李冬永 許青文 徐鵬遠(yuǎn)

昆明醫(yī)科大學(xué)第二附屬醫(yī)院胃腸外科(650000)

Ghrelin/GHS-R激動(dòng)劑和MTL/MTL-R激動(dòng)劑與胃腸動(dòng)力關(guān)系的研究進(jìn)展

李冬永*許青文 徐鵬遠(yuǎn)#

昆明醫(yī)科大學(xué)第二附屬醫(yī)院胃腸外科(650000)

Ghrelin和胃動(dòng)素(MTL)主要由消化道分泌，有促進(jìn)胃腸道運(yùn)動(dòng)的作用。胃腸動(dòng)力疾病(DGIM)是主要由神經(jīng)支配調(diào)節(jié)障礙導(dǎo)致的胃腸動(dòng)力或感覺性疾病，以惡心、嘔吐、腹痛、腹脹為主要癥狀。越來(lái)越多研究表明，ghrelin、MTL及其受體激動(dòng)劑與DGIM發(fā)生關(guān)系密切。本文就ghrelin/GHS-R激動(dòng)劑和MTL/MTL-R激動(dòng)劑與DGIM關(guān)系的研究進(jìn)展作一綜述。

胃促生長(zhǎng)素； 受體, 胃促生長(zhǎng)素； 促胃動(dòng)素； 受體, 促胃動(dòng)素； 胃腸動(dòng)力疾病

目前胃腸動(dòng)力疾病(disorder of gastrointestinal motility, DGIM)系指由神經(jīng)支配調(diào)節(jié)障礙導(dǎo)致的胃腸動(dòng)力或感覺性疾病，而無(wú)器質(zhì)性病變且生化異常的消化道功能性疾病稱為功能性胃腸病(functional gastrointestinal disorders, FGIDs)。2016年羅馬Ⅳ標(biāo)準(zhǔn)認(rèn)為FGIDs即為腸-腦互動(dòng)異常，強(qiáng)調(diào)其與動(dòng)力紊亂、黏膜和免疫功能改變、內(nèi)臟高敏感、腸道菌群改變和中樞神經(jīng)系統(tǒng)處理功能異常有關(guān)。DGIM、FGIDs均伴有胃腸道癥狀，DGIM可伴隨胃腸或全身結(jié)構(gòu)、形態(tài)異常，而FGIDs無(wú)結(jié)構(gòu)、形態(tài)、生化異常。DGIM分為局部神經(jīng)源性或肌源性動(dòng)力和繼發(fā)全身性疾病，以惡心、嘔吐、腹痛、腹脹、易飽為主要癥狀。隨著生活節(jié)奏加快、精神壓力增加，DGIM發(fā)病率增高，臨床上30%～40%的消化道疾病為DGIM，嚴(yán)重影響患者的生活質(zhì)量。目前對(duì)DGIM發(fā)病機(jī)制并不完全清楚，可能與神經(jīng)激素因素、飲食習(xí)慣、心理因素等相關(guān)。Ghrelin是一種生長(zhǎng)激素釋放肽，與其特異性受體(GHS-R)結(jié)合后可產(chǎn)生一系列生物學(xué)效應(yīng)。胃動(dòng)素(MTL)是一種活性多肽，通過(guò)與MTL受體(MTL-R)結(jié)合來(lái)發(fā)揮作用。本文就ghrelin/GHS-R、MTL/MTL-R激動(dòng)劑與DGIM關(guān)系的研究進(jìn)展作一綜述。

