李 越，沈 磊，羅和生

武漢大學(xué)人民醫(yī)院消化內(nèi)科，湖北 武漢 430060

專題·炎癥性腸病

Nrf2/ARE通路在炎癥性腸病中的研究進(jìn)展

李 越，沈 磊，羅和生

武漢大學(xué)人民醫(yī)院消化內(nèi)科，湖北 武漢 430060

Nrf2(nuclear factor-erythroid 2-related factor-2)能激活細(xì)胞抗氧化機(jī)制并抑制炎癥反應(yīng)，在機(jī)體抗氧化應(yīng)激中起關(guān)鍵作用。Nrf2/ARE通路能夠緩解包括炎癥性腸病(inflammatory bowel disease，IBD)在內(nèi)的多種炎癥相關(guān)疾病。IBD是目前臨床治療的難點(diǎn)之一，其發(fā)病機(jī)制尚未闡明，多項(xiàng)研究表明氧化損傷在IBD的發(fā)生、發(fā)展過(guò)程中起重要作用。本文就Nrf2/ARE通路在IBD中的研究進(jìn)展作一概述。

炎癥性腸?。籒rf2/ARE通路；抗氧化

Nrf2屬于CNC(cap’n’collar)轉(zhuǎn)錄因子家族成員，連接于Ⅱ相解毒/抗氧化酶和相關(guān)氧化應(yīng)激反應(yīng)蛋白啟動(dòng)區(qū)的抗氧化反應(yīng)元件部位，調(diào)控抗氧化基因的表達(dá)，在機(jī)體對(duì)抗氧化應(yīng)激反應(yīng)中起關(guān)鍵作用[1]。研究[2]表明，Nrf2/ARE通路在抗炎癥反應(yīng)、抗腫瘤、神經(jīng)保護(hù)等方面也發(fā)揮重要作用。炎癥性腸病(inflammatory bowel disease，IBD)是指一組腸道慢性非特異性炎癥性疾病，包括潰瘍性結(jié)腸炎(ulcerative colitis，UC)和克羅恩病(Crohn’s disease，CD)。IBD不僅嚴(yán)重影響患者的身體健康及生活質(zhì)量，還有增加罹患結(jié)直腸癌風(fēng)險(xiǎn)的趨勢(shì)。目前IBD的發(fā)病機(jī)制尚不明確，一般認(rèn)為是遺傳易感性、免疫功能失調(diào)、腸道菌群失衡、環(huán)境因素共同作用的結(jié)果[3]。近年來(lái)，氧化損傷在IBD的發(fā)生、發(fā)展中的作用日益突顯，Nrf2/ARE通路能夠緩解炎癥相關(guān)的多種疾病，包括IBD[4]，本文就Nrf2/ARE通路在IBD中的研究進(jìn)展作一概述。

1 Nrf2的概述

Nrf2是具有亮氨酸拉鏈結(jié)構(gòu)的CNC轉(zhuǎn)錄因子家族成員之一[5]，Moi等[6]首次發(fā)現(xiàn)它能與β-珠蛋白基因啟動(dòng)子上的NF-E2/AP-1重復(fù)序列結(jié)合，是CNC轉(zhuǎn)錄因子家族成員中活力最強(qiáng)的轉(zhuǎn)錄調(diào)節(jié)因子。Nrf2含有多個(gè)穩(wěn)定的結(jié)構(gòu)域，包括N端疏水結(jié)構(gòu)域、與胞漿Kelch樣ECH結(jié)合蛋白1(Kelch-like ECH associating protein 1，Keap1)相結(jié)合的結(jié)構(gòu)域、轉(zhuǎn)錄活性結(jié)構(gòu)域、CNC結(jié)構(gòu)域、基礎(chǔ)結(jié)構(gòu)域及亮氨酸拉鏈結(jié)構(gòu)域[7]。Nrf2通過(guò)亮氨酸拉鏈結(jié)構(gòu)域與sMaf蛋白或Jun蛋白形成異二聚體，再與抗氧化反應(yīng)原件(antioxidant response element，ARE)相結(jié)合，從而啟動(dòng)目標(biāo)基因轉(zhuǎn)錄[8]。生理狀況下，Nrf2位于細(xì)胞質(zhì)中，并與細(xì)胞質(zhì)的Keap1蛋白相結(jié)合而處于非活性狀態(tài)，且通過(guò)泛素蛋白酶體途徑不斷被降解；當(dāng)受到氧化應(yīng)激信號(hào)刺激后，Nrf2立即與變構(gòu)的Keap1解偶聯(lián)，并轉(zhuǎn)位入核與sMaf蛋白形成異二聚體，再與基因中ARE上的相應(yīng)位點(diǎn)結(jié)合，以啟動(dòng)ARE調(diào)控的Ⅱ相解毒酶及抗氧化蛋白基因的轉(zhuǎn)錄及翻譯[9]。

