TY - JOUR T1 - The Effect of N-Acetylcysteine on Fibrosis in Experimental Rat Chronic Pancreatitis TT - Deneysel Kronik Pankreatitte N-Asetil Sistein Uygulamasinin Pankreatik Fibroz Üzerine Etkisi AU - Ocal, Ramazan AU - Tascı, İlker AU - Devecı, Mehmet Salih AU - Comert, Bilgin AU - Isık, Ahmet Turan AU - Mas, Mehmet Refik PY - 2019 DA - March JF - Muğla Sıtkı Koçman Üniversitesi Tıp Dergisi JO - MMJ PB - Mugla Sitki Kocman University WT - DergiPark SN - 2148-8118 SP - 26 EP - 32 VL - 6 IS - 1 LA - en AB - In this study, weaimed to assess the effect of N-acetylcysteine on fibrosis, atrophy andoxidative stress with chronic pancreatitis in an animal model. Chronicpancreatitis is stimulated by injection of 0.4 ml, 2% trinitrobenzene sulfanicacid (TNBS) into major pancreatic ducts of the rats. 60 Sprague-Dawley ratswere randomized into four group; Group I (n=15): saline (control), Grup II(n=15): fibrosis + N-acetylcysteine (NAC), Grup III (n=15): fibrosis (TNBS),Grup IV: ethanol. At the end of the 8th week, all rats were sacrificed, and ratpancreatic tissues, oxidative stress markers and progression of fibrosis andatrophy were examined. superoxide dismutase (SOD) and glutation peroxidase(GSH-Px) activities were significantly higher with respect to TNBS group(respectively p<0.001 and p<0.001); whereas tissue malondialdehyde (MDA)levels were found significantly lower in NAC group (p<0.001). Histopathological analysis of the tissuesrevealed that histopathological score of NAC group was significantly lower thanTNBS group (p<0.003), and was found a significant relation between increasein oxidative stress and histopathological score (histopathological score/MDA:p<0.03, SOD: p<0.04, GSH-Px: p<0,02). In conclusion, administration ofNAC decreases oxidative stress in chronic pancreatitis and has beneficialeffects on fibrosis and atrophy. KW - Animal Model KW - Experimental Chronic Pancreatitis KW - Fibrosis KW - N-Acetylcysteine N2 - Bu çalışmada,N-asetilsisteinin, kronik pankreatit hayvan modelinde fibrozis, atrofi veoksidatif stres üzerindeki etkisini değerlendirmeyi amaçladık. Kronikpankreatit, ratların ana pankreatik kanallarına 0.4 ml, %2’lik trinitrobenzensülfanik asit (TNBS) enjeksiyonu ile uyarılır. 60 Sprague-Dawley sıçanı dörtgruba randomize edildi; Grup I (n= 15): salin (sham), Grup II (n= 15): fibrozis+ N-asetilsistein (NAC), Grup III (n= 15): fibrozis (TNBS), Grup IV: etanol. 8.haftanın sonunda tüm ratlar sakrefiye edildi ve pankreatik dokular, oksidatifstres belirteçleri, fibrozis ve atrofi progresyonları incelendi. NAC grubundadoku malondialdehid (MDA) düzeyleri anlamlı olarak düşük bulunurken (p <0.001);süperoksit dismutaz (SOD) ve glutation peroksidaz (GSH-Px) aktiviteleri TNBSgrubuna göre anlamlı olarak yüksek bulundu (sırasıyla p <0.001 ve p <0.001).Dokulardaki histopatolojik incelemede NAC grubunun histopatolojik skorunun TNBSgrubundan anlamlı derecede düşük olduğu izlenirken (p<0.003) oksidatif stresile histopatolojik skordaki artış arasında anlamlı bir ilişki olduğu saptandı(histopatolojik skor/MDA: p<0.03, SOD: p<0.04, GSH-Px: p<0.02). Sonuçolarak, NAC uygulaması kronik pankreatitte oksidatif stresi azaltmakta olupfibrozis ve atrofi üzerinde yararlı etkilere sahiptir. CR - 1. Gupte AR, Forsmark CE. Chronic pancreatitis. Curr Opin Gastroenterol. 2014;30(5):500-5. CR - 2. Patel M, Fine DR. Fibrogenesis in the pancreas after acinar cell injury. Scand J Surg. 2005;94(2):108-11. CR - 3. Goh KL. Chronic pancreatitis: aetiology, epidemiology and clinical presentation. Med J Malaysia. 2005;60(Suppl B):94-8. CR - 4. Dryden GW Jr, Deaciuc I, Arteel G, McClain CJ. Clinical implications of oxidative stress and antioxidant therapy. Curr Gastroenterol Rep. 2005;7(4):308-16. CR - 5. Kakizaki S, Hamada T, Yoshinaga T, et al. Alcoholic chronic pancreatitis with simultaneous multiple severe complications-extrahepatic portal obliteration, obstructive jaundice and duodenal stricture. Hepatogastroenterology. 