ROS在高氧腸道中的作用

趙 敏，劉冬妍

中國(guó)醫(yī)科大學(xué)附屬盛京醫(yī)院實(shí)驗(yàn)研究中心，遼寧 沈陽(yáng) 110004

ROS在高氧腸道中的作用

趙 敏，劉冬妍

中國(guó)醫(yī)科大學(xué)附屬盛京醫(yī)院實(shí)驗(yàn)研究中心，遼寧 沈陽(yáng) 110004

氧氣吸入是治療一些疾病的重要手段，尤其可改善新生兒缺氧狀態(tài)。但長(zhǎng)時(shí)間的高氧治療會(huì)對(duì)機(jī)體器官產(chǎn)生嚴(yán)重的毒性作用。高氧能誘發(fā)線粒體產(chǎn)生活性氧(reactive oxygen species,ROS)進(jìn)而引起器官損傷。高氧環(huán)境中腸上皮細(xì)胞遭到破壞時(shí)伴隨著ROS的增加，激活NF-κB信號(hào)通路，進(jìn)而引起一系列的炎癥反應(yīng)，因此，ROS在高氧腸道損傷中發(fā)揮著重要作用。

高氧；腸上皮細(xì)胞；活性氧；過(guò)氧化氫；NF-κB

氧氣是人類生存所必需的，它是維持機(jī)體生長(zhǎng)發(fā)育必不可少的物質(zhì)，貫穿機(jī)體活動(dòng)的始終。氧氣吸入是治療一些疾病的重要手段，尤其可以改善新生兒缺氧狀態(tài)。但氧療使用不當(dāng)，如長(zhǎng)時(shí)間吸入高濃度的氧則對(duì)機(jī)體器官產(chǎn)生嚴(yán)重的毒性作用，氧的毒性取決于氧的濃度及吸氧時(shí)間。氧中毒造成的影響是全身性的，會(huì)對(duì)機(jī)體產(chǎn)生功能性或器質(zhì)性的損傷。由于各器官對(duì)氧的敏感程度不同，其損傷程度也不盡相同。當(dāng)前臨床搶救新生兒呼吸衰竭最有效的方法是氧療法，即機(jī)械通入高濃度的氧(簡(jiǎn)稱高氧)。此療法雖挽救患兒的生命，但長(zhǎng)時(shí)間高氧治療會(huì)引起肺、腦、眼等近隔器官損傷，如新生兒持續(xù)暴露在高氧環(huán)境中，過(guò)氧化氫(hydrogen peroxide，H2O2)不斷增加，并從脈絡(luò)膜擴(kuò)散到整個(gè)視網(wǎng)膜，最終導(dǎo)致不可逆轉(zhuǎn)的視網(wǎng)膜氧化損傷[1]。高氧誘發(fā)支氣管肺發(fā)育不良，抑制細(xì)胞增殖，降低細(xì)胞生存率[2]。近年來(lái)陸續(xù)報(bào)道，長(zhǎng)期高氧治療還可引起新生兒腎、肝、腸等遠(yuǎn)隔器官損傷[3-4]。

