任重陽(yáng) 葛義俊 張梅
摘 要:失眠是盡管有合適睡眠環(huán)境和機(jī)會(huì)仍對(duì)睡眠時(shí)間和(或)睡眠質(zhì)量不滿足,并影響日間功能的一種主觀體驗(yàn)。隨著社會(huì)進(jìn)步和生活節(jié)奏的加快,失眠的發(fā)病率逐漸升高并影響了人們的生活、工作。腺苷信號(hào)及免疫炎癥機(jī)制參與失眠的發(fā)生,成為近年來(lái)研究的熱點(diǎn)。本文將對(duì)失眠與腺苷信號(hào)及免疫功能的研究進(jìn)展進(jìn)行綜述,以期探索失眠機(jī)制研究的方向和臨床治療中新的作用靶點(diǎn)。
關(guān)鍵詞:失眠;睡眠障礙;腺苷;免疫穩(wěn)態(tài)
中圖分類號(hào):R741 文獻(xiàn)標(biāo)識(shí)碼:A DOI:10.3969/j.issn.1006-1959.2018.10.002
文章編號(hào):1006-1959(2018)10-0004-04
Research Progress of Insomnia and Adenosine Signaling and Immune Function
REN Chong-yang1,GE Yi-jun2,ZHANG Mei3
(1.Anhui University of Science and Technology,Huainan 232000,Anhui,China;2.Chaohu Hospital of Anhui Medical University,Chaohu 238000,Anhui,China;3.The First People's Hospital of Huainan City/The First Affiliated Hospital of Anhui University of Science and Technology,Huainan 232000,Anhui,China)
Abstract:Insomnia is a subjective experience that influences sleep time and/or sleep quality,despite having a suitable sleep environment and opportunity,and affects daytime function.With the progress of society and the acceleration of the pace of life,the incidence of insomnia is gradually increasing and affecting people's lives and work.Adenosine signal and immune inflammation mechanism participate in the occurrence of insomnia,which has become a hot topic in recent years.This article will review the research progress of insomnia and adenosine signal and immune function,in order to explore the direction of insomnia research and new targets in clinical treatment.
Key words:Insomnia;Sleep disorders;Adenosine;Immune homeostasis
