Hasan KAHRAMAN, Nurhan KÖKSAL, Ergül KURUTAŞ, Harun ÇIRALIK, Mahmut TOKUR, Selim BOZKURT, Betül KABAKCI, Vedat BALKAN

Protective effects of erythropoietin and n-acetylcysteine on methotrexate-induced lung injury in rats

Objective: Methotrexate (MTX) is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO) and N-acetyl-cysteine (NAC) on MTX-induced lung injury in rats. Study Design: Animal experiment. Material and Methods: Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and inflammation and congestion scores in lung tissues were evaluated. Results: In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p0.005). In group MTX both scores were significantly higher than in sham (p

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1. Camus P, Bonniaud P, Fanton A, Camus C, Baudaun N, Foucher P. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 2004;25:479-519. [CrossRef]
2. Salzer WL, Winick NJ, Wacker P, Lu X, Devidas M, Shuster JJ, et al. Plasma methotrexate, red blood cell methotrexate, and red blood cell folate values and outcome in children with precursor B-acute lymphoblastic leukemia:a report from the childrens on- cology group. J Pediatr Hematol Oncol 2012;34:e1-7.
3. Cronstein BN. Molecular therapeutics. Methotrexate and its mecha- nism of action. Arthritis Rheum 1996;39:1951-60. [CrossRef]
4. Kimura E, Nishimura K, Sakata K, Oga S, Kashiwagi K, Igarashi K. Methotrexate differentially affects growth of suspension and ad- herent cells. Int J Biochem Cell Biol 2004;36:814-25. [CrossRef]
5. Yamauchi Y, Okazaki H, Desaki M, Kohyama T, Kawasaki S, Ya- mamoto K, et al. Methotrexate induces interleukin-8 produc- tion by human bronchial and alveolar epithelial cells. Clin Sci 2004;106:619-25. [CrossRef]
6. Hsu DC, Katelaris CH. Long-term management of patients taking immunosuppressive drugs. Aust Prescr 2009;32:68-7.
7. Ohbayashi M, Suzuki M, Yashiro Y, Fukuwaka S, Yasuda M, Ko- hyama N, et al. Induction of pulmonary fibrosis by methotrex- ate treatment in mice lung in vivo and in vitro. J Toxicol Sci 2010;35:653-61. [CrossRef]
8. Arikan DC, Bakan V, Kurutas EB, Sayar H, Coskun A. Protective effect of tadalafil on ischemia/reperfusion injury of rat ovary. J Pediatr Surg 2010;45:2203-9. [CrossRef]
9. Eren I, Naziroglu M, Demirdas A. Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain. Neurochem Res 2007;32:1188-95. [CrossRef]
10. Beers MF. Oxygen therapy and pulmonary oxygen toxicity. In:Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI, eds. Fishmans Pulmonary Disease and Disorders, 4th ed. New York:Mc Graw Hill, 2008:2624-8.
11. Laskin JD, Black AT, Jan JH, Sinko PJ, Heindel ND, Sunil V, et al. Oxidants and antioxidants in sulfur mustard-induced injury. Ann NY Acad Sci 2010;1203:92-100. [CrossRef]
12. Erbayraktar S, Lanerolle N, Lotbiniere A, Knisely JP, Erbayraktar Z, Yilmaz O, et al. Carbamylated erythropoietin reduces radiosur- gically-induced brain injury. Mol Med. 2006;12:74-80. [CrossRef]
13. Hardee ME, Arıcasoy MO, Blackwell KL, Kirkpatrick JP, De- whirst MW. Erythropoietin biology in cancer. Clin Cancer Res 2006;12:332-9. [CrossRef]
14. Contaldo C, Meier C, Elsherbiny A, Harder Y, Trentz O, Menger MD, et al. Human recombinant erythropoietin protects the striated muscle microcirculation of the dorsal skinfold from postischemic injury in mice. Am J Physiol Heart Circ Physiol 2007;293:274-83. [CrossRef]
15. Cuzzocrea S, Mazzon E, Di Paola R, Patel NS, Genovese T, Muià C, et al. Erythropoietin reduces the development of ex- perimental inflammatory bowel disease. J Pharmacol Exp Ther 2004;311:1272-80. [CrossRef]
16. Campos R, Shimizu MH, Volpini RA, de Bragança AC, Andrade L, Lopes FD, et al. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventila- tion. Am J Physiol Lung Cell Mol Physiol 2012;302:L640-50. [CrossRef]
17. Maeda T, Miyazono Y, Ito K. Oxidative stress and enhanced para- cellular permeability in the small intestine of methotrexate-treated rats. Cancer Chemother Pharmacol 2010;65:1117-23. [CrossRef]
