組胺及組胺受體的研究進(jìn)展

馮小倩武曦譚穎徽

作者單位： 400037 重慶，第三軍醫(yī)大學(xué)新橋醫(yī)院口腔科

【關(guān)鍵詞】組胺；組胺受體；免疫；感染；炎癥

組胺(histamine)是一種自體活性物質(zhì)，它以無(wú)活性結(jié)合型存在于肥大細(xì)胞和嗜堿性粒細(xì)胞的顆粒中。在體內(nèi)組胺由組氨酸經(jīng)組氨酸脫羧酶(histidine decarboxylase, HDC)脫羧基而成，具有多種生物活性作用，包括過(guò)敏反應(yīng)，炎性反應(yīng)等。肥大細(xì)胞和嗜堿性粒細(xì)胞致敏后能通過(guò)脫顆粒釋放組胺，并與組胺受體結(jié)合，從而產(chǎn)生生物學(xué)效應(yīng)，包括過(guò)敏性反應(yīng)和炎癥反應(yīng)。最新研究發(fā)現(xiàn) ，組胺是免疫反應(yīng)中重要的調(diào)控者[1]。

一、 組胺及組胺受體

組胺是一種重要的化學(xué)介質(zhì)，由多種細(xì)胞生成，包括肥大細(xì)胞，嗜堿性粒細(xì)胞，嗜鉻細(xì)胞，血小板，樹(shù)突狀細(xì)胞，以及T細(xì)胞等，其功能影響機(jī)體的多種生理機(jī)能，包括細(xì)胞增殖，分化，造血過(guò)程，胚胎發(fā)育，組織再生，以及傷口愈合。在不同的微生物源性感染中，組胺廣泛存在于各種炎癥以及感染性疾病中，主要調(diào)控宿主免疫反應(yīng)，具有正、負(fù)雙向的調(diào)控作用[2-8]。組胺的活化有賴(lài)于其相應(yīng)的4個(gè)受體。按被發(fā)現(xiàn)順序命名為H1R、H2R、H3R和H4R。HRs屬G蛋白偶聯(lián)受體(G-protein-coupled receptors, GPCRs)家族成員，通過(guò)偶聯(lián)激活特異性G蛋白進(jìn)行信號(hào)轉(zhuǎn)導(dǎo)。這四種受體在在表達(dá)、信號(hào)轉(zhuǎn)導(dǎo)及其生理功能等方面均不同：組胺1型受體(histamine 1 receptor, H1R)屬于G蛋白偶聯(lián)受體超家族，主要分布于內(nèi)皮和平滑肌等多種細(xì)胞，調(diào)節(jié)血管舒張和支氣管收縮。組胺2型受體(histamine 2 receptor, H2R)能與 cAMP 系統(tǒng)偶聯(lián)，主要調(diào)節(jié)胃酸分泌。組胺3型受體(histamine 3 receptor, H3R)主要在神經(jīng)系統(tǒng)作為突觸前自身受體的方式進(jìn)行表達(dá)。組胺4型受體(histamine 4 receptor，H4R) 是最新發(fā)現(xiàn)的受體，它與H3R有相似的生物學(xué)和藥理學(xué)特性。然而不同的是，H4R在細(xì)胞上的表達(dá)更廣泛，包括角質(zhì)形成細(xì)胞，朗格漢斯細(xì)胞，中性粒細(xì)胞，淋巴細(xì)胞和樹(shù)突狀細(xì)胞[9-11]。最新研究表明，H4R敲除小鼠，其血清中IL-4和α型干擾素(interferon-α, IFN-α)分泌濃度顯著降低，同時(shí)Invariant NKT (iNKT)細(xì)胞數(shù)量及功能受損[12]。同時(shí)，Ohsawa等[13]研究發(fā)現(xiàn)， H1R和H4R拮抗劑的聯(lián)合使用能抑制皮膚瘙癢和炎癥，這種治療方式可能對(duì)慢性皮炎有一定的療效。