失眠(insomnia)是臨床上最常見(jiàn)的睡眠障礙,表現(xiàn)為入睡困難,夜間維持困難、早醒及無(wú)恢復(fù)感睡眠等方面,影響人的情緒狀態(tài)與認(rèn)知功能。其發(fā)病機(jī)制目前尚不明確,以往集中于睡眠-覺(jué)醒調(diào)節(jié)腦區(qū)釋放神經(jīng)遞質(zhì)的研究,新的研究發(fā)現(xiàn)腺苷信號(hào)及免疫炎癥因子在失眠發(fā)病起重要作用,其中星形膠質(zhì)細(xì)胞是聯(lián)系的橋梁[1]。同時(shí)對(duì)失眠患者腺苷信號(hào)及免疫標(biāo)志物的探索也在不斷進(jìn)行,其外周血也發(fā)現(xiàn)了一系列腺苷信號(hào)指標(biāo)的變化。通過(guò)了解其中的聯(lián)系并探索其通路機(jī)制,可能為發(fā)現(xiàn)失眠機(jī)制奠定基礎(chǔ)。
1失眠與腺苷信號(hào)的關(guān)系
1.1腺苷信號(hào) 腺苷是在人體內(nèi)參與能量代謝,是中樞神經(jīng)系統(tǒng)內(nèi)的重要神經(jīng)調(diào)質(zhì)[1]。腺苷的產(chǎn)生與代謝是一個(gè)動(dòng)態(tài)過(guò)程,其主要來(lái)源于星形膠質(zhì)細(xì)胞(astrocytes,AC),由兩種方式產(chǎn)生。①三磷酸腺苷(ATP)在胞外被水解成二磷酸腺苷(ADP),繼而轉(zhuǎn)變?yōu)橐涣姿嵯佘眨ˋMP),這個(gè)過(guò)程需要三磷酸二磷酸水解酶(CD39)參與,最終外核苷酸酶(CD73)將AMP轉(zhuǎn)化為腺苷。②AC通過(guò)囊泡運(yùn)輸?shù)确绞街苯臃置谙佘?。在腺苷代謝方面,腺苷脫氨酶(ADA)能水解腺苷,產(chǎn)物是肌苷。腺苷激酶(AK)則能磷酸化腺苷生成AMP。同時(shí)腺苷發(fā)揮作用需要受體的介導(dǎo)。腺苷產(chǎn)生和代謝過(guò)程中的關(guān)鍵酶及腺苷受體共同調(diào)控腺苷水平穩(wěn)定,組成腺苷信號(hào)系統(tǒng),維持生理情況下的內(nèi)環(huán)境穩(wěn)態(tài)。
1.2腺苷信號(hào)發(fā)揮促眠作用 腺苷發(fā)揮著促眠的作用,主要機(jī)制是抑制興奮性神經(jīng)元的活性,并介導(dǎo)其它神經(jīng)遞質(zhì)調(diào)節(jié)睡眠覺(jué)醒過(guò)程。研究發(fā)現(xiàn)[2],腺苷抑制下丘腦結(jié)節(jié)乳頭體核組胺能神經(jīng)元的神經(jīng)傳遞,延長(zhǎng)了大鼠NREM睡眠;在腹外側(cè)視前區(qū),腺苷刺激γ-氨基丁酸神經(jīng)元,促進(jìn)大鼠睡眠。用微量滲析技術(shù)檢測(cè)貓基底前腦膽堿能神經(jīng)元胞外腺苷濃度,發(fā)現(xiàn)其隨覺(jué)醒時(shí)間的延長(zhǎng)升高,在睡眠恢復(fù)期間下降,提示腺苷水平隨睡眠壓力增高[3]。報(bào)道稱[3],使用腺苷轉(zhuǎn)運(yùn)抑制劑升高胞外腺苷水平,增加睡眠及慢波活動(dòng)。Zielinski等[4]通過(guò)基因技術(shù)敲除小鼠CD73基因,減少胞外腺苷,發(fā)現(xiàn)小鼠睡眠剝奪后失去了NREM睡眠增加的效應(yīng)。腺苷對(duì)神經(jīng)元的活性由P1類受體及嘌呤能離子通道型受體(P2X7R)介導(dǎo),P1類受體包括A1、A2a、A2b和A3受體。Rai等[5]的研究發(fā)現(xiàn)在穹隆外側(cè)經(jīng)微量滲析灌流腺苷A1受體激動(dòng)劑,抑制下丘腦神經(jīng)元放電,促進(jìn)睡眠。腺苷信號(hào)對(duì)睡眠的調(diào)節(jié)作用是腺苷參與失眠發(fā)病的基礎(chǔ)。
