内质网应激在百草枯上调缺氧诱导因子1α中的作用

黄赛; 孟潇潇; 谢晖; 王金凤; 朱勇; 王瑞兰; 陆伦根

doi:10.13201/j.issn.1009-5918.2014.12.010

内质网应激在百草枯上调缺氧诱导因子1α中的作用

- 1. 上海交通大学附属第一人民医院危重病科(上海, 201602);
- 2. 上海交通大学附属第一人民医院消化科
基金项目:
国家自然科学基金资助项目 (No:81272071, No:81471891)

详细信息

通讯作者: 王瑞兰,E-mail:wangyusun@hotmail.com; 陆伦根

中图分类号: R-33

收稿日期: 2014-08-15

The role of endoplasmic reticulum stress in parquat-induced hypoxia-inducible factor 1α up-regulation

- 1. Department of Intensive Care Medicine, First People's Hospital Affiliated Shanghai Jiao Tong University, Shanghai 201620, China;
- 2. Department of Gastroenterology, First People's Hospital Affiliated Shanghai Jiao Tong University, Shanghai 201620, China

More Information

Corresponding authors: WANG Ruilan ; LU Lungen

Received Date: 15 August 2014

摘要

摘要: 目的:探讨内质网应激在百草枯(PQ)上调缺氧诱导因子1α(HIF-1α)中的作用。方法:将60只雄性SD大鼠按照随机数字表法分为对照组(10只)和染毒组(50只),染毒组按照50 mg/kg的标准将20%的PQ用生理盐水稀释到1 ml进行一次性灌胃,于灌胃后2、6、12、24、48 h处死动物取肺组织。提取肺组织总蛋白,采用Western Blotting检测HIF-1α和内质网应激标志物GRP78、XBP1的表达。选择ERS抑制剂4-苯基丁酸进行预处理,再施以PQ暴露,Western Blot和免疫荧光检测肺组织中GRP78及HIF-1α的表达。结果:染毒后2 h肺组织中HIF-1α、GRP78和XBP1蛋白表达均较对照组明显升高,随时间延长,逐步增高。采用4-苯基丁酸抑制处理后,与PQ处理组比较,大鼠肺组织中GRP78、HIF-1α表达减少。结论:PQ进入肺组织后,可能通过诱导ERS上调HIF-1α的表达参与肺纤维化。
- 百草枯 /
- 中毒 /
- 缺氧诱导因子1α /
- 内质网应激 /
- 肺纤维化
Abstract: Objective:To investigate the role of endoplasmic reticulum stress in paraquat-induced hypoxia-inducible factor 1α up-regulation.Method:60 healthy Sprague-Dawley rats were randomly divided into control group (n=10) and paraquat poisoning group (n=50).The control group was treated with saline,and the paraquat poisoning group were received intragastric infusion of 20% paraquat solution (50 mg·kg^-1).Rats of paraquat poisoning group were subsequently divided into five subgroups (n=10) and lung tissues were collected at 2 h,6 h,12 h,24 h,48 h after paraquat poisoning.HIF-1α and endoplasmic reticulum stress markers,including GRP78,XBP1were measured by Western Blot.After treating with an endoplasmic reticulum stress inhibitor 4-Phenybutyric acid,we then measured the expression of GRP78 and HIF-1α by Western Blot and immunofluorescence.Result:HIF-1α and endoplasmic reticulum stress markers,including GRP78,XBP1 were significantly increased at 2 h,and increased with times.Western Blot and immunofluorescence results showed that 4-Phenybutyric acid significantly decreased the levels of GRP78 and HIF-1α.Conclusion:Our study demonstrated that paraquat poisoning could up regulate the HIF-1α level via endoplasmic reticulum stress.
- paraquat /
- poisoning /
- hypoxia-inducible factor 1α /
- endoplasmic reticulum stress /
- pulmonary fibrosis

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参考文献(22)