二、組胺與自身免疫性疾病

大量研究證實(shí)組胺及組胺受體在自身免疫疾病中發(fā)揮重要作用。除了肥大細(xì)胞可表達(dá)組胺受體外，它還能在類(lèi)風(fēng)濕性關(guān)節(jié)炎患者滑膜細(xì)胞中進(jìn)行表達(dá)，因此組胺同樣可以調(diào)節(jié)滑膜細(xì)胞的相關(guān)功能[14-15]。已有研究證實(shí)，類(lèi)風(fēng)濕性關(guān)節(jié)炎患者其血清中組胺水平升高。然而，組胺直接注射到關(guān)節(jié)腔內(nèi)并不能促進(jìn)宿主炎癥反應(yīng)的發(fā)生。奇怪的是，類(lèi)風(fēng)濕性關(guān)節(jié)炎患者，其滑膜液組胺水平比健康對(duì)照組低[16]。推測(cè)其可能的原因可能與組胺受體表達(dá)水平的升高以及組胺消耗的增加有關(guān)。這與類(lèi)風(fēng)濕性關(guān)節(jié)炎患者中瘦素水平降低的機(jī)制類(lèi)似[17]。

在所有自身免疫性疾病模型中，自身免疫性腦脊髓膜炎(experimental autoimmune encephalomyelitis, EAE)作為一個(gè)多發(fā)性硬化模型，其研究進(jìn)展最快。有研究發(fā)現(xiàn)，H1R基因是百日咳毒素誘導(dǎo)自身免疫致敏的關(guān)鍵基因。Ma等[18]發(fā)現(xiàn)H1R缺陷小鼠對(duì)EAE有重要保護(hù)作用，H2R缺陷小鼠也能減弱EAE對(duì)宿主的損傷。與H1R缺陷小鼠細(xì)胞細(xì)胞因子的分泌不同，H2R缺陷小鼠是通過(guò)增加單核細(xì)胞趨化因子1的分泌發(fā)揮保護(hù)性作用。然而，HDC缺陷與H3R缺陷小鼠都表現(xiàn)為EAE臨床癥狀及病理加重[19-20]。因此，在中樞神經(jīng)系統(tǒng)的自身免疫性炎癥中，H3R可能有抑制炎癥的作用。有趣的是，有研究表明肥大細(xì)胞缺陷小鼠EAE癥狀減輕，因此肥大細(xì)胞釋放組胺可能與EAE的發(fā)生有關(guān)[21]。然而組胺的其它來(lái)源途徑還需進(jìn)一步確定。

有研究顯示，在豚鼠哮喘模型中，H4R受體通過(guò)上調(diào)脂皮質(zhì)蛋白(LC-1)參與其免疫調(diào)節(jié)和炎癥反應(yīng)[22]。后續(xù)研究發(fā)現(xiàn)，小鼠哮喘模型H4R還能通過(guò)調(diào)節(jié)樹(shù)突狀細(xì)胞(dendritic cells, DCs)的活化而使宿主致敏[23]。H4R基因在系統(tǒng)性紅斑狼瘡患者的表達(dá)明顯上調(diào)[24]。另外過(guò)敏性鼻炎患者在接觸天然花粉后，H2R數(shù)量不僅在調(diào)節(jié)性T細(xì)胞上表達(dá)上調(diào)，同時(shí)，外周血中T淋巴細(xì)胞H2R的表達(dá)也增高[25]。

組胺在其它自身免疫性疾病患者中的表達(dá)也升高，包括克羅恩病、潰瘍性結(jié)腸炎、關(guān)節(jié)炎、哮喘等。組胺是通過(guò)其受體發(fā)揮損傷作用的，應(yīng)用相應(yīng)的組胺受體拮抗劑可以減輕自身免疫性疾病的損傷作用。

