Experimental Study of Protective Effects of N-Acetylcysteine on The Intestinal Barrier in Rats with Severe Acute Pancreatitis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Yingzhen ¹ ,  NIU Tianping ² , CAO Yunhua ¹ , WANG Jun ² , LI Zili ² , XIAO Wen ² , ZHANG Youcheng ¹ , WANG Shiwen. ³

1.Department of General Surgery， The Second Hospital of Lanzhou University， Lanzhou 730030， Gansu Province， China;;
2.Emergency Medical Rescue Center of Gansu Province， Lanzhou 730030， Gansu Province， China;;
3.Department of General Surgery， The Second People’s Hospital of Gansu Province， Lanzhou 730030， Gansu Province， China;

Corresponding author：

NIU Tianping, Email: niutp120@hotmail.com

Keywords：

N-acetylcysteine; Severe acute pancreatitis; Intestinal barrier; Apoptosis; Oxidization; Rat

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Objective 　To investigate the effects of N-acetylcysteine （NAC） on the intestinal barrier in rats with severe acute pancreatitis （SAP） and its possible mechanism.
Methods 　Eighty Wistar rats were randomly （random number method） divided into normal control group （CON group， n=8）， sham operation group （SO group， n=24）， SAP group （n=24）， and NAC group （n=24）， then the rats of latter 3 groups were sub-divided into 6， 12， and 24 hours group， each time point group enrolled 8 rats， respectively. Rats of CON group didn’t receive any treatment. SAP rat models were established by injecting 5.0% sodium taurocholate into the biliary-pancreatic duct for SAP group and NAC group， while rats of SO group were injected normal saline instead of sodium taurocholate. The rats of NAC group were given an intraperitoneal injection of NAC at 1 hour before operation， and the rats of SO group and SAP group were given an intraperitoneal injection of normal saline instead at the same time. Rats of CON group were sacrificed to get ileum （about 5cm） and blood from right ventricular （5mL） for further test， and rats of the other 3 groups were sacrificed at 6， 12， and 24hours after operation. Then the levels of amylase （AMY）， C-reactive protein （CRP）， endotoxin， D-lactic acid， and diamine oxidase （DAO） in plasma， the levels of superoxide dismutase （T-SOD）， myeloperoxidase （MPO）， and malondialdehyde （MDA） in ileum tissues were tested. Apoptosis of mucosal cells in ileum tissues was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling （TUNEL）. Pathological changes in ileum tissues were observed and scored. Expression levels of bax and bcl-2mRNA in ileum tissues were determined by real-time
fluorescence quantitative PCR （real-time PCR）， and related proteins were tested by Western blot method， respectively.
Results 　Compared with SAP group at the same time point， the levels of CRP in NAC group were lower at all the 3 time points （P＜0.05） and AMY were lower at 12 and 24 hours （P＜0.05）， levels of DAO， endotoxin， and D-lactic acid were lower at 12 and 24 hours （P＜0.05）， but level of DAO was higher than SAP group at 6 hours （P＜0.05）. Compared with SAP group at the same time point， the levels of MPO and MDA in ileum tissues were lower in NAC group at all the 3 time points （P＜0.05）， but levels of T-SOD increased significantly at 12 and 24 hours （P＜0.05）. Compared with SAP group at the same time point， the apoptosis indexes were lower in NAC group at all the 3 time points （P＜0.01）， and pathologic scores of ileum tissues were lower at 12 and 24 hours （P＜0.05）. The pathological changes under a light microscope were observed better in NAC group than that of SAP group at each time point. Moreover， compared with SAP group at the same time point， the expression levels of bax mRNA and protein were lower in NAC group at all the 3 time points （P＜0.05）， while higher in bcl-2 mRNA and protein （P＜0.05）.
Conclusions 　NAC can protect the function of small intestinal barrier， and can alleviate SAP-induced injury of the intestinal mucosa. In addition to antioxidant effects， the underlying mechanisms also may include the anti-apoptotic effects.

Citation： WANG Yingzhen,NIU Tianping,CAO Yunhua,WANG Jun,LI Zili,XIAO Wen,ZHANG Youcheng,WANG Shiwen.. Experimental Study of Protective Effects of N-Acetylcysteine on The Intestinal Barrier in Rats with Severe Acute Pancreatitis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(3): 271-279. doi: Copy