一、Ghrelin/GHS-R

Ghrelin是含28個(gè)氨基酸的多肽，為GHS-R天然內(nèi)源性配體，主要由胃黏膜泌酸X/A樣細(xì)胞分泌。Ghrelin屬于腦腸肽，80%～90%的ghrelin分布于胃體，中樞、腎、心臟等亦有分布。Ghrelin在體內(nèi)有兩種存在方式，分別為活性酰基化和無(wú)活性去?；；痝hrelin結(jié)合GHS-R可促進(jìn)生長(zhǎng)激素釋放。此外，ghrelin還具有調(diào)節(jié)胃腸動(dòng)力、能量代謝、影響心血管等作用，并能參與炎癥和免疫反應(yīng)，對(duì)顱腦創(chuàng)傷具有保護(hù)神經(jīng)的作用。GHS-R分布于胃腸道、下丘腦、心臟、肺等，可分為GHS-R1a和GHS-R1b兩種類型。Ghrelin主要與GHS-R1a結(jié)合，可經(jīng)磷脂酶C、三磷酸肌醇、甘油二酯等途徑使胞質(zhì)內(nèi)Ca2+濃度增加而發(fā)揮效應(yīng)。

二、MTL/MTL-R

MTL主要分布于十二指腸、近端空腸、胃竇部等，亦可見于大腦、外周神經(jīng)組織。MTL-R是一種G蛋白偶聯(lián)受體，分布于消化系統(tǒng)和中樞系統(tǒng)。在消化道中主要存在于平滑肌細(xì)胞，其濃度從胃竇部到回腸逐漸降低，MTL-R與GHS-R序列有52%的相似性。

三、Ghrelin和MTL釋放

進(jìn)食后，循環(huán)中g(shù)hrelin濃度和GHS-R敏感性均增加，然后逐漸降低，其程度依賴于食物量，而與胃擴(kuò)張程度無(wú)關(guān)[1]。生理劑量或低劑量ghrelin對(duì)胃腸動(dòng)力的作用不明顯[1]，人體ghrelin釋放量與饑餓程度相關(guān)，刺激腦極后區(qū)[2]、下丘腦[3]和迷走神經(jīng)傳入神經(jīng)元上的GHS-R，誘發(fā)饑餓感。

便秘型腸易激綜合征(IBS)胃十二指腸黏膜中g(shù)hrelin濃度較低，腹瀉型IBS中較高，兩者血漿ghrelin濃度無(wú)明顯差異。乳糜瀉患者ghrelin水平明顯高于腹瀉型IBS患者和健康者。血液ghrelin濃度改變與胃食管反流病、胃炎、Hp感染、功能性消化不良相關(guān)。通過(guò)視覺刺激達(dá)到惡心時(shí)，血液ghrelin濃度偏低[4]。Ghrelin能抑制嘔吐，促進(jìn)癌癥惡病質(zhì)患者食欲，同時(shí)減少惡心感。

MTL的釋放與移行性復(fù)合運(yùn)動(dòng)(MMC)相關(guān)。MTL分泌高峰出現(xiàn)在MMCⅢ相。此時(shí)，MTL主要通過(guò)刺激腸道膽堿能活動(dòng)[5-6]或迷走神經(jīng)來(lái)誘發(fā)MMCⅢ相活動(dòng)，引發(fā)胃強(qiáng)烈收縮和小腸明顯分節(jié)運(yùn)動(dòng)；也有研究認(rèn)為可能與5-羥色胺(5-HT)相關(guān)[6]。同時(shí)MTL能通過(guò)刺激迷走神經(jīng)[7]和刺激ghrelin釋放來(lái)增加饑餓感[8]，IBS患者中可見血漿ghrelin和MTL濃度的共變，而在健康者無(wú)此現(xiàn)象，其機(jī)制尚不清楚。

四、促進(jìn)胃排空

雖然ghrelin的釋放與MMC無(wú)明顯相關(guān)性[9]，但外源性ghrelin能誘發(fā)MMCⅢ相[10]，治療4周后能促進(jìn)胃排空。然而糖尿病胃輕癱患者應(yīng)用GHS-R激動(dòng)劑TZP-102治療12周后并不能改善癥狀或促進(jìn)胃排空[11]，這是否與激動(dòng)劑作用受體類型有關(guān)有待進(jìn)一步研究。