1 活性氧的產(chǎn)生和作用機(jī)制

高氧環(huán)境下，上皮細(xì)胞間連接減弱，誘發(fā)炎癥反應(yīng)，導(dǎo)致上皮細(xì)胞的損傷[5]，這是因?yàn)樵诟哐醐h(huán)境下，各組織高氧導(dǎo)致其活性氧(reactive oxygen species，ROS)產(chǎn)生增多[6]。ROS是體內(nèi)氧的單電子還原產(chǎn)物，是電子在未能傳遞到末端氧化酶之前漏出呼吸鏈并消耗約2%的氧所生成的。ROS和先天性抗氧化防御系統(tǒng)在生理性細(xì)胞信號(hào)通路和許多病理狀態(tài)下發(fā)揮重要作用，其中包括神經(jīng)退行性疾病和氧中毒，是高氧引起器官毒性損傷的最主要根源[7]。ROS在線粒體中產(chǎn)生，主要包括氧離子及H2O2[8]。一些還原型輔酶Ⅱ(triphosphopyridine nucleotide，NADPH)氧化酶(oxidase，NOX)家族的酶在上皮細(xì)胞和內(nèi)皮細(xì)胞中誘導(dǎo)ROS的產(chǎn)生，通過(guò)影響細(xì)胞傳導(dǎo)的信號(hào)通路，最終導(dǎo)致高氧誘導(dǎo)的機(jī)體損傷[9-10]。一方面，線粒體由狀態(tài)Ⅲ向狀態(tài)Ⅳ轉(zhuǎn)換中，高氧的環(huán)境和高還原狀態(tài)的呼吸鏈?zhǔn)勾罅侩娮勇┏霾⑦€原氧分子而形成ROS。另一方面，細(xì)菌和毒素可同時(shí)刺激上皮細(xì)胞，導(dǎo)致浸潤(rùn)的肥大細(xì)胞、中性粒細(xì)胞與單核巨噬細(xì)胞釋放ROS。腸黏膜屏障發(fā)生損傷時(shí)，腸黏膜Th1細(xì)胞因子如腫瘤壞死因子-α(tumor necrosis factor，TNF-α)、IL-1等可刺激上皮細(xì)胞產(chǎn)生ROS，因而Ruh等[11]認(rèn)為ROS增多是腸道炎癥一系列反應(yīng)的第一步。ROS還能直接或間接調(diào)整信號(hào)分子如蛋白激酶、轉(zhuǎn)錄因子、促凋亡因子和抗凋亡因子等導(dǎo)致每個(gè)器官的氧化損傷[9，12]。

機(jī)體在正常情況下，體內(nèi)ROS的產(chǎn)生和清除處于動(dòng)態(tài)平衡，此時(shí)，ROS對(duì)機(jī)體有利而無(wú)害。ROS是氧代謝的常規(guī)副產(chǎn)物，在細(xì)胞信號(hào)傳導(dǎo)和保持機(jī)體平衡起很大作用。在復(fù)雜的生物體系中，生理上產(chǎn)生的ROS作為第二信使信號(hào)影響細(xì)胞增殖和分化[13]。在細(xì)胞中ROS的產(chǎn)生需要多種酶的催化。過(guò)氧化物歧化酶(superoxide dismutase，SOD)是一種活性物質(zhì)，能消除機(jī)體在新陳代謝過(guò)程中產(chǎn)生的有害物質(zhì)。通常，細(xì)胞都會(huì)通過(guò)SOD的作用來(lái)減少ROS對(duì)細(xì)胞的損傷作用。某些小分子，如維生素C、維生素E、尿酸及谷胱甘肽也作為細(xì)胞抗氧化物質(zhì)發(fā)揮著重要作用[14]。在高氧環(huán)境中，高氧引起的氧化損傷能誘發(fā)線粒體ROS產(chǎn)生和抗氧化蛋白的表達(dá)[15]。高氧還能增加ROS適應(yīng)性抗氧化反應(yīng)，其發(fā)病機(jī)制部分是通過(guò)增強(qiáng)巨噬細(xì)胞促炎反應(yīng)實(shí)現(xiàn)的[16]。在內(nèi)皮細(xì)胞、巨噬細(xì)胞中由于ROS形成和硫氫化鈉的減少可導(dǎo)致血管生成素-2釋放[17]。有文獻(xiàn)[18]報(bào)道，在高氧環(huán)境下通過(guò)P物質(zhì)(substance P，SP)治療能夠降低ROS的水平，減少細(xì)胞的凋亡，改善細(xì)胞的生存狀態(tài)。SP是高氧誘導(dǎo)細(xì)胞損傷和死亡的保護(hù)因子，通過(guò)激活(sonic hedgehog)信號(hào)通路，提高AECⅡs細(xì)胞的生存狀態(tài)。