1.3失眠與腺苷信號(hào)的關(guān)系 各種手段阻斷腺苷的促眠效應(yīng)將會(huì)使睡眠減少,導(dǎo)致失眠的發(fā)生。Palchykova等[6]發(fā)現(xiàn)使小鼠AK基因過(guò)度表達(dá),胞外腺苷水平降低導(dǎo)致小鼠失眠的發(fā)生。同樣有報(bào)道[5]稱,藥理學(xué)或基因手段抑制小鼠腺苷受體的表達(dá),小鼠也會(huì)出現(xiàn)失眠狀況。Sharma等[7]發(fā)現(xiàn)乙醇能增加小鼠的失眠,這種情況通過(guò)腺苷信號(hào)的介導(dǎo),其腦內(nèi)的腺苷與調(diào)節(jié)睡眠覺(jué)醒的神經(jīng)遞質(zhì)發(fā)生了明顯變化,提示AC釋放的腺苷參與了失眠的發(fā)生。國(guó)內(nèi)學(xué)者證實(shí)[8],失眠可能存在膠質(zhì)細(xì)胞的功能損害,而AC的功能損害與腺苷信號(hào)的改變密切相關(guān)。以上研究證實(shí),腺苷信號(hào)參與了失眠的發(fā)生,提示我們對(duì)此進(jìn)行更深入地探索。
2失眠與免疫功能的關(guān)系
睡眠對(duì)人體的免疫功能有明顯影響,如睡眠不足會(huì)誘導(dǎo)機(jī)體的固有免疫應(yīng)答,提高淋巴細(xì)胞的功能,抑制NK細(xì)胞的增殖,失眠也會(huì)誘導(dǎo)外周血和腦內(nèi)炎癥因子的表達(dá)[9]。研究發(fā)現(xiàn)[10],失眠的年輕男性外周血白細(xì)胞計(jì)數(shù)升高,也有報(bào)道失眠后外周血淋巴細(xì)胞、單核細(xì)胞計(jì)數(shù)升高。研究發(fā)現(xiàn)[11],失眠患者血漿IL-1和核轉(zhuǎn)錄因子(NF-kB)水平升高。同樣我們關(guān)注到失眠患者的TNF-α水平升高,而研究人員在兔腦室內(nèi)注入TNF-α后,發(fā)現(xiàn)NREM睡眠延長(zhǎng),且這種效應(yīng)會(huì)被IL-1增強(qiáng)[9]。TNF、IL-1受體基因敲處的小鼠比正常小鼠的NREM睡眠減少[11]。國(guó)外的一項(xiàng)Meta分析顯示[12],睡眠不足與IL-6和C反應(yīng)蛋白密切相關(guān),失眠患者體內(nèi)有明確的慢性低度炎癥狀態(tài),且基礎(chǔ)實(shí)驗(yàn)顯示IL-1、IL-6及TNF-α等細(xì)胞因子互相作用,調(diào)節(jié)睡眠覺(jué)醒過(guò)程。Van Leeuwen的研究發(fā)現(xiàn)[13],數(shù)晚失眠增加了淋巴細(xì)胞的活性且增加了IL-1β、IL-6和IL-17的產(chǎn)生,失眠對(duì)于心臟疾病的影響也是通過(guò)這些炎性細(xì)胞因子介導(dǎo)的,這些物質(zhì)是急性冠脈綜合癥的危險(xiǎn)因素。睡眠與免疫炎癥因子互相作用成為學(xué)者研究的熱點(diǎn),但目前為止其作用機(jī)制尚不明確,需要更多基礎(chǔ)研究去了解其中的機(jī)制及信號(hào)轉(zhuǎn)導(dǎo)通路。
3腺苷與免疫功能聯(lián)系
