral lung tissue of LPS-treated mice, hydrogen peroxide and protein nitration levels were significantly increased. Pre-treatment with GSH-ethyl ester (GSH-EE) prevented this increase in oxidative stress. LPS also increased the lactate/pyruvate ratio, attenuated SOD2 protein levels, and decreased ATP levels in the mouse lung indicative of mitochondrial dysfunction. Again, GSH-EE treatment preserved the mitochondrial function. Finally, our studies showed that LPS induced an increase in the mitochondrial translocation of Bax, caspase 3 activation, and nuclear DNA fragmentation and these parameters were all prevented with GSH-EE. Thus, this study suggests that GSH-EE supplementation may reduce the mitochondrial dysfunction associated with ALI.
Highlights
Acute lung injury (ALI) is an acute inflammatory disorder associated with both high morbidity and mortality in afflicted patients even under intensive care
We found that the acute increases in both oxidative and nitrosative stress in endothelial cells led to a significant increase in cellular apoptosis, which was attenuated by pre-treatment with GSH-ethyl ester (GSH-EE) (Wiseman et al, 2010)
There was a significant reduction in GSH levels in LPS-treated mouse lung when compared to controls (Figure 1A) that was preserved with GSH-EE supplementation
Summary
Acute lung injury (ALI) is an acute inflammatory disorder associated with both high morbidity and mortality in afflicted patients even under intensive care. Lipopolysaccharide (LPS) from the outer cell wall of Gram-negative bacteria that cause sepsis is the most common indirect pulmonary insult leading to ALI (Erickson et al, 2009). LPS provokes damage to the alveolar-capillary membrane and the adhesion, activation, and sequestration of polymorphonuclear neutrophils (PMN), which result in the deterioration of gas exchange (Nagase et al, 2003). Several therapies, such as corticosteroids, prostacyclins, exogenous surfactants, ketoconazole, and nitric oxide, have shown promising outcomes, the estimated mortality rate in ALI is 38.5% (Rubenfeld et al, 2005). There is a further need to study the pathophysiology of ALI and identify therapeutic targets to improve patient outcome
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