18. Srivastava RK, Rahman Q, Kashyap MP, Lohani M, Pant AB. Ameliorative effects of dimetylthiourea and n-acetylcysteine on nanoparticles induced cyto-genotoxicity in human lung cancer cells-A549. PLoS one 2011;6:e25767. [CrossRef]
19. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in ani- mal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8. [CrossRef]
20. Fridovich I. Superoxide dismutase. Adv Enzymol Relat Areas Mol Biol 1974;41:35-97.
21. Beutler E. Red Cell Metabolism. 2nd ed. New York:Grune and Stratton Company. 1975:261-5.
22. Lowry OH, Rosebrough NJ, Farr A. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:265-75.
23. Atalay C, Dogan N, Aykan S, Gundogdu C, Keles MS. The effica- cy of spironolactone in the treatment of acute respiratory distress syndrome-induced rats. Singapore Med J 2010;51:501-5.
24. Ciralik H, Bulbuloglu E, Cetinkaya A, Kurutas EB, Celik M, Polat A. Effects of N-acetylcysteine on methotrexate-induced small in- testinal damage in rats. Mt Sinai J Med 2006;73:1086-92.
25. Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken B. N-acetyl- cysteine ameliorates methotrexate-induced oxidative liver dam- age in rats. Med Sci Monit 2006;12:274-8.
26. Garipardic M, Bakan V, Davutoğlu M, Sayar H, Kurutaş EB. Oxi- dative stress and protective effect of erythropoietin on metho- trexate-induced esophageal damage. J Pediatr Hematol Oncol 2010;32:108-12. [CrossRef]
27. http://www.uptodate.com/contents/methotrexate-induced- lung-injury?source=search_result&search=mtx+lung&selectedTi tle=1%7E150.
28. Chikura B, Sathi N, Lane S, Dawson JK. Variation of immunologi- cal response in methotrexate-induced pneumonitis. Rheumatol- ogy 2008;47:1647-50. [CrossRef]
29. Hargreaves MR, Mowat AG, Benson MK. Acute pneumonitis as- sociated with low dose methotrexate treatment for rheumatoid arthritis:report of five cases and review of published reports. Tho- rax 1992;47:628-33. [CrossRef]
30. Rabie T, Marti HH. Brain Protection by Erythropoietin:A Manifold Task. Physiology 2008;23:263-74. [CrossRef]
31. Kobayashi T, Yanase H, Iwanaga T, Sasaki R, Nagao M. Epididymis is a novel site of erythropoietin production in mouse reproduc- tive organs. Biochem Biophys Res Commun 2002;296:145-51. [CrossRef]
32. Fandrey J, Bunn HF. In vivo and in vitro regulation of erythro- poietin mRNA:measurement by com-petitive polymerase chain reaction. Blood 1993;81:617-23.
33. Maiese K, Li F, Chong ZZ. New avenues of exploration for eryth- ropoietin. JAMA 2005;293:90-5. [CrossRef]
34. Brines M, Cerami A. Discovering erythropoietins extra-hema- topoietic functions:biology and clinical promise. Kidney Int 2006;70:246-50. [CrossRef]
35. Kumral A, Gonenc S, Acikgoz O, Sonmez A, Genc K, Yilmaz O. Erythropoietin increases glutathione peroxidase enzyme activity and decreases lipid peroxidation levels in hypoxicischemic brain injury in neonatal rats. Biol Neonate 2005;87:15-8. [CrossRef]
36. Guneli E, Cavdar Z, Islekel H, Sarioglu S, Erbayraktar S, Kiray M, et al. Erythropoietin protects the intestine against ischemia/ re- perfusion injury in rats. Mol Med 2007;13:509-17. [CrossRef]
37. Tascilar O, Cakmak G C, Tekin IO, Tekin IO, Emre AU, Ucan BH, et al. Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis. World J Gastroen- terol 2007;46:6172-82. [CrossRef]
38. Yildirim E, Ozisik K, Solaroglu I, Kaptanoglu E, Beskonakli E, Sargon MF, et al. Protective effect of erythropoietin on type II pneumocyte cells after traumatic brain injury in rats. J Trauma 2005;58:1252-8. [CrossRef]
39. Bakan V, Garipardic M, Okumuş M, Ciralik H, Atli Y, Ozbağ D, et al. The protective effect of erythropoietin on the acute phase of corrosive esophageal burns in a rat model. Pediatr Surg Int 2010;26:195-201. [CrossRef]
40. Wu H, Ren B, Zhu J, Dong G, Xu B, Wang C, et al. Pretreatment with recombined human erythropoietin attenuates ischemia- reperfusion-induced lung injury in rats. Eur J Cardiothorac Surg 2006;29:902-7. [CrossRef]
41. Rahman I, MacNee W. Lung glutathione and oxidative stress:implications in cigarette smoke-induced airway disease. Am J Physiol 1999;277:1067-88.