2 ROS對(duì)腸道的影響

腸上皮是抵抗腸道微生物的第一道防線。由于出生前胎兒腸道處于相對(duì)低氧的環(huán)境中，出生后新生兒腸絨毛和黏膜將繼續(xù)分化和生長(zhǎng)，因此出生后長(zhǎng)期高氧治療將引起新生兒腸道發(fā)育異常，如高氧可損傷腸道，使腸黏膜增厚，一氧化氮合酶Ⅱ(NOSⅡ)蛋白含量減少，腸絨毛結(jié)構(gòu)改變和調(diào)整NOS，并影響新生兒腸道屏障功能使腸黏膜增厚[3]。因此，由低氧環(huán)境突然暴露在高氧環(huán)境及新生兒不成熟的抗氧化調(diào)節(jié)系統(tǒng)，新生兒腸道更易發(fā)生炎癥反應(yīng)[19]。當(dāng)高氧激發(fā)肺等近隔器官的氧化應(yīng)激反應(yīng)時(shí)，ROS大量生成并釋放入血，隨血液循環(huán)到腸道，激活炎癥信號(hào)[20]，進(jìn)而引起腸道炎癥反應(yīng)及腸組織損傷，使腸道微環(huán)境發(fā)生變化；其次在高氧作用下肺部發(fā)生炎癥反應(yīng)，大量炎性細(xì)胞因子釋放入血，通過(guò)呼吸暴發(fā)脫顆粒釋放ROS入血，隨血液循環(huán)到腸道，損傷腸黏膜；再有肺組織通氣或換氣功能障礙可能導(dǎo)致腸組織供氧不足使腸道ROS產(chǎn)生增多而導(dǎo)致腸黏膜改變，繼發(fā)引起腸道微環(huán)境變化。有文獻(xiàn)[21]報(bào)道，腸上皮細(xì)胞的氧化損傷與ROS、SOD、谷胱甘肽有關(guān)。

ROS在控制正常的腸道微生物群和致病菌中發(fā)揮著重要作用[22]。腸上皮細(xì)胞是腸黏膜屏障組成中最重要的細(xì)胞成分，腸黏膜屏障遭到破壞時(shí)伴隨著ROS的增加，ROS作為細(xì)胞內(nèi)第二信使可以激活多種轉(zhuǎn)錄因子，調(diào)控致炎細(xì)胞因子和化學(xué)因子的過(guò)度表達(dá)，加重腸黏膜屏障功能的損傷。過(guò)氧化氫酶作為ROS的清除劑，減少腸黏膜內(nèi)ROS的數(shù)量，減弱ROS的第二信使作用，從而起到保護(hù)腸黏膜的作用。ROS在細(xì)胞信號(hào)傳導(dǎo)、生長(zhǎng)和維持體內(nèi)平衡中發(fā)揮重要作用[23]，并在黏膜防御中發(fā)揮著重要作用，上皮細(xì)胞NADPH氧化酶類在腸道感染時(shí)通過(guò)擾亂細(xì)菌信號(hào)發(fā)揮早期抗菌防御的作用[24]。體外和體內(nèi)腸道共生菌接觸上皮細(xì)胞能迅速產(chǎn)生ROS[25]，ROS急劇增多時(shí)，產(chǎn)生氧化應(yīng)激導(dǎo)致明顯的細(xì)胞因子結(jié)構(gòu)損傷。小腸黏膜損傷早期，ROS的產(chǎn)生對(duì)小腸上皮細(xì)胞通透性的增加起到重要作用[26]。ROS可誘導(dǎo)細(xì)胞因子的產(chǎn)生[27]，而細(xì)胞因子又在腸道ROS的產(chǎn)生中起到重要作用，如TNF-α是一種能夠直接殺傷腫瘤細(xì)胞而對(duì)正常細(xì)胞無(wú)明顯毒性的細(xì)胞因子。TNF-α在腸上皮細(xì)胞的高表達(dá)預(yù)示它們可能是腸道損傷的指示因子。其能通過(guò)誘發(fā)細(xì)胞內(nèi)線粒體ROS(mitochondrial ROS，mtROS)的產(chǎn)生引起細(xì)胞損傷，加重腸道炎癥和腸道損傷。在腸上皮細(xì)胞中，TNF-α誘導(dǎo)細(xì)胞凋亡，ROS調(diào)控機(jī)體健康與疾病平衡過(guò)程。在線粒體電子傳遞鏈中產(chǎn)生氧代謝產(chǎn)物，對(duì)細(xì)胞信號(hào)傳導(dǎo)起著重要作用，線粒體內(nèi)的抗氧化劑(phenyl-tert-butynitrone，PBN)能夠抵抗TNF或ROS誘導(dǎo)的腸上皮細(xì)胞損傷[19]。在小鼠小腸上皮細(xì)胞系(mouse intestinal epithelial cell line,MODE-K)細(xì)胞中，由TNF-α導(dǎo)致的細(xì)胞死亡中過(guò)多的ROS主要來(lái)源于線粒體和氮氧化物[28]。同時(shí)ROS也是引起腸道缺血再灌注損傷的原因之一[29]。文獻(xiàn)[30]指出益生乳酸桿菌GG能夠誘導(dǎo)體內(nèi)體外腸上皮細(xì)胞ROS的產(chǎn)生并能夠阻止TNF-α誘導(dǎo)激活NF-κB信號(hào)通路。

