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Oxidants and Redox Signaling in Acute Lung Injury

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Acute lung injury (ALI) and its more severe form of clinical manifestation, the acute respiratory distress syndrome is associated with significant dysfunction in air exchange due to inflammation of the lung parenchyma. Several factors contribute to the inflammatory process, including hypoxia (inadequate oxygen), hyperoxia (higher than normal partial pressure of oxygen), inflammatory mediators (such as cytokines), infections (viral and bacterial), and environmental conditions (such as cigarette smoke or noxious gases). However, studies over the past several decades suggest that oxidants formed in the various cells of the lung including endothelial, alveolar, and epithelial cells as well as lung macrophages and neutrophils in response to the factors mentioned above mediate the pathogenesis of ALI. Oxidants modify cellular proteins, lipids, carbohydrates, and DNA to cause their aberrant function. For example, oxidation of lipids changes membrane permeability. Interestingly, recent studies also suggest that spatially and temporally regulated production of oxidants plays an important role antimicrobial defense and immunomodulatory function (such as transcription factor activation). To counteract the oxidants an arsenal of antioxidants exists in the lung to maintain the redox status, but when overwhelmed tissue injury and exacerbation of inflammation occurs. We present below the current understanding of the pathogenesis of oxidant‐mediated ALI. © 2011 American Physiological Society. Compr Physiol 1:1365‐1381, 2011.

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Figure 1. Figure 1.

Some examples of oxidant generation. Reduction of molecular oxygen leads to the formation of superoxide and hydrogen peroxide. In the presence of iron, reduction of oxygen leads to formation of hydroxyl radicals. Superoxide reacts with nitric oxide to form peroxynitrite radicals.

Figure 2. Figure 2.

Activated NADPH oxidase assembly at the membrane. The various subunits assemble at the membrane upon activation and catalyze the conversion of molecular oxygen to superoxide radical.

Figure 3. Figure 3.

Interconversion of glutathione (GSH) and GSSA in the presence of respiratory distress syndrome and enzymes. ROS are reduced by GSH non‐enzymatically but reduction of H2O2 requires the presence of GSH peroxidase. The GSSA formed as a result of both reactions is reduced back to GSH in the presence of GSH reduction and NADPH.

Figure 4. Figure 4.

Activation of transcription factors NFκB and Nrf2 and their subsequent translocation from the cytoplasm into the nucleus. See text for details.

Figure 1.

Some examples of oxidant generation. Reduction of molecular oxygen leads to the formation of superoxide and hydrogen peroxide. In the presence of iron, reduction of oxygen leads to formation of hydroxyl radicals. Superoxide reacts with nitric oxide to form peroxynitrite radicals.

Figure 2.

Activated NADPH oxidase assembly at the membrane. The various subunits assemble at the membrane upon activation and catalyze the conversion of molecular oxygen to superoxide radical.

Figure 3.

Interconversion of glutathione (GSH) and GSSA in the presence of respiratory distress syndrome and enzymes. ROS are reduced by GSH non‐enzymatically but reduction of H2O2 requires the presence of GSH peroxidase. The GSSA formed as a result of both reactions is reduced back to GSH in the presence of GSH reduction and NADPH.

Figure 4.

Activation of transcription factors NFκB and Nrf2 and their subsequent translocation from the cytoplasm into the nucleus. See text for details.

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J. Vidya Sarma, Peter A. Ward. Oxidants and Redox Signaling in Acute Lung Injury. Compr Physiol 2011, 1: 1365-1381. doi: 10.1002/cphy.c100068