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Oxygen—Friend or foe?
Br. vet.J. (1995). 151,225
GUEST
EDITORIAL
OXYGEN~FRIEND
O R FOE?
Oxygen, while essential to life, can also prove toxic in some circumstances (Halliwell & Gutteridge, 1984). In particular, partial reduction of molecular oxygen, resulting in the addition of only a single electron, can radically alter its chemical nature. The literature suggests that the extreme reactivity imposed on molecular combinations of oxygen by a single unpaired electron, collectively known as oxyradicals, contributes to ischemia-repeffusion injuries, exercise-induced muscular soreness and pathophysiological changes during respiratory, gastrointestinal and other systemic diseases (Doelman & Bast, 1990; Gutteridge & Halliwell, 1990; Mills et al., 1994). Susceptibility to such diseases may increase during oxidative stress, a status where oxyradicals overwhelm the existing antioxidant defences. It must be noted, however, that oxyradicals also contribute to normal physiological processes because by-products indicative of lipid peroxidation (the selfpropagating damage to biomembranes initiated by oxyradicals) are detected in the plasma of clinically health), individuals (Kneepkens et al., 1994; Schaur et al., 1994). Furthermore, 2-5% of molecular oxygen involved with electron transfer during oxidative phosphorylation in the mitochondria produce the superoxide radical (02"-). Oxyradicals may also initiate apoptosis (programmed cell death) and be responsible for the aging process (Forrest et al., 1994), particularly since the ratio of tissue antioxidants to pro-oxidants has been shown to affect tissue life span (Lopez-Torres et al., 1993). Manipulation of the antioxidant capacity of an individual has been the conventional approach to the control of oxidative stress. The review by Forsyth and Guilford (1995) elsewhere in this issue is a timely description of the mechanisms by which oxyradicals can cause tissue damage and provides a comprehensive summary of the antioxidant defences available. Although Forsyth and Guilford (1995) concentrate on one aspect of oxyradical-mediated disease, namely ischaemia-reperfusion injury, the principles of multifactorial antioxidant defences existing at different levels (extracellular, within biomembranes and intercellularly) apply to all aspects of clinical oxyTadical research. To date, clinical manipulation of antioxidant defences in veterinary medicine has had limited application, although oxyradical scavengers, particularly vitamin E and dimethyl sulphoxide (DMSO), have been used therapeutically for a range of conditions, including equine rhabdomyolysis syndrome (ERS), topical and systemic inflammatory conditions and ischemia-reperfusion injuries. Early interest in the role of antioxidants in veterinary medicine focused on the oxyradical scavengers, vitamin E and selenium (Aikawa et al., 1984), particularly since Davies et al. (1982) 0007-1935/95/030225-03/$08.00/0
© 1995Bailli~reTindall
226
BRITISH VETERINARY JOURNAL, 151, 3
reported a 40% decrease in exercise endurance in rats fed a diet that was deficient in vitamin E. However, further studies have not demonsu'ated enhanced endurance during exercise in animals by increasing the intake of oxyradical scavengers above accepted nutritional requirements (Brady et al., 1978). Current investigations in human medicine are also targeting specific aspects of antioxidant therapy. For example, a deficiency of glutathione, a tripeptide with potent antioxidant capacity, has been reported in the alveolar epithelial lining fluid (ELF) of patients with debilitating respiratory diseases, such as adult respiratory distress syndrome (ARDS) and cystic fibrosis (Roum et al., 1993). Administration of aerosolized glutathione to patients with ARDS or cystic fibrosis is a promising compliment on conventional therapy for certain respiratory diseases (Buhl et al., 1990). As summarized by Forsyth and Guilford (1995), the antioxidant defences of an individual consist of a complex and often synergistic array of enzymes, scavengers and metabolic products that combine to protect against oxyradicals and their deleterious effects. However, oxyradicals may also be a part of the normal physiology of an individual