Protective Effects of Erythropoietin and N-Acetylcysteine on Methotrexate-Induced Lung Injury in Rats

Year 2013, Volume: 2013 Issue: 1, 99 - 104, 01.01.2013

Hasan Kahraman Ergül Kurutaş Mahmut Tokur Selim Bozkurt Harun Çıralık Betül Kabakcı Nurhan Köksal Vedat Balkan

https://doi.org/10.5152/balkanmedj.2012.078

Abstract

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 (p<0.005). In EPO group MDA, CAT, and SOD were higher, but not significant than those in group NAC (p>0.005). In group MTX both scores were significantly higher than in sham (p<0.005). The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005). Conclusion: EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups. Turkish Başlık: Eritropoietin ve N-Asetilsistein'in Ratlarda, Metotreksat ile Oluşturulan Akciğer Hasarı Üzerine Koruyucu Etkisi Anahtar Kelimeler: Metotreksat, akciğer, oksidatif hasar, eritropoetin, N-asetil-sistein Amaç: Metotreksat (MTX)'ın akciğer dokusu üzerine zararlı etkileri olduğu bilinmektedir. Biz sıçanlarda MTX ile oluşturulan akciğer hasarı üzerine, eritropoietin (EPO) ve N-asetil-sistein (NAC)' in etkilerini araştırmayı amaçladık. Gereç ve Yöntemler: Yirmi altı dişi Sprague-Dawley sıçan 4 gruba ayrıldı. Sham grubuna, 0.3 ml serum fizyolojik; MTX grubuna, 5 mg/kg MTX; EPO grubuna, 5mg/kg MTX ve 2000 IU/kg EPO; NAC grubuna, 5 mg/kg MTX ile 200 mg/kg NAC 4 gün boyunca hergün, günde bir kez uygulandı. Malondialdehit (MDA), süperoksit dismutaz (SOD), katalaz (CAT) ve akciğer dokusunda inflamasyon ve konjesyon skorları değerlendirildi. Bulgular: MTX grubunda sham, EPO ve NAC gruplarındakine göre MDA anlamlı olarak yüksek, CAT ve SOD ise anlamlı olarak düşük idi. MDA, CAT ve SOD EPO grubunda, NAC grubundakine göre anlamlı olmayarak yüksek idi. Her iki skor MTX grubunda, sham grubundakine göre anlamlı olarak yüksek bulunmuştur. Konjesyon skoru MTX grubunda EPO ve NAC gruplarındakine göre anlamlı olarak yüksek saptandı. Sonuç: EPO ve NAC sıçanlarda MTX ile oluşturulan akciğer hasarı üzerine önemli koruyucu etkileri var. MTX grubunda azalmış antioksidan kapasite ve yüksek MDA düzeyi oksidatif hasara neden olmuş olabilir. Ayrıca, EPO ve NAC gruplarında yüksek antioksidan kapasite ve düşük MDA düzeyi oksidatif strese karşı oluşan bir yanıt olabilir.

Keywords

Methotrexate, lung, oxidative damage, erythropoietin, N-acetyl-cysteine

Protective Effects of Erythropoietin and N-Acetylcysteine on Methotrexate-Induced Lung Injury in Rats