三、組胺與炎癥

有研究發(fā)現(xiàn)，克羅恩病和潰瘍性結(jié)腸炎患者中，組胺表達(dá)明顯升高[26-27]。Sander等[28]發(fā)現(xiàn)腸道內(nèi)表達(dá)H1R、H2R、H4R的細(xì)胞有很多種，包括上皮細(xì)胞等。有趣的是，在這些細(xì)胞表面并沒(méi)有檢測(cè)到H3R的表達(dá)，目前，組胺及組胺受體對(duì)調(diào)節(jié)腸道免疫功能的作用還知之甚少。有研究表明，在2,4,6-三硝基苯磺酸誘導(dǎo)的急性結(jié)腸炎模型中， H4R拮抗劑的使用能減輕大鼠的炎癥反應(yīng)[29]。在這項(xiàng)研究中，應(yīng)用H4R拮抗劑JNJ 7777120或者 JNJ 10191584能使腸道黏膜增厚，從而減輕大鼠腸道損傷。同時(shí)也可使腫瘤壞死因子-α(tumor necrosis factor-α, TNF-α)的產(chǎn)生減少和減輕中性粒細(xì)胞的聚集，這些結(jié)果均提示H4R可能影響該模型的免疫反應(yīng)。在關(guān)節(jié)炎動(dòng)物模型中，HDC缺陷小鼠的炎癥減輕。后續(xù)研究發(fā)現(xiàn)該現(xiàn)象并不存在于H1R、H2R缺陷小鼠，提示H3R、H4R在本病的病程中可能具有一定作用[30]。

體內(nèi)存在多種細(xì)胞因子，參與促進(jìn)組胺合成。TNF-α、IL-1可與人粒細(xì)胞-巨噬細(xì)胞集落刺激因子(granulocyte-macrophage-colony stimulating factor, GM-CSF)協(xié)同誘導(dǎo)嗜堿粒細(xì)胞合成組胺，同時(shí)，脂多糖(lipopolysaccharide, LPS)刺激巨噬細(xì)胞后可使組胺合成[31]。 Dy等[32]研究發(fā)現(xiàn)細(xì)胞因子IL-3能與LPS協(xié)同促進(jìn)巨噬細(xì)胞合成組胺。有研究發(fā)現(xiàn)，一定程度的炎癥條件下，由肥大細(xì)胞合成和分泌的組胺、肝素、類(lèi)胰蛋白酶、細(xì)胞因子等能夠刺激成纖維細(xì)胞增殖以及形成胞外基質(zhì)積聚，并使組織纖維化[33]。相反的，組胺的過(guò)度增加會(huì)加重TNF-α、IL-1、LPS對(duì)牙齦成纖維細(xì)胞的炎癥刺激，增強(qiáng)局部組織免疫反應(yīng)，進(jìn)一步加重牙周組織的破壞[34]。組胺能通過(guò)刺激牙齦成纖維細(xì)胞IL-2、IL-4表達(dá)升高，間接促使前列腺素E2(prostaglandin E2, PGE2)的分泌表達(dá)[34-35]。PGE2作為一種炎癥介質(zhì)和強(qiáng)效促進(jìn)骨吸收的刺激因子，能夠加速破骨細(xì)胞的形成，增強(qiáng)破骨細(xì)胞前體的融合，抑制鈣化，促進(jìn)骨吸收[36-37]。組胺通過(guò)脫顆?，F(xiàn)象由肥大細(xì)胞和嗜堿性粒細(xì)胞釋放并與組胺受體結(jié)合后，產(chǎn)生生物學(xué)效應(yīng)，使機(jī)體發(fā)生炎癥反應(yīng)。當(dāng)炎癥進(jìn)行性加重時(shí)，造成對(duì)組織的破壞。在炎癥早期階段，局部組織中分離的組胺參與了早期炎癥反應(yīng)，并促進(jìn)炎癥發(fā)展[38]。組胺-組胺受體通路在組胺脫羧酶的作用下被激活，有研究證實(shí)，先天缺乏組胺脫羧酶的大鼠，其骨組織只含有少量的破骨細(xì)胞，破骨細(xì)胞的生成也受到了抑制，這說(shuō)明組胺與破骨細(xì)胞生長(zhǎng)以及骨組織損傷關(guān)系密切[39]。