腺苷具有抑制免疫的功能,能抑制T淋巴細(xì)胞的免疫反應(yīng)[14]。一項(xiàng)研究發(fā)現(xiàn)[14],腺苷、腺苷A2受體、CD39和CD73的共表達(dá)能增強(qiáng)Treg細(xì)胞抑制免疫反應(yīng)的功能,腺苷信號(hào)也可以增加T淋巴細(xì)胞的耐受和Treg細(xì)胞的增殖。Ohta等[15]發(fā)現(xiàn)刺激腺苷受體會(huì)產(chǎn)生對(duì)T淋巴細(xì)胞、NK細(xì)胞、巨噬細(xì)胞/樹(shù)突狀細(xì)胞及中性粒細(xì)胞活性和功能的抑制。腺苷A2a受體的激活可以誘導(dǎo)兩種程序死亡因子CTLA-4和PD-1作用于T淋巴細(xì)胞,使其發(fā)生凋亡。Sokolic[16]的研究證明,ADA的缺乏會(huì)造成淋巴細(xì)胞減少,并且導(dǎo)致一些免疫相關(guān)的疾病。Lappas等[17]發(fā)現(xiàn),A2a受體在外周主要分布于淋巴細(xì)胞,并且抑制炎性細(xì)胞因子的產(chǎn)生及其效應(yīng),A2a及A2b受體存在于抗原提呈細(xì)胞(APCs),影響T淋巴細(xì)胞的激活。已知CD4+T細(xì)胞分化為輔助性T細(xì)胞1(Th1),分泌IFN-γ和TNFα,Hynes[18]報(bào)道稱,腺苷A2a受體和G蛋白共同促進(jìn)cyclic AMP的產(chǎn)生,cyclic AMP可以激活PKA信號(hào)通路,從而減少I(mǎi)FN-γ和TNFα的分泌。那么腺苷信號(hào)與免疫的存在聯(lián)系,這種聯(lián)系在中樞神經(jīng)系統(tǒng)及外周均有發(fā)現(xiàn),這種聯(lián)系與失眠的發(fā)生是否會(huì)有關(guān)聯(lián),對(duì)腦內(nèi)AC調(diào)節(jié)睡眠覺(jué)醒是否有影響,是否影響失眠患者外周腺苷信號(hào)及免疫炎癥指標(biāo)的表達(dá)?
4失眠與腺苷信號(hào)、免疫功能的調(diào)節(jié)關(guān)系
以往認(rèn)為,失眠的病理生理學(xué)機(jī)制是機(jī)體“過(guò)度覺(jué)醒”狀態(tài),失眠患者體內(nèi)下丘腦-垂體-腎上腺皮質(zhì)(HPA)系統(tǒng)過(guò)度激活,HPA軸的亢進(jìn)引起神經(jīng)遞質(zhì)失衡,最終發(fā)生失眠[19]。但從HPA軸亢進(jìn)這個(gè)角度無(wú)法將失眠的發(fā)病機(jī)制與免疫功能的改變聯(lián)系起來(lái),且沒(méi)有對(duì)腦區(qū)內(nèi)HPA軸水平與睡眠調(diào)節(jié)的關(guān)系做合理解釋。
腺苷可能成為聯(lián)系失眠與免疫功能的橋梁。一項(xiàng)研究提示我們關(guān)注腺苷與免疫的節(jié)律性問(wèn)題,Wistar大鼠血液中的腺苷水平在白天睡眠優(yōu)勢(shì)時(shí)段較低,此時(shí)恢復(fù)機(jī)體免疫功能,夜晚開(kāi)始到午夜活動(dòng)優(yōu)勢(shì)時(shí)段逐漸達(dá)到頂峰,此時(shí)睡眠壓力增大,免疫功能下降[20]。研究證實(shí)AC是腺苷產(chǎn)生的場(chǎng)所,且能分泌各種免疫因子,在睡眠過(guò)程中起到代謝腦組織有害產(chǎn)物的作用[21]。有報(bào)道[22]全身感染能導(dǎo)致NREM睡眠和慢波活動(dòng)的增加,注入脂多糖(LPS)模擬出的感染有同樣的效應(yīng),且這種效應(yīng)可能來(lái)源于腦內(nèi)腺苷水平的升高;研究者通過(guò)基因敲出得到的dnsnare小鼠進(jìn)行研究,這種小鼠腦內(nèi)的AC不能表達(dá)正常的SNARE蛋白(soluble N-ethylmaleimide-sensitive fusion protein attachment protein),此蛋白缺失使囊泡釋放受阻,所以造成腺苷釋放的減少,小鼠感染后不出現(xiàn)NREM睡眠和慢波活動(dòng)增加的情況,證明AC釋放的腺苷與LPS感染導(dǎo)致的NREM睡眠增多、慢波活動(dòng)增加關(guān)系密切,此研究的結(jié)果推測(cè)LPS造成的炎癥反應(yīng)通過(guò)調(diào)節(jié)AC功能及腺苷的積累而影響睡眠的穩(wěn)態(tài)。