Abstract

References

• 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]
• 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 children’s oncology group. J Pediatr Hematol Oncol 2012;34:e1-7.
• Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum 1996;39:1951-60. [CrossRef]
• Kimura E, Nishimura K, Sakata K, Oga S, Kashiwagi K, Igarashi K. Methotrexate differentially affects growth of suspension and adherent cells. Int J Biochem Cell Biol 2004;36:814-25. [CrossRef]
• Yamauchi Y, Okazaki H, Desaki M, Kohyama T, Kawasaki S, Yamamoto K, et al. Methotrexate induces interleukin-8 production by human bronchial and alveolar epithelial cells. Clin Sci 2004;106:619-25. [CrossRef]
• Hsu DC, Katelaris CH. Long-term management of patients taking immunosuppressive drugs. Aust Prescr 2009;32:68-7.
• Ohbayashi M, Suzuki M, Yashiro Y, Fukuwaka S, Yasuda M, Kohyama N, et al. Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro. J Toxicol Sci 2010;35:653-61. [CrossRef]
• 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]
• 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]
• Beers MF. Oxygen therapy and pulmonary oxygen toxicity. In:Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI, eds. Fishman’s Pulmonary Disease and Disorders, 4th ed. New York:Mc Graw Hill, 2008:2624-8.
• 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]
• Erbayraktar S, Lanerolle N, Lotbiniere A, Knisely JP, Erbayraktar Z, Yilmaz O, et al. Carbamylated erythropoietin reduces radiosurgically-induced brain injury. Mol Med. 2006;12:74-80. [CrossRef]
• Hardee ME, Arıcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer. Clin Cancer Res 2006;12:332-9. [CrossRef]
• 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]
• Cuzzocrea S, Mazzon E, Di Paola R, Patel NS, Genovese T, Muià C, et al. Erythropoietin reduces the development of experimental inflammatory bowel disease. J Pharmacol Exp Ther 2004;311:1272-80. [CrossRef]
• 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 ventilation. Am J Physiol Lung Cell Mol Physiol 2012;302:L640-50. [CrossRef]
• Maeda T, Miyazono Y, Ito K. Oxidative stress and enhanced paracellular permeability in the small intestine of methotrexate-treated rats. Cancer Chemother Pharmacol 2010;65:1117-23. [CrossRef]
• 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]
• Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8. [CrossRef]
• Fridovich I. Superoxide dismutase. Adv Enzymol Relat Areas Mol Biol 1974;41:35-97.
• Beutler E. Red Cell Metabolism. 2nd ed. New York:Grune and Stratton Company. 1975:261-5.
• Lowry OH, Rosebrough NJ, Farr A. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:265-75.
• Atalay C, Dogan N, Aykan S, Gundogdu C, Keles MS. The efficacy of spironolactone in the treatment of acute respiratory distress syndrome-induced rats. Singapore Med J 2010;51:501-5.
• Ciralik H, Bulbuloglu E, Cetinkaya A, Kurutas EB, Celik M, Polat A. Effects of N-acetylcysteine on methotrexate-induced small intestinal damage in rats. Mt Sinai J Med 2006;73:1086-92.
• Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken B. N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats. Med Sci Monit 2006;12:274-8.
• Garipardic M, Bakan V, Davutoğlu M, Sayar H, Kurutaş EB. Oxidative stress and protective effect of erythropoietin on methotrexate-induced esophageal damage. J Pediatr Hematol Oncol 2010;32:108-12. [CrossRef] http://www.uptodate.com/contents/methotrexate-inducedlung-injury?source=search_result&search=mtx+lung&selectedTi tle=1%7E150.
• Chikura B, Sathi N, Lane S, Dawson JK. Variation of immunological response in methotrexate-induced pneumonitis. Rheumatology 2008;47:1647-50. [CrossRef]
• Hargreaves MR, Mowat AG, Benson MK. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis:report of five cases and review of published reports. Thorax 1992;47:628-33. [CrossRef]
• Rabie T, Marti HH. Brain Protection by Erythropoietin:A Manifold Task. Physiology 2008;23:263-74. [CrossRef]
• Kobayashi T, Yanase H, Iwanaga T, Sasaki R, Nagao M. Epididymis is a novel site of erythropoietin production in mouse reproductive organs. Biochem Biophys Res Commun 2002;296:145-51. [CrossRef]
• Fandrey J, Bunn HF. In vivo and in vitro regulation of erythropoietin mRNA:measurement by com-petitive polymerase chain reaction. Blood 1993;81:617-23.
• Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA 2005;293:90-5. [CrossRef]
• Brines M, Cerami A. Discovering erythropoietin’s extra-hematopoietic functions:biology and clinical promise. Kidney Int 2006;70:246-50. [CrossRef]
• 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]
• Guneli E, Cavdar Z, Islekel H, Sarioglu S, Erbayraktar S, Kiray M, et al. Erythropoietin protects the intestine against ischemia/ reperfusion injury in rats. Mol Med 2007;13:509-17. [CrossRef]
• 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 Gastroenterol 2007;46:6172-82. [CrossRef]
• 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]
• 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]
• Wu H, Ren B, Zhu J, Dong G, Xu B, Wang C, et al. Pretreatment with recombined human erythropoietin attenuates ischemiareperfusion-induced lung injury in rats. Eur J Cardiothorac Surg 2006;29:902-7. [CrossRef]
• Rahman I, MacNee W. Lung glutathione and oxidative stress:implications in cigarette smoke-induced airway disease. Am J Physiol 1999;277:1067-88.