and, indeed, are an essential component of the early response to disease, such as during the respiratory burst of neutrophils. Antioxidant defences act to confine oxyradicals, while oxidative stress occurs when pro-oxidants overwhelm antioxidants, suggesting that the total antioxidant capacity must be considered without undue emphasis on any particular antioxidant defence. Strong homeostatic controls exist to regulate antioxidant levels, although a compensatory increase in some aspects of antioxidant defences has been reported in response to specific deficiencies of individual antioxidants (Cutler, 1984). In addition, continued oxidant stress can deplete antioxidants, such as the decrease in vitamin E concentrations in the alveolar ELF of smokers (Pacht el al., 1986). Ideally, a measure of the individuals total antioxidant capacity may indicate susceptibility to oxidant stress and possible prophylactic therapeutic intervention prior to a surge in pro-oxidant activity, such as may occur during disease, surgery or exercise. Unfortunately, such a measure does not exist, although measurement of the peroxyl radical (OH'-) trapping capacity of biological fluids correlates positively with resistance to disease (Lindeman et al., 1989; Uotila et al., 1992). However, as Gutteridge (1986) points out, the peroxyl radical trapping capacity would be meaningless without due consideration of the availability of the transition metals iron and copper to facilitate the production of the peroxyl radical. The clinical application of oxyradical research requires a thorough understanding of antioxidant defences, their homeostatic controls and the possible oxidant stresses that may challenge the individual. Forsyth and Guildford (1995) emphasize a specific form of oxidant stress, namely ischaemia-reperfusion injury. The most extreme form of ischaemia-reperfusion injury occurs during organ transplantation, yet improved organ survival and subsequent function has been achieved by incorporating a combination of antioxidants (e.g. allopurinol, glutathione, mannitol) in the reperfusate (Bryan et al., 1994). Consideration of the principles of oxidant stress and antioxidant defences may supplement the clinicians therapeutic approach to a variety of disease conditions where oxyradicals are active. P. MILLS Department of Physiology, The Animal Health Trust, P.O. Box 5, Newmarket, Suffolk CB8 7DW, UK
OXYGEN--FRIEND OR FOE?
227
REFERENCES
AI~WA, K. M., QUINTAN1LHA,A. T., DE LUMEN, B. O., BROOKS, G. A. & PACKER,L. (1984). Exercise endurance-training alters vitamin E tissue levels and red blood cell hemolysis in rodents. Bioscience Reports 4, 253-7. BRADY,P. S., Ku, P. K. & ULLREY,D. E. (1978). Lack of effect of selenium supplementation on the response of the equine erythrocyte glutathione system and plasma enzymes to exercise. Journal of Animal Science 47, 492-6. BR':AN, C. L., PATEFIELD,A.J., COHEN,D., NIELSEN,J. L., EIvDKNUEL,B. & CALHOON,J. A. (1994). Assessment of injury in transplanted and nontransplanted lungs after 6 h of cold storage with glutathione.Journal of Applied Physiology 76, 1232-41. BUHL, R., VOGELMEIER,C., CmTENDEN,M. et al. (1990). Augmentation of glutathione in the fluid lining the epithelium of the lower respiratory tract by directly administering glutathione aerosol. Proceedings on the National Academy of Science, USA 87, 4063-7. CUTt.ER, R. G] (1984). Antioxidants, aging and longevity. In Free Radicals and Biology Vol. VI, ed. W. A. Pryor, pp. 371-427. Orlando: Academic Press. DAXqES, K. J. A., QUINTANILKA,A. T., BROOKS,G. A. & PACKER,L. (1982). Free radicals and tissue damage produced by exercise, Biochemica Biophysica Research Communications 107, 1198-2O5. DOELMAN, C. J. A. & BAST, A. (1990). Oxygen radicals in lung pathology. Free Radicals in Biology and Medicine 9, 381-400. FORREST,v.J., KANc.,Y.