Lyudmil TERZIEV GEORGIEV, Veneta SHOPOVA LYUBENOVA, Violeta DANCHEVA YORDANOVA, Galya STAVREVA TZVETANOVA, Angelina STOYANOVA MILCHEVA

Effects of L-2-oxоthiazolidine-4-carboxylic acid on the lung antioxidant defense system in an asthma mouse model

Aim: We aimed to study the effect of a glutathione precursor, L-2-охоthiazolidine-4-carboxylic acid (OTCA), on the lung antioxidant defense system in an animal asthma model. Materials and methods: The study was carried out on 24 female C57BL/6 mice. The mice were divided into 4 treatment groups: group 1control group; group 2injected with ovalbumin (OVA) and given an OVA inhalant; group 3treated with OTCA and phosphate-buffered saline inhalant; and group 4injected with OVA and OTCA and given an OVA inhalant. Under sodium pentobarbital anesthesia the animals were killed by exsanguination 48 h after the last inhalation to obtain a lung homogenate. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GP) and the content of nonprotein sulfhydryl (NPSH) groups in lung homogenate were investigated. Results: OVA decreased the activities of SOD (P = 0.007), CAT (P = 0.004), and GP (P = 0.05) and the NPSH content (P = 0.0008) in the lung homogenate compared with the control animals. Treatment with OVA and OTCA (group 4) resulted in a signifi cant increase in the activities of CAT (P = 0.01) and GP (P = 0.05) and the NPSH content (P = 0.002) compared to the OVA group (group 2). Conclusion: OTCA (160 mg/kg) restored the activities of basic enzymes in the lung antioxidant defense system in an OVA-induced asthma mouse model 48 h after the last nebulization.

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1. Lukacs NW. Cytokines in allergic eosinophilic airway inflammation. Biol Signals 1996; 5: 209-14.
2. Wild JS, Sur S. CpG oligonucleotide modulation of allergic inflammation. Allergy 2001; S6: 365-76.
3. Beasley R, Crane J, Lai CK, Pearce N. Prevalence and etiology of asthma. J Allergy Clin Immunol 2000; 105: 466-72.
4. Crystal RJ. Oxidants and respiratory tract epithelial injury: pathogenesis and strategies for therapeutic intervention. Am J Med 1991; 91: S39-S44.
5. MacPherson JC, Comhair SA, Erzurum SC, Klein DF, Lipscomb MF, Kavuru MS et al. Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J Immunol 2001; 166: 57 63-72.
6. Dworski R. Oxidant stress and asthma. Thorax 2000; 55: S51-S53.
7. Nadeem A, Chhabra SK, Massod A, Raj HG. Increased oxidative stress and altered levels of antioxidants in asthma. J Allergy Clin Immunol 2003; 111: 72-8.
8. Blesa S, Cortijo J, Martinez-Losa M, Mata M, Seda E, Santangelo F et al. Effectiveness of oral N-acetylcysteine in a rat experimental model of asthma. Pharmacol Res 2002; 45: 135-40.
9. MacNee W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001; 429: 195-207.
10. Masella R, Di Benedetto R, Vari R, Filesi C, Giovannini C. Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 2005; 16: 577-86.
11. van der Vliet A, ONeill CA, Cross CE, Koostra JM, Volz WG, Halliwell B et al. Determination of low-molecular-mass antioxidant concentrations in human respiratory tract lining fluids. Am J Physiol 1999; 276: L289-L296.
12. Porta P, Aebi S, Summer K, Lauterburg BH. L-2-oxothiazolidine- 4-carboxylic acid, a cysteine prodrug: pharmacokinetics and effects on thiols in plasma and lymphocytes in human. J Pharmacol Exp Th er 1991; 25: 331-4.
13. Oiry J, Puy JY, Mialocq P, Clayette P, Fretier P, Jaccard P et al. Synthesis and in vitro anti-HIV activity in human monocytederived macrophages of 2-oxothiazolidine-4(R)-carboxylic acid derivates. J Med Chem 1999; 42: 4733-40.
14. Maral I, Puget K, Michelson H. Comparative study of SOD, catalase and GSH-Px levels in erythrocytes of different animals. Biochem Biophys Res Commun 1977; 77: 1532-5.
15. Koroljuk MA, Ivanova LI, Maiorova IG, Tokarev VE. A method of determining catalase activity. Lab Delo 1988; 1: 16-9 (in Russian).
16. Pereslegina IA. Salivary antioxidant enzymes activity in normal children. Lab Delo 1989; 11: 20-3 (in Russian).
17. DeLucia AJ, Mustafa MG, Hussain MZ, Cross CE. Ozone interaction with rodent lung. III. Oxidation of reduced glutathione and formation of mixed disulfi des between protein and nonprotein sulfh ydryls. J Clin Invest 1975; 55: 794-802.
18. Emelyanov A, Fedoseev G, Abulimity A, Rudinski K, Fedoulov A, Karabanov A et al. Elevated concentrations of exhaled hydrogen peroxide in asthmatic patients. Chest 2001; 120: 1136-9.
19. Matsunaga K, Yanagisawa S, Ichikawa T, Ueshima K, Akamatsu K, Hirano T et al. Airway cytokine expression measured by means of protein array in exhaled breath condensate. Correlation with physiologic properties in asthmatic patients. J Allergy Clin Immunol 2006; 118: 84-90.
20. Fukagawa NK, Hercules E, Ajami AM. L-2-[13C]oxothiazolidine- 4-carboxylic acid: a probe for precursor mobilization for glutathione synthesis. Am J Physiol Endocrinol Metab 2000; 278: E171-E176.
21. Meister A, Anderson ME. Glutathione. Annu Rev Biochem 1983; 52: 711-60.
22. Meister A, Anderson ME, Hwang O. Intracellular cysteine and glutathione delivery systems. J Am Coll Nutr 1986; 5: 137-51.
23. Brown LA, Perez JA, Harris FL, Clark RH. Glutathione supplements protect preterm rabbits from oxidative lung injury. Am J Physiol 1996; 270: L446-L451.
24. Mesina JE, Page RH, Hetzel FW, Chopp M. Administration of L-2-oxothiazolidine-4-carboxylate increases glutathione levels in rat brain. Brain Res 1989; 478: 181-3.
25. Lee KS, Kim SR, Park SJ, Min KH, Lee KY, Jin SM et al. Antioxidant down-regulates interleukin-18 expression in asthma. Mol Pharmacol 2006; 70: 1184-93.
26. Lee YC, Lee KS, Park SJ, Park HS, Lim JS, Park KH et al. Blockade of airway hyperresponsiveness and inflammation in a murine model of asthma by a prodrug of cysteine, L-2- oxothiazolidine-4-carboxylic acid. FASEB J 2004; 18: 1917-19.
27. Lee KS, Park HS, Park SJ, Kim SR, Min KH, Jin SM et al. A prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid, regulates vascular permeability by reducing vascular endothelial growth factor expression in asthma. Mol Pharmacol 2005; 68: 1281-90.