1.	孙备，董承刚，王刚，等. 重症急性胰腺炎死亡的高危因素分析[J]. 中华外科杂志， 2007， 45(23)：1619-1622.
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7.	Oz S， Okay E， Karadenizli A， et al. N-acetylcysteine improves intestinal barrier in partially hepatectomized rats[J]. ANZ J Surg， 2007， 77(3)：173-176.
8.	邹忠东，张再重，王瑜，等. N-乙酰半胱氨酸对重症急性胰腺炎大鼠肠道屏障功能障碍与二次打击的保护作用[J]. 中华实验外科杂志， 2009， 26(1)：64-66.
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11.	Leveau P， Wang X， Sun Z， et al. Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant[J]. Biochem Pharmacol， 2005， 69(9)：1325-1331.
12.	王强，王湘英，黄硕，等. 重症急性胰腺炎大鼠胃肠动力障碍机理的实验研究[J]. 中国普外基础与临床杂志， 2012， 19(4)：419-423.
13.	李奇智，吴新民，郭亚民. 相关细胞因子在重症急性胰腺炎相关肺损伤中的作用[J]. 中国普外基础与临床杂志， 2011， 18(3)：258-260.
14.	Zayat M， Lichtenberger LM， Dial EJ. Pathophysiology of LPS-induced gastrointestinal injury in the rat：role of secretory phospholipase A2[J]. Shock， 2008， 30(2)：206-211.
15.	Peng Y， Gallagher SF， Landmann R， et al. The role of p65NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis[J]. J Gastrointest Surg， 2006， 10(6)：837-847.
16.	Gómez-Cambronero LG， Sabater L， Pereda J， et al. Role of cytokines and oxidative stress in the pathophysiology of acute pancreatitis：therapeutical implications[J]. Curr Drug Targets Inflamm Allergy， 2002， 1(4)：393-403.
17.	Tadao M， Yuji O. Role of free radicals in the development of severe acute pancreatitis[J]. Nippon Rinsho， 2004， 62(11)：2015-2020.
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19.	Dryden GW Jr， Deaciuc I， Arteel G， et al. Clinical implications of oxidative stress and antioxidant therapy[J]. Curr Gastroenterol Rep， 2005， 7(4)：308-316.
20.	Czakó L， Hegyi P， Takács T， et al. Effects of octreotide on acute necrotizing pancreatitis in rabbits[J]. World J Gastroenterol， 2004， 10(14)：2082-2086.
21.	Telek G， Regöly-Mérei J， Kovács GC， et al. The first histologicaldemonstration of pancreatic oxidative stress in human acutepancreatitis[J]. Hepatogastroenterology， 2001， 48(41)：1252-1258.
22.	Sevillano S， De la Mano AM， De dios I， et al. Major pathologicalmechanisms of acute pancreatitis are prevented by N-acetylcysteine[J]. Digestion， 2003， 68(1)：34-40.
23.	Sevillano S， De la Mano AM， Manso MA， et al. N-acetylcysteine prevents intra-acinar oxygen free radical production in pancreatic duct obstruction-induced acute pancreatitis[J]. Biochim BiophysActa， 2003， 1639(3)：177-184.
24.	Xu GF， Lu Z， Gao J， et al. Effect of ecoimmunonutrition supportson maintenance of integrity of intestinal mucosal barrier in severe acute pancreatitis in dogs[J]. Chin Med J (Engl)， 2006， 119(8)：656-661.
25.	Abu-Hilal M， Mcphail MJ， Marchand L， et al. Malondialdehyde and superoxide dismutase as potential markers of severity in acute pancreatitis[J]. JOP， 2006， 7(2)：185-192.
26.	Park BK， Chung JB， Lee JH， et al. Role of oxygen free radicals in patients with acute pancreatitis[J]. World J Gastroenterol， 2003， 9(10)：2266-2269.
27.	Baregamian N， Song J， Jeschke MG， et al. IGF-1 protects intestinalepithelial cells from oxidative stress-induced apoptosis[J]. J Surg Res， 2006， 136(1)：31-37.