-H., McCLAIN,D. E., ROBINSON,D. H. & RAMAKRISHNAN,N. (1994). Oxidative stress-induced aptosis prevented by trolox. Free Radicals in Biology and Medicine 16, 675-84. FORSS'rH, W. G. & GUILFORD,S. F. (1994). Ischaemic-reperfusion injury--a small animal perspective. British Veterinary Journal 151,281-298. GUI"I'ERIDGE,J. M. C. (1986). Aspects to consider when detecting and measuring lipid peroxidatio 9. Free Radical Research Communications I, 173-84. GUYrEmDGE,J. M. C. & HALLI~LL, B. (1990). The measurement and mechanism of lipid peroxidation in biological systems. T.I.B.S. 15, 129-35. HALLIWELL,B. & GUTTEmDGE,J. M. C. (1984). Lipid peroxidation, oxygen radicals, cell damage and antioxidant therapy. Lancet 1, 1396-7. KNEEPKENS, C. M. F., LEPAGE, G. & Roy, C. C. (1994). The potential of the hydrocarbon breath test as a measure of lipid peroxidation. Free Radical Research Communications 17, 127-60. LINDEMAN,J., VAN ZOEREN-GROBBEN,D., SCHRIJVER,J., SPEEK,A., POORTHUIS,B. & BERGER, H. (1989). The total free radical-trapping ability of cord blood plasma in preterm and term babies. Pediatric Research 26, 20-4. LOPEz-ToRRES, M., PEREZ-CAMPO,R., RoJAs, C., CADENAS,S. & BARJA,G. (1993). Simultaneous induction of SOD, glutathione reductase, GSH and ascorbate in liver and kidney correlates with survival during aging. Free Radicals in Biology and Medicine 15, 133-42. MILLS,P. C., NG,J. C., THORNTON,J, S~X~qUGHT,A. A. & AUER, D. E. (1994). Exercise-induced •conn.ective tissue turnover and lipid peroxidation in horses. British Veterinary Journal 150, 53-63. PACHT, E. R., KASEFa,H., MOFbklvlMED,J.R., CORNWELL,D. G. & DAWS,W. B. (1986). Deficiency of vitamin E in the alveolar fluid of cigarette smokers. Journal of Clinical Investigation 77, 789-796. RooM, J. H., BUHL, R., McELVANEV,N. G., BOROK, Z. & CRYSTAL,R. G. (1993). Systemic deficiency of glutadaione in cystic fibrosis. Journal of Applied Physiology 75, 2419-24. SCHAUR, R. J., DUSSING,G., KINK, E., SCHAUENSTEIN,E., POSCH, W., KUKOVETZ,E. & EGGER,G. (1994). The lipid peroxidation product 4-hydroxynonenal is formed by--and is able to attract--rat neutrophils in vivo. Free Radical Research 20, 365-73. UOTILA,J., METsA-KETELA,T. 8¢ TUII~b~.LA,R. (1992). Plasma peroxyl radical-trapping capacity in severe preeclampsia is strongly related to tlric acid. Clinical and Experimental Hypersensitivity B l l , 71-80.
GUEST
EDITORIAL
OXYGEN~FRIEND
O R FOE?
Oxygen, while essential to life, can also prove toxic in some circumstances (Halliwell & Gutteridge, 1984). In particular, partial reduction of molecular oxygen, resulting in the addition of only a single electron, can radically alter its chemical nature. The literature suggests that the extreme reactivity imposed on molecular combinations of oxygen by a single unpaired electron, collectively known as oxyradicals, contributes to ischemia-repeffusion injuries, exercise-induced muscular soreness and pathophysiological changes during respiratory, gastrointestinal and other systemic diseases (Doelman & Bast, 1990; Gutteridge & Halliwell, 1990; Mills et al., 1994). Susceptibility to such diseases may increase during oxidative stress, a status where oxyradicals overwhelm the existing antioxidant defences. It must be noted, however, that oxyradicals also contribute to normal physiological processes because by-products indicative of lipid peroxidation (the selfpropagating damage to biomembranes initiated by oxyradicals) are detected in the plasma of clinically health), individuals (Kneepkens et al., 1994; Schaur et al., 1994). Furthermore, 2-5% of molecular oxygen involved with electron transfer during oxidative phosphorylation in the mitochondria produce the superoxide radical (02"-). Oxyradicals may also initiate apoptosis (programmed cell death) and be responsible for the aging process (Forrest et al., 1994), particularly since the ratio of tissue antioxidants to pro-oxidants has been shown to affect tissue life span (Lopez-Torres et al., 1993). Manipulation of the antioxidant capacity of an individual has been the conventional approach to the control of oxidative stress. The review by Forsyth and Guilford (1995) elsewhere in this issue is a timely description of the mechanisms by which oxyradicals can cause tissue damage and provides a comprehensive summary of the antioxidant defences available. Although Forsyth and Guilford (1995) concentrate on one aspect of oxyradical-mediated disease, namely ischaemia-reperfusion injury, the principles of multifactorial antioxidant defences existing at different levels (extracellular, within biomembranes and intercellularly) apply to all aspects of clinical oxyTadical research. To date, clinical manipulation of antioxidant defences in veterinary medicine has had limited application, although oxyradical scavengers, particularly vitamin E and dimethyl sulphoxide (DMSO), have been used therapeutically for a range of conditions, including equine rhabdomyolysis syndrome (ERS), topical and systemic inflammatory conditions and ischemia-reperfusion injuries. Early interest in the role of antioxidants in veterinary medicine focused on the oxyradical scavengers, vitamin E and selenium (Aikawa et al., 1984), particularly since Davies et al. (1982) 0007-1935/95/030225-03/$08.00/0