3 NF-κB通路參與ROS調(diào)控

NF-κB為一個(gè)轉(zhuǎn)錄因子蛋白家族，包括5個(gè)亞單位：Rel(cRel)、P65(RelA、NF-κB3)、RelB和P50(NF-κB1)、P52(NF-κB2)。NF-κB是一種重要的信號(hào)分子，在不同的細(xì)胞類型及各種組織中參與高氧所導(dǎo)致的生理反應(yīng)[31]。NF-κB也可以調(diào)節(jié)炎癥反應(yīng)和肺上皮細(xì)胞的損傷或死亡[32]。有文獻(xiàn)[33]報(bào)道，氧化應(yīng)激和NF-κB核酸因子的激活在炎癥性腸病(inflammatory bowel disease, IBD)的發(fā)病機(jī)理中起著關(guān)鍵作用。IBD時(shí)，白細(xì)胞滲透進(jìn)入腸道組織，導(dǎo)致ROS誘發(fā)腸道損傷[34]。

同時(shí)，ROS作為基因表達(dá)的重要信號(hào)分子在細(xì)胞因子誘導(dǎo)的基因表達(dá)中也發(fā)揮著重要作用，當(dāng)其在高水平表達(dá)時(shí)可能導(dǎo)致氧化應(yīng)激和細(xì)胞損傷[35]。隨著ROS產(chǎn)生的增加，細(xì)胞凋亡率逐漸增加[36]。ROS直接參與NF-κB炎癥通路，REL-A和REL-B二聚化后形成有功能的NF-κB，它調(diào)控著基因編碼急性期反應(yīng)蛋白、細(xì)胞因子、細(xì)胞黏附分子和免疫調(diào)節(jié)分子等。通過(guò)調(diào)控多種基因的表達(dá)，NF-κB參與免疫反應(yīng)、炎癥反應(yīng)、細(xì)胞凋亡、腫瘤發(fā)生等多種生物進(jìn)程。適當(dāng)?shù)腞OS對(duì)阻止NF-κB通路的過(guò)度活化是必需的，但過(guò)高的ROS水平會(huì)對(duì)細(xì)胞和基因結(jié)構(gòu)造成損傷，異常的ROS通過(guò)細(xì)胞毒作用或抑制NF-κB活性將引起腸道損傷，引起腸道炎癥病變[30，37]。當(dāng)機(jī)體受到高氧刺激時(shí)，機(jī)體產(chǎn)生的H2O2增加，受損組織可以釋放ROS使?jié)舛冉档?，表明ROS可以協(xié)調(diào)組織的炎癥反應(yīng)[38]。Jin等[39]研究發(fā)現(xiàn)H2O2誘導(dǎo)的氧化應(yīng)激能增加細(xì)胞的凋亡。H2O2可以顯著增加細(xì)胞內(nèi)的自由基，導(dǎo)致嚴(yán)重的DNA損傷同時(shí)顯著降低超氧化物歧化酶、谷胱甘肽過(guò)氧化物酶、過(guò)氧化氫酶、脂肪酶的激活[40]。