2005;52(64):1274-7. CR - 6. Gullo L, Migliori M, Brunetti MA, Manca M. Alcoholic pancreatitis: new insights into an old disease. Curr Gastroenterol Rep. 2005;7(2):96-100. CR - 7. Apte MV, Wilson JS. Mechanisms of pancreatic fibrosis. Dig Dis. 2004;22(3):273-9. CR - 8. Connelly E. Chronic pancreatitis debilitating for the patient, frustrating to manage. JAAPA. 2004;17(12):14-6. CR - 9. Bruno MJ. Chronic pancreatitis. Gastrointest Endosc Clin N Am. 2005;15(1):55-62. CR - 10. Schneider A, Whitcomb DC, Singer MV. Animal models in alcoholic pancreatitis-what can we learn? Pancreatology. 2002;2(3):189-203. CR - 11. Azima B, Kao RL, Youngberg G, Williams D, Browder W. A new animal model of reversible acute pancreatitis. J Surg Res. 1996;63(2):419-24. CR - 12. Zhou D, Wang W, Cheng X, Wei J, Zheng S. Antioxidant therapy for patients with chronic pancreatitis: A systematic review and meta-analysis. Clin Nutr. 2015;34(4):627-34. CR - 13. Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593-7. CR - 14. De Vries N, De Flora S. N-Acetyl-l-Cysteine. J Cell Biochem. 1993;17F:S270-7. CR - 15. Sevillano S, De la Mano AM, De Dios I, Ramudo L, Manso MA. Major pathological mechanisms of acute pancreatitis are prevented by N-acetylcysteine. Digestion. 2003;68(1):34-40. CR - 16. Yağcı G, Gül H, Simsek A, et al. Beneficial effects of N-acetylcysteine on sodium taurocholate-induced pancreatitis in rats. J Gastroenterol. 2004;39(3):268-76. CR - 17. Choudhury S, Ghosh S, Gupta P, Mukherjee S, Chattopadhyay S. Inflammation-induced ROS generation causes pancreatic cell death through modulation of Nrf2/NF-κB and SAPK/JNK pathway. Free Radic Res. 2015;49(11):1371-83. CR - 18. Haber PS, Keogh GW, Apte MV. Pancreatic stellate cells are activated in human and experimental pancreatitis. Gut. 1999;44:534-41. CR - 19. Puig-Divi V, Molero X, Slas A. Induction of chronic pancreatic disease by trinitrobenzene sulfonic acid infusion into rat pancreatic ducts. Pancreas. 1996;13(4):417-24. CR - 20. Aydın A, Orhan H, Sayal A, Ozata M, Sahin G, Işimer A. Oxidative stress and nitric oxide related parameters in type ıı diabetes mellitus: effects of glycemic control. Clin Biochem. 2001;34(1):65-70. CR - 21. Richard MJ, Arnaud J, Jurkowitz C, et al. Trace elements and lipid peroxidation abnormalities ın patients with chronic renal failure. Nephron. 1991;57(1):10-5. CR - 22. Braganza JM, Scott P. Bilton D. Evidence for early oxidative stress in acute pancreatitis. Int J Pancreatol. 1995;17(1):69-81. CR - 23. Mathew P, Wyllie R, VanLente F, Steffen RM, Kay MH. Antioxidants In Hereditary Pancreatitis. Am J Gastroenterol. 1996;91(8):1558-62. CR - 24. Morris-Stiff GJ, Bowrey DJ, Oleesky D. The antioxidant profiles of patients with recurrent acute and chronic pancreatitis. Am J Gastroenterol. 1999;94(8):2136-40. CR - 25. Van Gossum A, Closset P, Noel E, Cremer M, Neve J. Deficiency in antioxidant factors in patients with alcohol-related chronic pancreatitis. Dig Dis Sci. 1996;41(6):1225-31. CR - 26. Matsumura N, Ochi K, Ichimura M, Mizushima T, Harada H, Harada M. Study on free radicals and pancreatic fibrosis–pancreatic fibrosis induced by repeated injections of superoxyde dismutase inhibitor. Pancreas. 2001;22(1):53-7. CR - 27. Rose P, Fraine E, Hunt LP, Acheson DW, Braganza JM. Dietary antioxidants and chronic pancreatitis. Hum Nutr Clin Nutr. 1986;40(2):151-64. CR - 28. Castano H, Unzueta G, Agustín Domínguez D, et al. Pancreatic fibrosis in rats and ıts response to antioxidant treatment. JOP. 2005;6(4):316-24. CR - 29. Mas R, Işık AT, Yamanel L, et al. Antioxidant treatment with taurine ameliorates chronic pancreatitis in an experimental rat model. Pancreas. 2006;33(1):77-81. CR - 30. Ozturk K, Tasci I, Yasar M, et al. Effects of rapamycin treatment on pancreatic fibrosis, cellular apoptosis and oxidative stress in experimental chronic pancreatitis model. Acta Gastroenterol Belg. 2015;78(1):3-7. CR - 31. Sapronov NS, Khnychenko LK, Polevschikov AV. Effects of taurine derivatives on primaryy ımmune response. Bull Exp Biol Med. 2001;131(2):142-4. CR - 32. Denham W, Fink G, Yang J, Ulrich P, Tracey K, Norman J. Small molecule ınhibition of tnf gene processing during acute pancreatitis prevents cytokine cascade progression and attenuates pancreatitis severity. Am Surg. 1997;63(12):1045-9. CR - 33. Ethride RT, Hashimoto K, Chung DH, Ehlers RA, Rajaraman S, Evers BM. Selective inhibition of NF-kappa B attenuates the severity of cerulein-induced acute pancreatitis. J Am Coll Surg. 2002;195(4):497-505. CR - 34. Hughes CB, Grewal HP, Gaber LW, et al. Anti-TNFα therapy ımproves survival and ameliorates the pathophysiological sequale in acute pancreatitis in the rat. Am J Surg. 1996;171(2); 274-80. CR - 35. Ahn BO, Kim HG, Lee HS, et al. Effects of taurine on cerulein-induced acute pancreatitis in the rat. Pharmacology. 