Free-radical mediated injury

Williams, A.T. and Burk, R.F. (1990). Carbon tetrachloride hepatotoxicity, an example of free radical-mediated injury. Semin. Liver Dis. 10, 279-284. 

The brain has a number of characteristics that make it especially susceptible to free- radical-mediated injury. Brain lipids are highly enriched in polyunsaturated fatty acids and many regions of the brain, for example, the substantia nigra and the striatum, have high concentrations of iron. Both these factors increase the susceptibility of brain cell membranes to lipid peroxidation. Because the brain is critically dependent on aerobic metabolism, mitochondrial respiratory activity is higher than in many other tissues, increasing the risk of free radical Teak from mitochondria conversely, free radical damage to mitochondria in brain may be tolerated relatively poorly because of this dependence on aerobic metabolism. 

Lipid peroxidation is one of the major sources of free-radical mediated injury that directly damages membranes and generates a number of secondary products. In particular, markers of lipid peroxidation have been found to be elevated in brain tissues and body fluids in several neurodegenerative diseases, and the role of lipid peroxidation has been extensively discussed in the context of their pathogenesis. Peroxidation of membrane lipids can have numerous effects, including increased membrane rigidity, decreased activity of membrane-bound enzymes (e.g., sodium pumps), altered activity of membrane receptors, and altered permeability [Anzai et al., 1999 Yehuda et al., 2002], In addition to effects on phospholipids, lipid-initiated radicals can also directly attack membrane proteins and induce lipid-lipid, lipid-protein, and protein-protein cross-linking, all of which obviously have effects on membrane function. 

Due to a high concentration of substrate polyunsaturated fatty acids (PUFAs) in cells, lipid peroxidation is a major outcome of free radical-mediated injury (Montine et al, 2002a, b). A critically important aspect of hpid peroxidation... 

Free radical-mediated injury can be attenuated by several growth factors. Iron catalyzes the formation of hydroxyl radical. Its damaging effect on neurons (hippocampal and cortical) can be inhibited by pretreatment with FGF-2 (Zhang et al.,... 

Stein, CM, Tanner, SB, Awad, JA, Roberts, LJ, II and Morrow, JD (1996) Evidence of free radical mediated injury (isoprostane overproduction) in scleroderma. Arf/trtft s Rheum, 39, 1146-1150. 

Ratych, KE. and Bulkley, G.B. (1986). Free-radical-mediated postischaemic reperfusion injury in the kidney. J. Free Rad. Biol. Med. 2, 311-319. 

Perler, B.A., Tohmer, A.G. and Bulkley, G.B. (1990). Inhibition of the compartment syndrome by the ablation of free radical-mediated reperfusion injury. Surgery 108, 40-47. 

Xanthine oxidase, a widely used source of superoxide, has been frequently applied for the study of the effects of superoxide on DNA oxidation. Rozenberg-Arska et al. [30] have shown that xanthine oxidase plus excess iron induced chromosomal and plasmid DNA injury, which was supposedly mediated by hydroxyl radicals. Ito et al. [31] compared the inactivation of Bacillus subtilis transforming DNA by potassium superoxide and the xanthine xanthine oxidase system. It was found that xanthine oxidase but not K02 was a source of free radical mediated DNA inactivation apparently due to the conversion of superoxide to hydroxyl radicals in the presence of iron ions. Deno and Fridovich [32] also supposed that the single strand scission formation after exposure of DNA plasmid to xanthine oxidase was mediated by hydroxyl radical formation. Oxygen radicals produced by xanthine oxidase induced DNA strand breakage in promotable and nonpromotable JB6 mouse epidermal cells [33]. 

Slater TF, Cheeseman KFI, Ingold KU. 1985. Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury. Philos Trans R Soc Lond [Biol] 311 633-645. 

Plasma malondialdehyde-like material, an indicator of lipid peroxidation, is increased in conditions of ischaemia, such as stroke [83, 84] and myocardial infarction [85]. Mitochondria extracted from hearts of vitamin-E-deficient rabbits showed a decreased mitochondrial function and an increased formation of oxygen radicals associated with a reduced superoxide dismutase activity. This was partially reversed by addition of vitamin E in vitro [86]. Measurement of in vitro susceptibility to lipid peroxidation in cardiac muscle from vitamin-E-deficient mice showed a highly significant negative correlation between the concentration of vitamin E and in vitro lipid peroxidation. The results indicate that short-term vitamin E deficiency may expose cardiac muscle to peroxidation injuries [ 87 ]. In rats, treatment for 2 days with isoprenaline increased lipid peroxide activity, as measured by malondialdehyde levels, in the myocardium. Vitamin-E-deficient animals were even more sensitive to this effect, and pretreatment with a-tocopheryl acetate for 2 weeks prevented the effect induced by isoprenaline. The authors [88] propose that free-radical-mediated increases in lipid peroxide activity may have a role in catecholamine-induced heart disease. 

B32. Bulkley, G. B., Free radical-mediated reperfusion injury A selective review. Hr. J. Cancer 8 Suppl.), 66-73 (1987). 

Considerable evidence is now accumulating that injury occurs almost exclusively during the reperfusion phase, and that the injury is due to oxygen free radical-mediated oxidative stress. Furthermore, some neuronal pathologies, such as Alzheimer s disease, may relate to lipid peroxidation of cell membranes by free radicals. 

Mattson, M.P., Cheng, B. and Smithswintosky, V.L. (1993b) Mechanisms of neurotrophic factor protection against cal-cium-and free radical-mediated excitotoxic injury - implications for treating neurodegenerative disorders. Exp. Neurol. 124 89-95. 

A long-standing and fundamental problem that has frustrated attempts to directly demonstrate free radical-mediated toxicity relates to the inability to verify various reaction products seen in vivo as being derived from specific radical species. The ability of various antioxidants, such as ascorbate, tocopherol, glutathione, and cysteine, to limit or prevent injury in various models is suggestive of oxidative pathology but offers little with regard to... 

Fig 24.7. Free radical-mediated cellular injury. Superoxide and the hydroxyl radical initiate lipid jjeroxidation in the cellular, mitochondrial, nuclear, and endoplasmic reticulum membranes. The increase in cellular permeability results in an influx of Ca, which causes further mitochondrial damage. The cysteine sulfhydryl groups and other amino acid residues on proteins are oxidized and degraded. Nuclear and mitochondrial DNA can be oxidized, resulting in strand breaks and other types of damage. RNOS (NO, NO2, and perox5mitrite) have similar effects. 

---