| REACTIVE OXYGEN SPECIES (ROS) AND OXIDATIVE STRESS (OXS)
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| ROS are reactive, strongly oxidizing forms of oxygen (Fig. 35.1)
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| Oxidative stress (OxS) is defined as a condition in which the rate of generation of ROS exceeds our ability to protect ourselves against them, resulting in an increase in oxidative damage to biomolecules (Fig. 35.2). OxS is a characteristic feature of inflammatory diseases in which cells of the immune system produce ROS in response to challenge. OxS may be localized, for instance in the joints in arthritis or in the vascular wall in atherosclerosis (see Boxes), or can be systemic, e.g. in systemic lupus erythrematosus (SLE), and possibly diabetes.
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| Supplemental oxygen therapy may be used for treatment of patients with hypoxemia, respiratory distress, or following exposure to poisons, such as carbon monoxide. Under normobaric conditions, the fraction of oxygen in air can be increased to nearly 100% using a facial mask or nasal cannula. However, patients develop chest pain, cough and alveolar damage within a few hours of exposure to 100% oxygen. Edema gradually develops and compromises pulmonary function, leading eventually to pulmonary fibrosis. The damage results from production of ROS in the lung. Rats can be protected from oxygen toxicity by gradually increasing the oxygen tension over a period of days. During this time, superoxide dismutase in lung tissue is induced and provides increased protection against oxygen toxicity. |
| The lung is not the only tissue affected by hyperoxia. Premature infants, especially those with acute respiratory distress syndrome (Chapter 26), often require supplemental oxygen for survival. During the 1950s, it was recognized that the high oxygen concentration used in incubators for premature infants increased the risk for blindness, resulting from retinopathy of prematurity (retrolental fibroplasia). |
| Among the ROS, OH• is the most reactive and damaging species; its half-life, measured in nanoseconds, is diffusion-limited, i.e. determined by the time to collision with a target biomolecule. The hydroperoxy radical (HOO•) and H2O2 are small, uncharged molecules that readily penetrate
membranes. At physiological pH, HOO• represents only a small fraction of total O2• (about 0.1%), but this radical is intermediate in reactivity, between O2• and OH•. Myeloperoxidase in the macrophage catalyzes the reaction of H2O2 with Cl- to produce another ROS, hypochlorous acid (HOCl).
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| ROS are formed by three major mechanisms in vivo: by reaction of oxygen with 'decompartmentalized' metal ions (Fig. 35.3); as a side reaction of electron transport (Fig. 35.4); or by normal enzymatic reactions, e.g. by the monoamine oxidase involved in dopamine metabolism (Chapter 18) and fatty acid oxidases in the peroxisome (Chapter 14).
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