在嚙齒類動(dòng)物中，胃腸蠕動(dòng)增加主要通過(guò)刺激腸膽堿能活動(dòng)和刺激迷走神元來(lái)實(shí)現(xiàn)的[2]。白兔[5]和人體胃[12]中g(shù)hrelin并不能刺激腸膽堿能活動(dòng)，提示ghrelin通過(guò)刺激迷走神經(jīng)促進(jìn)胃排空[13]。刺激胃排空的GHS-R激動(dòng)劑劑量高于非胃腸道GHS-R[1]，這可能是由于影響胃排空的GHS-R是低耦合或不敏感的。也有研究發(fā)現(xiàn)，去?；痝hrelin可抑制胃排空。但目前對(duì)GHS-R激動(dòng)劑刺激迷走神是一種短效還是長(zhǎng)效行為，及其對(duì)脊髓的作用并未完全明確。有研究發(fā)現(xiàn)餐后不適綜合征(PDS)患者活性ghrelin水平明顯低于健康者。其發(fā)病是否與ghrelin相關(guān)，以及是否可使用ghrelin及其受體激動(dòng)劑治療這類疾病等均有待進(jìn)一步研究。

低濃度MTL-R激動(dòng)劑通過(guò)刺激乙酰膽堿釋放增加腸膽堿能活動(dòng)，而高濃度可直接收縮平滑肌[5-6]。然而MTL直接通過(guò)調(diào)節(jié)神經(jīng)肌肉對(duì)調(diào)節(jié)食管和胃底部收縮的作用并不明顯[14]，低劑量MTL-R激動(dòng)劑誘發(fā)健康者胃竇部規(guī)則收縮，該作用可被阿托品阻斷，而大劑量可引起不規(guī)則的胃十二指腸收縮，誘發(fā)惡心、嘔吐癥狀[6]。因此使用紅霉素促進(jìn)胃動(dòng)力時(shí)劑量不宜過(guò)大。

Cajal間質(zhì)細(xì)胞(ICC)在胃輕癱時(shí)處于失調(diào)狀態(tài)[15]，引起胃不規(guī)則運(yùn)動(dòng)，從而可誘發(fā)惡心、嘔吐癥狀[16]。Xu等[17]發(fā)現(xiàn)兔子ICC中可見MTL-R表達(dá)，MTL對(duì)離體胃竇誘發(fā)電活動(dòng)和膽堿能活動(dòng)的收縮是一種長(zhǎng)短交替的收縮方式，這可能是由于ICC協(xié)調(diào)作用被破壞[6]。MTL-R激動(dòng)劑能提高糖尿病胃輕癱患者食欲，改善惡心、嘔吐癥狀，促進(jìn)胃排空，其機(jī)制是否與刺激ICC、調(diào)節(jié)胃不規(guī)則運(yùn)動(dòng)有關(guān)，以及是否涉及迷走神經(jīng)均不清楚，還需行更深入的研究。

五、減少惡心和增加食欲

惡心的發(fā)病機(jī)制較復(fù)雜，治療手段較少。當(dāng)饑餓時(shí)，惡心癥狀減弱，GHS-R激動(dòng)劑可通過(guò)增加食欲改善惡心癥狀。GHS-R激動(dòng)劑能改善癌癥患者惡病質(zhì)和嘔吐，皮下注射GHS-R激動(dòng)劑relamorelin可減輕胃輕癱患者惡心、嘔吐癥狀[18]，然而GHS-R激動(dòng)劑TZP-102并不能完全改善糖尿病胃癱患者的惡心、嘔吐癥狀[11]。上述研究結(jié)果的差異可能與個(gè)體對(duì)惡心、嘔吐癥狀評(píng)估是主觀行為相關(guān)。

六、促進(jìn)結(jié)直腸運(yùn)動(dòng)

GHS-R激動(dòng)劑可促進(jìn)結(jié)直腸運(yùn)動(dòng)，縮短住院時(shí)間。皮下注射GHS-R激動(dòng)劑引發(fā)清醒大鼠排便行為，全麻大鼠后，靜脈注射可引起結(jié)直腸推進(jìn)性收縮，切斷骨盆神經(jīng)后，該收縮被阻斷。六甲胺(一種自主神經(jīng)快速傳播拮抗劑)同樣可阻斷該收縮過(guò)程。在嚙齒類動(dòng)物中，骶髓自主神經(jīng)節(jié)前神經(jīng)元中可見GHS-R表達(dá)，應(yīng)用GHS-R激動(dòng)劑ulimorelin可引起結(jié)直腸推進(jìn)性收縮，該作用可被GHS-R拮抗劑YIL-781阻斷[19]。

