Protective effect of nuclear factor E2-related factor 2 overexpression against acute pancreatitis in rats

Xu FU; Peiwu LI; Li MA; Bei ZHANG; Li HAN; Yanfei MENG; Yingzhen WANG

doi:10.16016/j.1000-5404.201903071

您当前的位置：

首页 >

文章列表页 >

Protective effect of nuclear factor E2-related factor 2 overexpression against acute pancreatitis in rats

Basic Medicine | 更新时间：2026-01-09

- Protective effect of nuclear factor E2-related factor 2 overexpression against acute pancreatitis in rats
- Journal of Third Military Medical University Vol. 41, Issue 16, Pages: 1552-1558(2019)
- 作者机构：
  
  1.730030 兰州，兰州大学第二医院：急救中心
  2.730030 兰州，兰州大学第二医院：急诊医学实验室
  3.730030 兰州，兰州大学第二医院：急诊重症监护室
- 作者简介：
- 基金信息：
  
  the Health Science Research Program of Gansu Province(GSWSKY-2015-60);the Research Funds of Second Hospital of Lanzhou University(ynbskyjj2015-2-4);the Cuiying Sci-Tech Innovation Program of Second Hospital of Lanzhou University(CY2017-QN04)
- DOI：10.16016/j.1000-5404.201903071
  CLC： R394.3;R363.22;R576
- Received：08 March 2019，
  
  Revised：2019-05-08，
  
  Published：30 August 2019
- 稿件说明：
移动端阅览
Xu FU, Peiwu LI, Li MA, et al. Protective effect of nuclear factor E2-related factor 2 overexpression against acute pancreatitis in rats[J]. Journal of Third Military Medical University, 2019, 41(16): 1552-1558.
DOI：

Xu FU, Peiwu LI, Li MA, et al. Protective effect of nuclear factor E2-related factor 2 overexpression against acute pancreatitis in rats[J]. Journal of Third Military Medical University, 2019, 41(16): 1552-1558. DOI： 10.16016/j.1000-5404.201903071.

摘要

目的

探讨核因子E2相关因子2(nuclear factor E2-related factor 2

Nrf2)过表达对急性胰腺炎(acute pancreatitis

AP)大鼠的保护机制。

方法

32只雄性SD大鼠按照随机数字表法分为4组：阴性对照组(NC)，胰腺炎组(NC+AP)，过表达组(Nrf2

+/+

)，过表达胰腺炎组(Nrf2

+/+

+AP)。采用尾静脉注射法进行慢病毒转染，转染48 h后，采用蛙皮素联合脂多糖腹腔注射法建立大鼠AP模型。建模成功24 h后处死大鼠采集标本，采用对-硝基苯麦芽七糖苷法检测大鼠血清淀粉酶活性；RT-PCR检测胰腺Nrf2、HO-1和NQO1 mRNA相对表达量；Western blot检测Nrf2、HO-1和NQO1蛋白相对表达量；HE染色观察胰腺组织病理学改变并评分。

结果

胰腺炎组(200.72±14.56)U/dL及过表达胰腺炎组(184.60±11.75)U/dL血清淀粉酶水平均较阴性对照组(162.48±13.19)U/dL及过表达组(170.34±11.75)U/dL明显升高，差异有统计学意义(

0.01)，而过表达胰腺炎组较胰腺炎组明显降低，差异有统计学意义(

0.05)；过表达胰腺炎组中Nrf2、HO-1和NQO1 mRNA表达量分别为(2.78±0.59)、(1.51±0.18)、(1.61±0.22)，较阴性对照组显著升高，且过表达胰腺炎组Nrf2 mRNA表达高于胰腺炎组，差异均有统计学意义(

0.05)；过表达胰腺炎组中Nrf2、HO-1和NQO1蛋白表达量分别为(2.78±0.59)、(1.51±0.18)、(1.61±0.22)，均较阴性对照组显著升高，且过表达胰腺炎组Nrf2和NQO1蛋白表达量明显高于胰腺炎组(

0.05)；胰腺炎组及过表达胰腺炎组胰腺组织HE染色均符合AP的表现，阴性对照组及过表达组胰腺组织病理检查除部分血管周围和胰腺间质偶尔可见少量炎性细胞浸润外，余未见明显异常改变，而过表达组胰腺组织改变较胰腺炎组有所改善，胰腺病理学损伤评分也明显降低。

结论

过表达Nrf2基因对蛙皮素联合脂多糖诱导的AP大鼠的胰腺具有一定的保护作用，这种作用可能与通过Nrf2的过表达，诱导其下游抗氧化酶HO-1及NQO1的表达有关。

Abstract

Objective

To investigate the protective effect of nuclear factor E2-related factor 2 (Nrf2) overexpression against acute pancreatitis (AP) in rats and the possible mechanism.