1. 孙备，董承刚，王刚，等. 重症急性胰腺炎死亡的高危因素分析[J]. 中华外科杂志， 2007， 45(23)：1619-1622.
2. 王琛，樊勇. 急性胰腺炎常见并发症及防治[J]. 中国普外基础与临床杂志， 2010， 17(10)：1107-1108.
3. 闫堃，黎一鸣，纪宗正，等. 缓释泵法制备急性胰腺炎大鼠模型[J]. 中国普外基础与临床杂志， 2011， 18(7)：717-721.
4. Tayman C， Tonbul A， Kosus A， et al. N-acetylcysteine may preventsevere intestinal damage in necrotizing enterocolitis[J]. J PediatrSurg， 2012， 47(3)：540-550.
5. Takatsuka S， Morita T， Horikiri Y， et al. Absorption enhancement of poorly absorbed hydrophilic compounds from various mucosal sites by combination of mucolytic agent and non-ionic surfactant[J]. Int J Pharm， 2007， 338(1-2)：87-93.
6. Johnson ST， Bigam DL， Emara M， et al. Effects of N-acetylcysteine on intestinal reoxygenation injury in hypoxic newborn piglets resuscitated with 100% oxygen[J]. Neonatology， 2009， 96(3)：162-170.
7. Oz S， Okay E， Karadenizli A， et al. N-acetylcysteine improves intestinal barrier in partially hepatectomized rats[J]. ANZ J Surg， 2007， 77(3)：173-176.
8. 邹忠东，张再重，王瑜，等. N-乙酰半胱氨酸对重症急性胰腺炎大鼠肠道屏障功能障碍与二次打击的保护作用[J]. 中华实验外科杂志， 2009， 26(1)：64-66.
9. 黎君友，于燕，郝军，等. 分光光度法测定血和小肠组织二胺氧化酶活性[J]. 氨基酸和生物资源， 1996， 18(4)：28-30.
10. Chiu CJ， Mcardle AH， Brown R， et al. Intestinal mucosal lesionin low-flow states. Ⅰ. A morphological， hemodynamic， and meta-bolic reappraisal[J]. Arch Surg， 1970， 101(4)：478-483.
11. Leveau P， Wang X， Sun Z， et al. Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant[J]. Biochem Pharmacol， 2005， 69(9)：1325-1331.
12. 王强，王湘英，黄硕，等. 重症急性胰腺炎大鼠胃肠动力障碍机理的实验研究[J]. 中国普外基础与临床杂志， 2012， 19(4)：419-423.
13. 李奇智，吴新民，郭亚民. 相关细胞因子在重症急性胰腺炎相关肺损伤中的作用[J]. 中国普外基础与临床杂志， 2011， 18(3)：258-260.
14. Zayat M， Lichtenberger LM， Dial EJ. Pathophysiology of LPS-induced gastrointestinal injury in the rat：role of secretory phospholipase A2[J]. Shock， 2008， 30(2)：206-211.
15. Peng Y， Gallagher SF， Landmann R， et al. The role of p65NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis[J]. J Gastrointest Surg， 2006， 10(6)：837-847.
16. Gómez-Cambronero LG， Sabater L， Pereda J， et al. Role of cytokines and oxidative stress in the pathophysiology of acute pancreatitis：therapeutical implications[J]. Curr Drug Targets Inflamm Allergy， 2002， 1(4)：393-403.
17. Tadao M， Yuji O. Role of free radicals in the development of severe acute pancreatitis[J]. Nippon Rinsho， 2004， 62(11)：2015-2020.
18. Sha H， Ma Q， Jha RK. Trypsin is the culprit of multiple organ injury with severe acute pancreatitis[J]. Med Hypotheses， 2009， 72(2)：180-182.
19. Dryden GW Jr， Deaciuc I， Arteel G， et al. Clinical implications of oxidative stress and antioxidant therapy[J]. Curr Gastroenterol Rep， 2005， 7(4)：308-316.
20. Czakó L， Hegyi P， Takács T， et al. Effects of octreotide on acute necrotizing pancreatitis in rabbits[J]. World J Gastroenterol， 2004， 10(14)：2082-2086.
21. Telek G， Regöly-Mérei J， Kovács GC， et al. The first histologicaldemonstration of pancreatic oxidative stress in human acutepancreatitis[J]. Hepatogastroenterology， 2001， 48(41)：1252-1258.
22. Sevillano S， De la Mano AM， De dios I， et al. Major pathologicalmechanisms of acute pancreatitis are prevented by N-acetylcysteine[J]. Digestion， 2003， 68(1)：34-40.
23. Sevillano S， De la Mano AM， Manso MA， et al. N-acetylcysteine prevents intra-acinar oxygen free radical production in pancreatic duct obstruction-induced acute pancreatitis[J]. Biochim BiophysActa， 2003， 1639(3)：177-184.
24. Xu GF， Lu Z， Gao J， et al. Effect of ecoimmunonutrition supportson maintenance of integrity of intestinal mucosal barrier in severe acute pancreatitis in dogs[J]. Chin Med J (Engl)， 2006， 119(8)：656-661.
25. Abu-Hilal M， Mcphail MJ， Marchand L， et al. Malondialdehyde and superoxide dismutase as potential markers of severity in acute pancreatitis[J]. JOP， 2006， 7(2)：185-192.
26. Park BK， Chung JB， Lee JH， et al. Role of oxygen free radicals in patients with acute pancreatitis[J]. World J Gastroenterol， 2003， 9(10)：2266-2269.
27. Baregamian N， Song J， Jeschke MG， et al. IGF-1 protects intestinalepithelial cells from oxidative stress-induced apoptosis[J]. J Surg Res， 2006， 136(1)：31-37.

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Experimental Study of Protective Effects of N-Acetylcysteine on The Intestinal Barrier in Rats with Severe Acute Pancreatitis

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