體外實(shí)驗(yàn)中，ghrelin不能引起結(jié)直腸平滑肌收縮。有研究還顯示，ghrelin和relamorelin能降低結(jié)腸平滑肌興奮性。體內(nèi)應(yīng)用ghrelin對(duì)結(jié)直腸收縮作用不明顯，口服GHS-R激動(dòng)劑EX-1314、EX-1315均能促進(jìn)大鼠排便。這是否與激動(dòng)受體的類型相關(guān)有待進(jìn)一步研究。中樞滲透性GHS-R激動(dòng)劑對(duì)嗎啡引起的腸麻痹、脊髓外傷所致結(jié)腸功能障礙[20]、帕金森大鼠便秘[21]、低纖維飲食誘發(fā)便秘[22]等均有一定程度的積極作用。不同GHS-R激動(dòng)劑對(duì)結(jié)直腸作用時(shí)限不同，如capromorelin作用短暫，而ulimorelin作用長(zhǎng)效，這種變構(gòu)差異還有待進(jìn)一步研究。目前研究發(fā)現(xiàn)注射80 mg/kg ulimorelin可加快胃輕癱患者腸運(yùn)動(dòng)次數(shù)，relamorelin治療14周后可減輕便秘癥狀和加快結(jié)腸傳輸作用[18]，capromorelin可縮短脊髓外傷便秘患者排便時(shí)間[23]。Gürkan等[24]發(fā)現(xiàn)兒童功能性便秘ghrelin水平低于健康兒童，給予飲食調(diào)節(jié)、乳果糖、灌腸治療兩個(gè)月后，ghrelin明顯升高，推測(cè)ghrelin是兒童功能性便秘的結(jié)果而非原因。該結(jié)論還需大樣本數(shù)據(jù)驗(yàn)證。

七、小結(jié)

近年ghrelin/GHS-R激動(dòng)劑和MTL/MTL-R激動(dòng)劑對(duì)DGIM的研究取得了較大進(jìn)展，可改善患者生活質(zhì)量。但目前促胃腸動(dòng)力藥物的不良反應(yīng)較多，臨床使用受限。隨著更多GHS-R和MTL-R激動(dòng)劑的不斷問(wèn)世，可為DGIM的防治提供新方法。

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AdvancesinStudyonRelationshipBetweenGhrelin/GHS-RAgonist,MTL/MTL-RAgonistandGastrointestinalMotility

LIDongyong,XUQingwen,XUPengyuan.

DepartmentofGastrointestinalSurgery,theSecondAffiliatedHospitalofKunmingMedicalUniversity,Kunming(650000)

XU Pengyuan, Email: pyxu778@sina.com

Ghrelin and motilin (MTL) are mainly secreted by digestive tract, and they both can promote gastrointestinal motility. Disorder of gastrointestinal motility (DGIM) is a gastrointestinal motility or sensory disease mainly caused by neuroregulatory disorder, its main symptoms are nausea, vomiting, abdominal pain and abdominal distension. More and more studies have indicated that ghrelin, MTL and their receptor agonists are closely related to DGIM. This article reviewed the advances in studies on relationship between ghrelin/GHS-R agonist, MTL/MTL-R agonist and DGIM.

Ghrelin; Receptors, Ghrelin; Motilin; Receptors, Motilin; Disorder Of Gastrointestinal Motility

10.3969/j.issn.1008-7125.2017.12.013

*現(xiàn)工作單位：保山市人民醫(yī)院普外科(678000)， Email: 1277578825@qq.com

#本文通信作者，Email: pyxu778@sina.com

(2016-12-26收稿；2017-01-17修回)