2 Nrf2/ARE通路的作用

Nrf2/ARE通路與腫瘤、IBD、神經(jīng)系統(tǒng)疾病、自身免疫性疾病等多種疾病的發(fā)生、發(fā)展密切相關(guān)，是治療多種疾病的潛在靶點(diǎn)[10]。研究[11]表明，褪黑素通過(guò)激活Nrf2/ARE通路抑制肌間神經(jīng)元的損傷而緩解IBD。組蛋白去乙酰化酶抑制劑也可通過(guò)激活Nrf2/ARE通路改善外傷導(dǎo)致的神經(jīng)元損傷[12]。Nrf2基因敲除小鼠對(duì)胡椒基丁醚誘導(dǎo)的肝癌有更高的易感性[13]。此外，Nrf2誘導(dǎo)劑蘿卜硫素、姜黃素等對(duì)減輕腦水腫、神經(jīng)功能障礙有一定作用[14]。Nrf2誘導(dǎo)劑二甲基富馬酸口服制劑能通過(guò)儲(chǔ)存髓磷脂、軸突、神經(jīng)元而有效緩解自身免疫性腦脊髓炎[15]。

3 Nrf2/ARE通路與IBD的發(fā)病

炎癥反應(yīng)是機(jī)體對(duì)抗感染和組織損傷的一種生理性的保護(hù)機(jī)制，但炎癥反應(yīng)紊亂又會(huì)產(chǎn)生多種炎癥相關(guān)疾病，如IBD等。Nrf2/ARE通路能負(fù)性調(diào)控炎癥調(diào)節(jié)因子和酶類(lèi)，如炎性細(xì)胞因子、炎癥趨化因子、細(xì)胞黏附分子、金屬蛋白酶、誘導(dǎo)型一氧化氮合酶(iNOS)、環(huán)氧合酶2(COX-2)等，抑制氧化應(yīng)激及促炎因子過(guò)表達(dá)的惡性循環(huán)是機(jī)體抵抗炎癥、組織損傷的必要條件[10]。在腦脊髓炎的小鼠模型中，與野生型小鼠相比，Nrf2缺陷的小鼠脊椎提取物中促炎細(xì)胞因子(IFN-γ、IL1-β、TNF-α和IL-12)、與炎癥相關(guān)的酶(iNOS等)、趨化因子(BLC和MIG)的基因表達(dá)水平明顯升高，提示Nrf2/ARE通路可調(diào)控自身免疫性神經(jīng)炎癥反應(yīng)[16]。杜鵑素可通過(guò)激活Nrf2/ARE通路調(diào)控的血紅素氧合酶1(HO-1)表達(dá)減輕炎癥反應(yīng)[17]。此外，Nrf2/ARE通路還可通過(guò)影響其他炎癥信號(hào)通路如核因子κB(nuclear factor-κB，NF-κB)來(lái)抑制機(jī)體的炎癥反應(yīng)[18]。

