Cell injury induced by free radicals, particularly reactive oxygen species, is an important mechanism of cell damage in many pathologic conditions, such as chemical and radiation injury, ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue), cellular aging, and microbial killing by phagocytes. Free radicals are chemical species that have a single unpaired electron in an outer orbit. Unpaired electrons are highly reactive and “attack” and modify adjacent molecules, such as inorganic or organic chemicals—proteins, lipids, carbohydrates, nucleic acids—many of which are key components of cell membranes and nuclei. Some of these reactions are autocatalytic, whereby molecules that react with free radicals are themselves converted into free radicals, thus propagating the chain of damage.

Reactive oxygen species (ROS) are a type of oxygenderived free radical whose role in cell injury is well established. ROS are produced normally in cells during mitochondrial respiration and energy generation, but they are degraded and removed by cellular defense systems. Thus, cells are able to maintain a steady state in which free radicals may be present transiently at low concentrations but do not cause damage. Increased production or decreased scavenging of ROS may lead to an excess of these free radicals, a condition called oxidative stress. Oxidative stress has been implicated in a wide variety of pathologic processes, including cell injury, cancer, aging, and some degenerative diseases such as Alzheimer disease. ROS are also produced in large amounts by activated leukocytes, particularly neutrophils and macrophages, during inflammatory reactions aimed at destroying microbes and cleaning up dead cells and other unwanted substances.

The following section discusses the generation and removal of ROS, and how they contribute to cell injury. The properties of some of the most important free radicals are summarized in Table 1.

Table1. Properties of the Principal Free Radicals Involved in Cell Injury

Generation of Free Radicals. Free radicals may be generated within cells in several ways (Fig. 2-20):

• The reduction-oxidation reactions that occur during normal metabolic processes. As a part of normal respiration, molecular O2 is reduced by the transfer of four electrons to H2 to generate two water molecules. This conversion is catalyzed by oxidative enzymes in the ER, cytosol, mitochondria, peroxisomes, and lysosomes. During this process small amounts of partially reduced intermediates are produced in which different numbers of electrons have been transferred from O2; these include superoxide anion (O2 ^{• −} , one electron), hydrogen peroxide (H2O2, two electrons), and hydroxyl ions (˙OH, three electrons).

• Absorption of radiant energy (e.g., ultraviolet light, x-rays). For example, ionizing radiation can hydrolyze water into ˙OH and hydrogen (H) free radicals.

• Rapid bursts of ROS are produced in activated leukocytes during inflammation. This occurs in a precisely controlled reaction carried out by a plasma membrane multiprotein complex that uses NADPH oxidase for the redox reaction (Chapter 3). In addition, some intracellular oxidases (e.g., xanthine oxidase) generate O2 ^{• −}.

• Enzymatic metabolism of exogenous chemicals or drugs can generate free radicals that are not ROS but have similar effects (e.g., CCl4 can generate ˙CCl3, described later in the chapter).

• Transition metals such as iron and copper donate or accept free electrons during intracellular reactions and catalyze free radical formation, as in the Fenton reaction H₂O₂ + Fe²⁺ → Fe³⁺ + ˙OH + OH−). Because most of the intracellular free iron is in the ferric (Fe3+) state, it must be reduced to the ferrous (Fe2+) form to participate in the Fenton reaction. This reduction can be enhanced by O2 • − , and thus sources of iron and O2 • − may cooperate in oxidative cell damage.

• Nitric oxide (NO), an important chemical mediator generated by endothelial cells, macrophages, neurons, and other cell types (Chapter 3), can act as a free radical and can also be converted to highly reactive peroxynitrite anion (ONOO−) as well as NO2 and NO3−.

Removal of Free Radicals. Free radicals are inherently unstable and generally decay spontaneously. O2 • − , for example, is unstable and decays (dismutates) spontaneously to O2 and H2O2 in the presence of water. In addition, cells have developed multiple nonenzymatic and enzymatic mechanisms to remove free radicals and thereby minimize injury (Fig. 1). These include the following:

• Antioxidants either block free radical formation or inactivate (e.g., scavenge) free radicals. Examples are the lipid-soluble vitamins E and A as well as ascorbic acid and glutathione in the cytosol.

• As we have seen, free iron and copper can catalyze the formation of ROS. Under normal circumstances, the reactivity of these metals is minimized by their binding to storage and transport proteins (e.g., transferrin, ferritin, lactoferrin, and ceruloplasmin), which prevents these metals from participating in reactions that generate ROS.

• A series of enzymes acts as free radical-scavenging systems and breaks down H2O2 and O2 • − . These enzymes are located near the sites of generation of the oxidants and include the following:

1. Catalase, present in peroxisomes, decomposes H2O2 (2H2O2 → O2 + 2H2O).

2. Superoxidase dismutases (SODs) are found in many cell types and convert O2 • − to H2O2 (2 2 O• − + 2H → H2O2 + O2). This group of enzymes includes both manganese- SOD, which is localized in mitochondria, and copperzinc-SOD, which is found in the cytosol.

3. Glutathione peroxidase also protects against injury by catalyzing free radical breakdown (H2O2 + 2GSH → GSSG [glutathione homodimer] + 2H2O, or 2˙OH + 2GSH → GSSG + 2H2O). The intracellular ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) is a reflection of the oxidative state of the cell and is an important indicator of the cell’s ability to detoxify ROS.

Fig1. The generation, removal, and role of reactive oxygen species (ROS) in cell injury. The production of ROS is increased by many injurious stimuli. These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and deoxyribonucleic acid (DNA), resulting in cell injury.

Pathologic Effects of Free Radicals. The effects of ROS and other free radicals are wide-ranging, but three reactions are particularly relevant to cell injury (Fig. 1):

• Lipid peroxidation in membranes. In the presence of O2, free radicals may cause peroxidation of lipids within plasma and organellar membranes. Oxidative damage is initiated when the double bonds in unsaturated fatty acids of membrane lipids are attacked by O2-derived free radicals, particularly by ˙OH. The lipid-free radical interactions yield peroxides, which are themselves unstable and reactive, and an autocatalytic chain reaction ensues (called propagation) that can result in extensive membrane damage.

• Oxidative modification of proteins. Free radicals promote oxidation of amino acid side chains, formation of covalent protein-protein cross-lins (e.g., disulfide bonds), and oxidation of the protein backbone. Oxidative modification of proteins may damage the active sites of enzymes, disrupt the conformation of structural proteins, and enhance proteasomal degradation of unfolded or misfolded proteins, raising havoc throughout the cell.

• Lesions in DNA. Free radicals are capable of causing single- and double-strand breaks in DNA, cross-linking of DNA strands, and formation of adducts. Oxidative DNA damage has been implicated in cell aging (discussed later in this chapter) and in malignant transformation of cells (Chapter 7).

The traditional thinking about free radicals was that they cause cell injury and death by necrosis, and, in fact, the production of ROS is a frequent prelude to necrosis. However, it is now clear that free radicals can trigger apoptosis as well. Recent studies have also revealed a role of ROS in signaling by a variety of cellular receptors and biochemical intermediates. In fact, according to one hypothesis, the major actions of O2 • − stem from its ability to stimulate the production of degradative enzymes rather than direct damage of macromolecules. It is also possible that these potentially deadly molecules, when produced under physiologic conditions in the “right” dose, serve important physiologic functions.

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