Methods

Thirty-two male SD rats were randomized into negative control group (NC)

AP group

Nrf2 overexpression group (Nrf2

+/+

) and Nrf2

+/+

+AP group. Nrf2 overexpression was induced by injection of a lentiviral vector carrying Nrf2 gen

e through the tail vein

and the empty viral vector was injected as the control in NC group and AP group. At 48 h after the lentivirus injection

rat models of AP were established in all but the NC group by intraperitoneal injections of lipopolysaccharide (LPS) and cerulein. At 24 h after successful modeling

the rats were sacrificed for detecting serum amylase activity and the expressions of Nrf2

heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the pancreas using RT-PCR and Western blotting. The histopathological changes of the pancreas were observed using HE staining and scored.

Results

Serum amylase levels were significantly higher in AP group (200.72±14.56 U/dL) and Nrf2

+/+

+AP group (184.60±11.75 U/dL) than in the NC group (162.48±13.19 U/dL) and Nrf2

+/+

group (170.34±11.75 U/dL;

0.01)

and was significantly lower in Nrf2

+/+

+AP group than in AP group (

0.05). Nrf2

HO-1 and NQO1 mRNA expressions in the pancreas were significantly increased in Nrf2

+/+

+AP group as compared with those in NC group (

0.05). The expression level of Nrf2 mRNA was significantly higher in Nrf2

+/+

+AP group than in AP group (

0.05). Similarly

the protein expressions of Nrf2

HO-1 and NQO1 in the pancreas were significantly higher in Nrf2

+/+

+AP group than in NC group

and the expressions of Nrf2 and NQO1 were significantly higher in Nrf2

+/+

+AP group than in AP group (

0.05). In NC group and Nrf2

+/+

group

HE staining revealed evident pathological changes typical of AP in the pancreas

where a few infiltrating inflammatory cells could be seen in the perivascular and pancreatic stroma. Such changes were alleviated in Nrf2

+/+

+AP group

which also had a significantly reduced score of pancreatic pathology as compared with that in AP group.

Conclusion

In the rat models of LPS- and cerulean-induced AP

overexpression of Nrf2 gene can alleviate the pancreatic injuries possibly by up-regulating the expressions of HO-1 and NQO1 in the pancreas.

关键词

Keywords

references

BANKS P A, BOLLEN T L, DERVENIS C, et al . Classification of acute pancreatitis: 2012: revision of the Atlanta classification and definitions by international consensus[J ] . Gut, 2013, 62(1): 102-111. DOI: 10.1136/ gutjnl-2012-302779.

PEERY A F, CROCKETT S D, MURPHY C C, et al . Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018[J ] . Gastroenterology, 2019, 156(1): 254-272.e11. DOI: 10.1053/j.gastro.2018.08.063.

TENNER S, BAILLIE J, DEWITT J, et al . American College of Gastroenterology guideline: management of acute pancreatitis[J ] . Am J Gastroenterol, 2013, 108(9): 1400-1415, 1416. DOI: 10.1038/ajg.2013.218.

SHEN H, BEN Q W, JIANG Y, et al . Body mass index and the risk and prognosis of acute pancreatitis: A meta-analysis[J ] . Eur J Gastroenterol Hepatol, 2011, 23(12): 1136-1143. DOI: 10.1097/MEG. 0b013e32834b0e0e.

KRISHNA S G, HINTON A, OZA V, et al . Morbid obesity is associated with adverse clinical outcomes in acute pancreatitis: A propensity-matched study[J ] . Am J Gastroenterol, 2015, 110(11): 1608-1619. DOI: 10.1038/ajg.2015.343.

PEERY A F, CROCKETT S D, BARRITT A S, et al . Burden of gastrointestinal, liver, and pancreatic diseases in the United States[J ] . Gastroenterology, 2015, 149(7): 1731-1741.e3. DOI: 10.1053/j.gastro.2015.08.045.

HAZRA N, GULLIFORD M. Evaluating pancreatitis in primary care: A population-based cohort study[J]. Br J Gen Pract, 2014, 64(622): e295-e301. DOI: 10.3399/bjgp14X679732.