© 1995Bailli~reTindall
226
BRITISH VETERINARY JOURNAL, 151, 3
reported a 40% decrease in exercise endurance in rats fed a diet that was deficient in vitamin E. However, further studies have not demonsu'ated enhanced endurance during exercise in animals by increasing the intake of oxyradical scavengers above accepted nutritional requirements (Brady et al., 1978). Current investigations in human medicine are also targeting specific aspects of antioxidant therapy. For example, a deficiency of glutathione, a tripeptide with potent antioxidant capacity, has been reported in the alveolar epithelial lining fluid (ELF) of patients with debilitating respiratory diseases, such as adult respiratory distress syndrome (ARDS) and cystic fibrosis (Roum et al., 1993). Administration of aerosolized glutathione to patients with ARDS or cystic fibrosis is a promising compliment on conventional therapy for certain respiratory diseases (Buhl et al., 1990). As summarized by Forsyth and Guilford (1995), the antioxidant defences of an individual consist of a complex and often synergistic array of enzymes, scavengers and metabolic products that combine to protect against oxyradicals and their deleterious effects. However, oxyradicals may also be a part of the normal physiology of an individual and, indeed, are an essential component of the early response to disease, such as during the respiratory burst of neutrophils. Antioxidant defences act to confine oxyradicals, while oxidative stress occurs when pro-oxidants overwhelm antioxidants, suggesting that the total antioxidant capacity must be considered without undue emphasis on any particular antioxidant defence. Strong homeostatic controls exist to regulate antioxidant levels, although a compensatory increase in some aspects of antioxidant defences has been reported in response to specific deficiencies of individual antioxidants (Cutler, 1984). In addition, continued oxidant stress can deplete antioxidants, such as the decrease in vitamin E concentrations in the alveolar ELF of smokers (Pacht el al., 1986). Ideally, a measure of the individuals total antioxidant capacity may indicate susceptibility to oxidant stress and possible prophylactic therapeutic intervention prior to a surge in pro-oxidant activity, such as may occur during disease, surgery or exercise. Unfortunately, such a measure does not exist, although measurement of the peroxyl radical (OH'-) trapping capacity of biological fluids correlates positively with resistance to disease (Lindeman et al., 1989; Uotila et al., 1992). However, as Gutteridge (1986) points out, the peroxyl radical trapping capacity would be meaningless without due consideration of the availability of the transition metals iron and copper to facilitate the production of the peroxyl radical. The clinical application of oxyradical research requires a thorough understanding of antioxidant defences, their homeostatic controls and the possible oxidant stresses that may challenge the individual. Forsyth and Guildford (1995) emphasize a specific form of oxidant stress, namely ischaemia-reperfusion injury. The most extreme form of ischaemia-reperfusion injury occurs during organ transplantation, yet improved organ survival and subsequent function has been achieved by incorporating a combination of antioxidants (e.g. allopurinol, glutathione, mannitol) in the reperfusate (Bryan et al., 1994). Consideration of the principles of oxidant stress and antioxidant defences may supplement the clinicians therapeutic approach to a variety of disease conditions where oxyradicals are active. P. MILLS Department of Physiology, The Animal Health Trust, P.O. Box 5, Newmarket, Suffolk CB8 7DW, UK
OXYGEN--FRIEND OR FOE?