4 Nrf2/ARE通路與IBD的治療

在醋酸誘導(dǎo)的IBD大鼠模型中，Nrf2、HO-1的表達(dá)量明顯下降，而低分子肝素的治療不僅阻止了Nrf2、HO-1表達(dá)水平的下降，還顯著提高了其表達(dá)，提示低分子肝素可能通過(guò)Nrf2/ARE通路來(lái)緩解IBD的氧化損傷[29]。與野生型小鼠相比，抗增殖蛋白轉(zhuǎn)基因的IBD小鼠表現(xiàn)出Nrf2 mRNA表達(dá)水平上調(diào)，核蛋白的轉(zhuǎn)位和DNA鍵合增加，腸道損傷情況減輕，表明抗增殖蛋白在機(jī)體應(yīng)對(duì)氧化應(yīng)激損傷時(shí)可調(diào)控Nrf2/ARE通路，并通過(guò)不斷促進(jìn)Nrf2的表達(dá)來(lái)減輕炎癥相關(guān)的氧化損傷，從而有效治療IBD[30]。異硫氰酸酯蘿卜硫素-Nrf2的誘導(dǎo)物降低了IBD小鼠的DAI、緩解IBD小鼠結(jié)腸的縮短，說(shuō)明異硫氰酸酯蘿卜硫素有潛力成為IBD的治療藥物[31]。在DSS誘導(dǎo)的IBD小鼠模型中，五倍子酸通過(guò)激活Nrf2/ARE通路增加抗氧化酶GR、GPx、NQO1等的表達(dá)，增強(qiáng)酶促防御系統(tǒng)，減少氧自由基，阻斷DSS誘導(dǎo)結(jié)腸炎的發(fā)生[32]。可可粉被認(rèn)為是Nrf2及其下游基因的強(qiáng)效誘導(dǎo)劑，對(duì)結(jié)腸炎誘導(dǎo)的結(jié)腸癌有一定的防護(hù)作用[33]。這些研究表明靶向調(diào)控Nrf2/ARE通路對(duì)IBD治療有一定的作用。

IBD嚴(yán)重影響了患者的身體健康及生活質(zhì)量，并與結(jié)腸炎誘導(dǎo)的結(jié)直腸癌密切相關(guān)[34]。目前IBD的治療藥物主要是美沙拉嗪、糖皮質(zhì)激素、免疫抑制劑和以TNF-α單抗為代表的生物制劑，然而，這些藥物在治療過(guò)程中存在一定的毒副反應(yīng)，出現(xiàn)藥物抵抗或不能耐受的現(xiàn)象。Nrf2/ARE通路與IBD的發(fā)生、發(fā)展密切相關(guān)，進(jìn)一步研究?jī)烧呗?lián)系的具體分子機(jī)制對(duì)于臨床研發(fā)治療IBD安全有效的藥物具有重要意義。

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(責(zé)任編輯：馬 軍)

Research progress of Nrf2/ARE signaling pathway in inflammatory bowel disease

LI Yue, SHEN Lei, LUO Hesheng

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China

Nuclear factor-erythroid 2-related factor-2 (Nrf2) can activate cellular protection against oxidative stresses and inhibit inflammatory response. Nrf2/ARE signaling pathway can attenuate several inflammatory diseases, including inflammatory bowel disease (IBD). IBD is one of the most difficult points in clinical treatment, its pathogenesis remains unclear. Numerous studies have indicated that oxidative damage is a key role of IBD. In this paper, the research progress of Nrf2/ARE signaling pathway in IBD was reviewed.

Inflammatory bowel disease; Nrf2/ARE signaling pathway; Antioxidant

李越，碩士，研究方向：木犀草素對(duì)實(shí)驗(yàn)性小鼠結(jié)腸炎的治療作用。E-mail：yzejy@126.com

沈磊，副教授，主任醫(yī)師，碩士生導(dǎo)師，研究方向：消化內(nèi)鏡的診斷與治療。E-mail：leishenwuhan@126.com

10.3969/j.issn.1006-5709.2016.07.001

R574.62

A

1006-5709(2016)07-0721-03

2016-01-12