DONNELLY P E, WINCH D E. Acute pancreatitis[J]. N Engl J Med, 2017, 376(6): 597. DOI: 10.1056/NEJMc1616177.

SCHMIDLIN C J, DODSON M B, MADHAVAN L, et al . Redox regulation by NRF2 in aging and disease[J ] . Free Radic Biol Med, 2019, 134: 702-707. DOI: 10.1016/j.freeradbiomed.2019.01.016.

SHA H C, MA Q Y, JHA R K. Trypsin is the culprit of multiple organ injury with severe acute pancreatitis[J]. Med Hypotheses, 2009, 72(2): 180-182. DOI: 10.1016/j.mehy.2008.09.007.

JEONG W S, JUN M, KONG A N. Nrf2: a potential molecular target for cancer chemoprevention by natural compounds[J]. Antioxid Redox Signal, 2006, 8(1/2): 99-106. DOI: 10.1089/ars.2006.8.99.

RUBIOLO J A, MITHIEUX G, VEGA F V. Resveratrol protects primary rat hepatocytes against oxidative stress damage: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes[J]. Eur J Pharmacol, 2008, 591(1/2/3): 66-72. DOI: 10.1016/j.ejphar.2008.06.067.

KIM S K, YANG J W, KIM M R, et al . Increased expression of Nrf2/ARE-dependent anti-oxidant proteins in Tamoxifen-res istant breast cancer cells[J ] . Free Radic Biol Med, 2008, 45(4): 537-546. DOI: 10.1016/j.freeradbiomed.2008.05.011.

WANG Y Z, ZHANG Y C, CHENG J S, et al . BML-111, a lipoxin receptor agonist, ameliorates 'two-hit'-induced acute pancreatitis-associated lung injury in mice by the upregulation of heme oxygenase-1[J ] . Artif Cells Nanomed Biotechnol, 2014, 42(2): 110-120. DOI: 10.3109/21691401.2013.794355.

WANG Y Z, ZHANG Y C, CHENG J S, et al . Protective effects of BML-111 on cerulein-induced acute pancreatitis-associated lung injury via activation of Nrf2/ARE signaling pathway[J ] . Inflammation, 2014, 37(4): 1120-1133. DOI: 10.1007/s10753-014-9836-y..

ZHANG F, FEI J, ZHAO B, et al . Protective effect of adenoviral transfer of heme oxygenase-1 gene on rats with severe acute pancreatitis[J ] . Am J Med Sci, 2014, 348(3): 224-231. DOI: 10.1097/MAJ.0000000000000225.

LEE J M, LI J, JOHNSON D A, et al . Nrf2, a multi-organ protector?[J ] . FASEB J, 2005, 19(9): 1061-1066. DOI: 10.1096/fj.04-2591hyp.

CHO H Y, REDDY S P, DEBIASE A, et al .Gene expression profiling of NRF2-mediated protection against oxidative injury[J ] . Free Radic Biol Med, 2005, 38(3): 325-343. DOI: 10.1016/j.freeradbiomed.2004.10.013.

YU X, KENSLER T. Nrf2 as a target for cancer chemoprevention[J]. Mutat Res, 2005, 591(1/2): 93-102. DOI: 10.1016/j.mrfmmm.2005.04.017.

LU Y F, LIU J, WU K C, et al . Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice[J ] . PLoS ONE, 2014, 9(3): e93013. DOI: 10.1371/journal.pone.0093013.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Effect of overexpression of TPX2 gene on apoptosis and invasion in human cervical cancer HeLa cells

Construction of MLO-Y4 cells with overexpression of Delta-like genes and their effects on osteogenic differentiation of bone marrow stromal cells

Geminin over-expression promotes differentiation in rat vascular smooth muscle cells from dedifferentiation

Exogenous Notch1 overexpression inhibits proliferation of K562 cells by arresting at G₁ phase

Overexpression of phospholipase cβ1 improves glucose-stimulated insulin secretion in INS cells

Related Author

Jian ZHENG

Shufang SONG

Haiping CHANG

Xiaolin TU

Cen LUO

Zhengsong XIE

Wei FENG

李林峪

Related Institution

Department of Obstetrics and Gynecology, the Affiliated Hospital of Inner Mongolia Medical College, Hohhot, Inner Mongolia Autonomous Region

Bone Development and Regeneration Platform, Life Science Institute, Chongqing Medical University

⁰