227
REFERENCES
AI~WA, K. M., QUINTAN1LHA,A. T., DE LUMEN, B. O., BROOKS, G. A. & PACKER,L. (1984). Exercise endurance-training alters vitamin E tissue levels and red blood cell hemolysis in rodents. Bioscience Reports 4, 253-7. BRADY,P. S., Ku, P. K. & ULLREY,D. E. (1978). Lack of effect of selenium supplementation on the response of the equine erythrocyte glutathione system and plasma enzymes to exercise. Journal of Animal Science 47, 492-6. BR':AN, C. L., PATEFIELD,A.J., COHEN,D., NIELSEN,J. L., EIvDKNUEL,B. & CALHOON,J. A. (1994). Assessment of injury in transplanted and nontransplanted lungs after 6 h of cold storage with glutathione.Journal of Applied Physiology 76, 1232-41. BUHL, R., VOGELMEIER,C., CmTENDEN,M. et al. (1990). Augmentation of glutathione in the fluid lining the epithelium of the lower respiratory tract by directly administering glutathione aerosol. Proceedings on the National Academy of Science, USA 87, 4063-7. CUTt.ER, R. G] (1984). Antioxidants, aging and longevity. In Free Radicals and Biology Vol. VI, ed. W. A. Pryor, pp. 371-427. Orlando: Academic Press. DAXqES, K. J. A., QUINTANILKA,A. T., BROOKS,G. A. & PACKER,L. (1982). Free radicals and tissue damage produced by exercise, Biochemica Biophysica Research Communications 107, 1198-2O5. DOELMAN, C. J. A. & BAST, A. (1990). Oxygen radicals in lung pathology. Free Radicals in Biology and Medicine 9, 381-400. FORREST,v.J., KANc.,Y.-H., McCLAIN,D. E., ROBINSON,D. H. & RAMAKRISHNAN,N. (1994). Oxidative stress-induced aptosis prevented by trolox. Free Radicals in Biology and Medicine 16, 675-84. FORSS'rH, W. G. & GUILFORD,S. F. (1994). Ischaemic-reperfusion injury--a small animal perspective. British Veterinary Journal 151,281-298. GUI"I'ERIDGE,J. M. C. (1986). Aspects to consider when detecting and measuring lipid peroxidatio 9. Free Radical Research Communications I, 173-84. GUYrEmDGE,J. M. C. & HALLI~LL, B. (1990). The measurement and mechanism of lipid peroxidation in biological systems. T.I.B.S. 15, 129-35. HALLIWELL,B. & GUTTEmDGE,J. M. C. (1984). Lipid peroxidation, oxygen radicals, cell damage and antioxidant therapy. Lancet 1, 1396-7. KNEEPKENS, C. M. F., LEPAGE, G. & Roy, C. C. (1994). The potential of the hydrocarbon breath test as a measure of lipid peroxidation. Free Radical Research Communications 17, 127-60. LINDEMAN,J., VAN ZOEREN-GROBBEN,D., SCHRIJVER,J., SPEEK,A., POORTHUIS,B. & BERGER, H. (1989). The total free radical-trapping ability of cord blood plasma in preterm and term babies. Pediatric Research 26, 20-4. LOPEz-ToRRES, M., PEREZ-CAMPO,R., RoJAs, C., CADENAS,S. & BARJA,G. (1993). Simultaneous induction of SOD, glutathione reductase, GSH and ascorbate in liver and kidney correlates with survival during aging. Free Radicals in Biology and Medicine 15, 133-42. MILLS,P. C., NG,J. C., THORNTON,J, S~X~qUGHT,A. A. & AUER, D. E. (1994). Exercise-induced •conn.ective tissue turnover and lipid peroxidation in horses. British Veterinary Journal 150, 53-63. PACHT, E. R., KASEFa,H., MOFbklvlMED,J.R., CORNWELL,D. G. & DAWS,W. B. (1986). Deficiency of vitamin E in the alveolar fluid of cigarette smokers. Journal of Clinical Investigation 77, 789-796. RooM, J. H., BUHL, R., McELVANEV,N. G., BOROK, Z. & CRYSTAL,R. G. (1993). Systemic deficiency of glutadaione in cystic fibrosis. Journal of Applied Physiology 75, 2419-24. SCHAUR, R. J., DUSSING,G., KINK, E., SCHAUENSTEIN,E., POSCH, W., KUKOVETZ,E. & EGGER,G. (1994). The lipid peroxidation product 4-hydroxynonenal is formed by--and is able to attract--rat neutrophils in vivo. Free Radical Research 20, 365-73. UOTILA,J., METsA-KETELA,T. 8¢ TUII~b~.LA,R. (1992). Plasma peroxyl radical-trapping capacity in severe preeclampsia is strongly related to tlric acid. Clinical and Experimental Hypersensitivity B l l , 71-80.