[1]	LEE E Y, HWANG K Y, YANG J O, et al.Predictors of survival after acute paraquat poisoning[J].Toxicol Ind Health, 2002, 18:201-206.
[2]	DINIS-OLIVEIRA R J, DUARTE J A, SANCHEZNAVARRO A, et al.Paraquat poisonings:mechanisms of lung toxicity, clinical features, and treatment[J].Critl Rev Toxicol, 2008, 38:13-71.
[3]	LEE J W, BAE S H, JEONG J W, et al.Hypoxia-inducible factor (HIF-1) alpha:its protein stability and biological functions[J].Exp Mol Med, 2004, 36:1-12.
[4]	GORDON S, TAYLOR P R.Monocyte and macrophage heterogeneity[J].Nat Rev Immunol, 2005, 5:953-964.
[5]	XIE H, TAN J T, WANG R L, et al.Expression and significance of HIF-1αin pulmonary fibrosis induced by paraquat[J].Exp Biol Med (Maywood), 2013, 238:1062-1068.
[6]	LEE S K, AMENO K, IN S W, et al.Levels of paraquat in fatal intoxications[J].Int J Legal Med, 1999, 112:198-200.
[7]	ROSE M S, SMITH L L, WYATT I.Evidence for energy-dependent accumulation of paraquat into rat lung[J].Nature, 252:314-315.
[8]	HIGGINS D F, KIMURA K, BERNHARDT W M, et al.Hypoxia promotes fibrogenesis in vivo via HIF-1stimulation of epithelial-to-mesenchymal transition[J].J Clin Invest, 2007, 117:3810-3820.
[9]	WEI H, BEDJA D, KOITABASHI N, et al.Endothelial expression of hypoxia-inducible factor 1protects the murine heart and aorta from pressure overload by suppression of TGF-beta signaling[J].Proc Natl Acad Sci (USA) 2012, 109:E841-850.
[10]	MOON J O, WELCH T P, GONZALEZ F J, et al.Reduced liver fibrosis in hypoxia-inducible factor-1alpha-deficient mice[J].Am J Physiol Gastrointest Liver Physiol, 2009, 296:G582-585.
[11]	徐榕, 王瑞兰, 吴欣, 等.百草枯中毒大鼠肺组织缺氧诱导因子-1α的表达变化[J].2011, 20 (9):945-950.
[12]	ELTZSCHIG H K, CARMELIET P.Hypoxia and inflammation[J].N Engl J Med 2011, 364:656-665.
[13]	PATEL J, LANDERS K, MORTIMER R H, et al.Regulation of hypoxia inducible factors (HIF) in hypoxia and normoxia during placental development[J].Placenta, 2010, 31:951-957.
[14]	SALMINEN A, KAUPPINEN A, SUURONEN T, et al.ER stress in Alzheimer's disease:a novel neuronal trigger for inflammation and Alzheimer's pathology[J].J Neuroinflammation, 2009, 6:41-41.
[15]	BÁNHEGYI G, MARGITTAI E, SZARKA A, et al.Crosstalk and barriers between the electron carriers of the endoplasmic reticulum[J].Antioxid Redox Signal, 2012, 16:772-780.
[16]	BAEK H A, KIM D S, PARK H S, et al.Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts[J].Am J Respir Cell Mol Biol, 2012, 46:731-739.
[17]	CHEN Y W, YANG Y T, HUNG D Z, et al.Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress[J].Arch Toxicol, 2012, 86:1547-1558.
[18]	GAWARAMMANA I B, BUCKLEY N A.Medical management of paraquat ingestion[J].Br J Clin Pharmacol, 2011, 72:745-757.
[19]	CHEN X, LLIOPOULOS D, ZHANG Q, et al.XBP-1promotes triple-negative breast cancer by controlling the HIF1αpathway[J].Nature, 2014, 508:103-107.
[20]	KIM H J, JEONG J S, KIM S R, et al.Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-Κb/HIF-1αsignaling pathway[J].Sci Rep, 2013, 1142:1-10.
[21]	PERLMUTTER D H.Chemical chaperones:apharmacological strategy for disorders of protein folding and trafficking[J].Perdiatr Res, 2002, 52:832-836.
[22]	ANJORE H, CHENG D S, DEGRYSE A L, et al.Alveolar epithelial cells undergo epithelial to mesenchymal transition in response to endoplasmic reticulum stress[J].J Biol Chem, 2011, 286:30972-30980.