2001;63(1):1-7. CR - 36. Gomez JA, Molero X, VaqueroE, Alonso A, Salas A, Malagelada JR. Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2004;287:162-9. CR - 37. Seo JY, Kim H, Seo JT, Kim KH. Oxidative stress induced cytokine production in isolated rat pancreatic aciner cells: effects of small-molecule antioxidants, Pharmacology. 2002;64(2):63-70. CR - 38. Kim H, Seo JY, Roh KH, Lim JW, Kim KH. Suppression of NF-κB activation and cytokine production by N-Acetylcystein in pancreatic aciner cells. Free Radic Biol Med. 2000;29(7):674-83. CR - 39. Okazaki I, Watanabe T, Hozawa S, Arai M, Maruyama K. Molecular mechanism of the reversibility of matrix metalloproteinase’s. Hepatology. 2000;15(1):26-32. CR - 40. De Caro L, Ghizzi A, Costa R, Longo A, Ventresca GP, Lodola E. Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers. Arzneim Forsch. 1989;39(3):382-5. CR - 41. Olsson B, Johansson M, Gabrielsson J, Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol. 1988;34(1):77-82. CR - 42. Wagner PD, Mathieu-Costello O, Bebout DE, et al. Protection against pulmonary O2 toxicity by N-acetylcysteine. Protection against pulmonary O2 toxicity by N-acetylcysteine. Eur Respir J. 1989;2(2):116-26. CR - 43. Demols A, Van Laethem JL, Quertinmont E, et al. N-acetylcysteine decreases severity of acute pancreatitis in mice. Pancreas. 2000;20(2):161-9. CR - 44. Kim H, Seo JY, Kim KH. NF-kappaB and cytokines in pancreatic acinar cells. J Korean Med Sci. 2000;15:53-4. CR - 45. Bhatia M, Brady M, Kang YK, et al. MCP-1 but not CINC synthesis is increased in rat pancreatic acini in response to cerulein hyperstimulation. Am J Physiol Gastrointest Liver Physiol. 2002;282(1):77-85. CR - 46. Haraldsen P, Sun ZW, Börjesson A, Olanders K, Lasson A, Andersson R. Multimodal management of value in fulminant acute pancreatitis? Pancreatology. 2003;3(1):14-25. CR - 47. Shi C, Zhao X, Wang X, Andersson R. Role of nuclear factor-kappaB, reactive oxygen species and cellular signaling in the early phase of acute pancreatitis. Scand J Gastroenterol. 2005;40(1):103-8. CR - 48. Eşrefoğlu M, Gül M, Ateş B, Yilmaz I. Ultrastructural clues for the protective effect of ascorbic acid and N-acetylcysteine against oxidative damage on caerulein-induced pancreatitis. Pancreatology. 2006;6(5):477-85. CR - 49. Kalyoncu NI, Alhan E, Ercin C, Kural BV. Effects of dual inhibitor of cyclooxygenase and 5-lipoxygenase on acute necrotizing pancreatitis in rats. Hepatogastroenterology. 2006;53(70):597-602. CR - 50. Sevillano S, de Dios I, de la Mano AM, Manso MA. N-acetylcysteine induces beneficial changes in the acinar cell cycle progression in the course of acute pancreatitis. Cell Prolif. 2003;36(5):279-89. CR - 51. Sevillano S, de la Mano AM, Manso MA. N-acetylcysteine prevents intra-acinar oxygen free radical production in pancreatic duct obstruction-induced acute pancreatitis. Biochim Biophys Acta. 2003;36(5):279-89. CR - 52. Asaumi H, Watanabe S, Taguchi M, Tashiro M, Otsuki M. Externally-applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species, Am J Physiol Gastrointest Liver Physiol. 2007;293(5):972-8. CR - 53. Menke A, Adler G. TGF Beta-induced fibrogenesis of the pancreas. Int J Gastrointest Cancer. 2002;31(1-3):41-6. CR - 54. Shek FWT, Benyon RC, Walker FM, et al. Expression of transforming growth factor-β1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol. 2002;160(5):1787-98. UR - https://dergipark.org.tr/en/pub/muskutd/issue//493785 L1 - https://dergipark.org.tr/en/download/article-file/674900 ER -