另一項(xiàng)研究顯示,睡眠不足導(dǎo)致血腦屏障功能異常,腺苷及炎癥介質(zhì)通透性增加,證明失眠可能來(lái)源于大腦關(guān)鍵區(qū)域腺苷及免疫的紊亂,且A2R介導(dǎo)了血腦屏障通透性的改變[23]。Chennaou的研究發(fā)現(xiàn)A2R在睡眠不足人群外周血表達(dá)增高[24],發(fā)現(xiàn)了外周血的腺苷信號(hào)變化的指標(biāo),A2R在外周血淋巴細(xì)胞中也介導(dǎo)了免疫狀態(tài)的變化,其中的機(jī)制有待更多的研究去探索其中的信號(hào)通路。研究發(fā)現(xiàn)[25],腺苷可以透過(guò)血腦屏障并且成為中樞神經(jīng)系統(tǒng)與外周聯(lián)系的紐帶,它具有明確的調(diào)節(jié)免疫系統(tǒng)并參與一些神經(jīng)系統(tǒng)疾病的作用,如阿爾茨海默病。至今沒(méi)有研究發(fā)現(xiàn)外周血腺苷水平變化與失眠等問(wèn)題的聯(lián)系,其與免疫之間的聯(lián)系也無(wú)從知曉,這一點(diǎn)的主要因素可能在于腺苷提取出體外后不穩(wěn)定,容易被相關(guān)代謝酶水解,導(dǎo)致檢測(cè)出現(xiàn)誤差。
近年來(lái),有學(xué)者持續(xù)關(guān)注另一種腺苷信號(hào)相關(guān)受體P2X7R與腺苷信號(hào)的作用,人在清醒時(shí)腦內(nèi)的ATP不斷水解為腺苷,通過(guò)P2X7R直接或間接的影響睡眠狀態(tài)并調(diào)節(jié)免疫炎性因子的釋放[26]。已經(jīng)證實(shí)[27],P2X7R也能表達(dá)于外周血的淋巴細(xì)胞,且在睡眠缺乏的患者身上檢測(cè)到其表達(dá)的增加。腺苷A1、A2受體與P2X7R共同調(diào)節(jié)機(jī)體的睡眠及免疫狀態(tài),但目前總體來(lái)說(shuō)腦內(nèi)神經(jīng)細(xì)胞特別是AC內(nèi)的腺苷信號(hào)、免疫炎癥因子的改變及對(duì)于睡眠的作用,及外周與中樞系統(tǒng)的聯(lián)系通路還沒(méi)有系統(tǒng)地研究和闡述,將來(lái)這些方向研究可能為失眠機(jī)制的發(fā)現(xiàn)作出貢獻(xiàn)。
5總結(jié)
失眠與腺苷信號(hào)及免疫功能調(diào)節(jié)關(guān)系密切。首先腺苷信號(hào)在機(jī)體內(nèi)促進(jìn)睡眠,無(wú)論是失眠患者還是失眠動(dòng)物模型其腺苷信號(hào)都發(fā)生了紊亂;失眠影響免疫炎癥物質(zhì)的表達(dá)且對(duì)這些物質(zhì)的阻斷或激活也能夠?qū)C(jī)體睡眠狀態(tài)產(chǎn)生影響;腺苷信號(hào)與免疫功能也聯(lián)系密切。從中發(fā)現(xiàn)腺苷可能成為聯(lián)系失眠與免疫功能的橋梁,在星形膠質(zhì)細(xì)胞中腺苷信號(hào)及免疫炎癥因子的變化可能是失眠發(fā)病的機(jī)制之一。這些研究進(jìn)展為提示我們進(jìn)行更深入的基礎(chǔ)實(shí)驗(yàn)并嘗試從這些方面對(duì)失眠進(jìn)行干預(yù)。
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收稿日期:2018-3-9;修回日期:2018-3-26
編輯/成森