4 展望

高氧環(huán)境中的ROS對(duì)機(jī)體的作用機(jī)制十分復(fù)雜，至今仍未完全闡明，深入了解ROS在高氧環(huán)境中對(duì)機(jī)體的影響將有助于我們認(rèn)識(shí)許多免疫性疾病的發(fā)生、發(fā)展過(guò)程，對(duì)探究病因和研究治療方法具有重要意義。近年來(lái)，相關(guān)研究已取得一定成果，如高氧動(dòng)物模型腸黏膜SIgA和腸道pIgR/SC的檢測(cè)；體外培養(yǎng)研究發(fā)現(xiàn)長(zhǎng)期過(guò)度高氧(60%、90%濃度高氧)可殺傷腸上皮細(xì)胞Caco-2，對(duì)其生長(zhǎng)有抑制作用，影響腸上皮細(xì)胞表達(dá)pIgR/SC，高氧環(huán)境中腸道損傷的相互作用機(jī)制已被部分揭示，但還有很多重要問(wèn)題沒(méi)有解決，如高氧環(huán)境中SIgA的作用機(jī)制、信號(hào)通路的改變過(guò)程、氧中毒的病理機(jī)制、如何應(yīng)對(duì)高氧對(duì)腸道免疫系統(tǒng)造成的損傷等。隨著基礎(chǔ)免疫學(xué)的研究進(jìn)展和學(xué)科間的滲透，研究ROS是否為高氧導(dǎo)致腸上皮細(xì)胞損傷的主要原因?qū)?huì)對(duì)機(jī)體各系統(tǒng)的免疫防御和疾病治療有重要的指導(dǎo)意義。探明ROS在高氧損傷腸道中的作用，為探討高氧對(duì)腸道屏障的變化及其機(jī)制作了鋪墊，為進(jìn)一步研究高氧對(duì)遠(yuǎn)隔器官影響奠定基礎(chǔ)，為深入探索防治氧療后遺癥新途徑奠定實(shí)驗(yàn)基礎(chǔ)。

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(責(zé)任編輯：馬 軍)

Role of ROS in the hyperoxia intestinal tract

ZHAO Min, LIU Dongyan

Research Center, Shengjing Hospital of China Medical University, Shenyang 110004, China

Oxygen is an important way for the treatment of some diseases, especially to improve newborn hypoxia state. But high oxygen treatment for a long time could have serious toxic effect on the body’s organs. Hyperoxia can induce mitochondria produce reactive oxygen species(ROS) and cause organ damage. Hyperoxia’s environment in intestinal epithelial cells were destroyed along with the increase of ROS, activity of the NF-κB signaling pathways, resulting in a series of inflammation, thus ROS plays an important role in hyperoxia intestinal injury.

Hyperoxia; Intestinal epithelial cells; ROS; H2O2; NF-κB

國(guó)家自然科學(xué)基金(30871158、81170604)，盛京自由研究者

趙敏，碩士，研究方向：黏膜免疫。E-mail：1021087960@qq.com

劉冬妍，教授，研究方向：黏膜免疫。E-mail：Liudy19701010@sina.com

10.3969/j.issn.1006-5709.2016.08.031

R574

A

1006-5709(2016)08-0948-04

2015-10-20