四、組胺與感染

組胺的合成與釋放可能是感染過(guò)程中的一種現(xiàn)象，但是具體的機(jī)制還有待進(jìn)一步明確。有研究表明動(dòng)物感染模型與組胺受體和HDC缺陷有關(guān)，這可以預(yù)測(cè)細(xì)菌本身與組胺的產(chǎn)生相關(guān)。在某些情況下，感染依賴(lài)于組胺的產(chǎn)生。有研究證實(shí)組胺在小鼠腸道耶爾森氏菌感染中作用顯著[40]。另有研究表明組胺可激活與傷口愈合和感染有關(guān)的角質(zhì)形成細(xì)胞的功能。組胺介導(dǎo)傷口愈合過(guò)程主要是通過(guò)H1R受體發(fā)揮作用，其他角質(zhì)形成細(xì)胞也一并參與其中[41]。

有研究證實(shí)呼吸道合胞病毒感染后組胺的四種受體水平均升高，其中H1R和H2R升高更為顯著，提示感染可能通過(guò)增加組胺受體水平而引起呼吸道反應(yīng)[42]。Ishii等[43]的研究結(jié)果提示慢性肝炎肝臟組胺水平明顯升高，說(shuō)明慢性肝炎時(shí)肥大細(xì)胞釋放組胺增多而形成高組胺血癥。

有研究證實(shí)感染HIV女性子宮頸病理切片中，肥大細(xì)胞數(shù)目升高，且HIV可以引起組織肥大細(xì)胞釋放組胺[44-45]。HIV抗原可以誘導(dǎo)嗜堿性粒細(xì)胞釋放組胺，且組胺的釋放量與血液中CD4+T淋巴細(xì)胞數(shù)成反比，這提示組胺可能與疾病進(jìn)程有一定相關(guān)性[46]。進(jìn)一步研究表明，HIV表面gp120糖蛋白或游離gp120可以與HIV特異性的IgE結(jié)合，從而誘導(dǎo)細(xì)胞脫顆粒釋放IL-4、組胺等[47]。

由于不同疾病組胺受體表達(dá)的多樣性，內(nèi)源性組胺可能出現(xiàn)不同的作用。這提示組胺受體拮抗劑可能參與多種疾病的致病過(guò)程。通過(guò)拮抗體內(nèi)組胺及組胺受體的作用，有望達(dá)到對(duì)相關(guān)疾病進(jìn)行干預(yù)，調(diào)節(jié)宿主免疫，從而達(dá)到對(duì)疾病的治療的目的。

五、組胺與腫瘤

上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition, EMT)是癌癥進(jìn)展中的一個(gè)關(guān)鍵過(guò)程。以往有研究證實(shí)部分腫瘤細(xì)胞能產(chǎn)生組胺，進(jìn)而影響腫瘤的生長(zhǎng)和侵襲。Porretti等[48]提出了組胺可能影響腫瘤細(xì)胞和正常細(xì)胞之間的相互作用，他們?cè)u(píng)估了正常乳腺組織成纖維細(xì)胞中的組胺受體包括H1R、H2R、和H4R的表達(dá)，這與乳腺癌組織中的表達(dá)有顯著差異。同樣的研究也證實(shí)了在肺和皮膚組織中，H1R、H2R、和H4R參與了成纖維細(xì)胞增殖、遷移、傷口愈合、炎癥等過(guò)程[49-52]。研究表明組胺通過(guò)上調(diào)H1R和下調(diào)H2R來(lái)調(diào)節(jié)基質(zhì)金屬蛋白酶2(matrix metalloproteinase 2, MMP2)的活性[48]。類(lèi)似的研究同樣表明組胺也可改變鼻和滑膜成纖維細(xì)胞中基質(zhì)金屬蛋白酶產(chǎn)生，通過(guò)影響正常細(xì)胞及腫瘤細(xì)胞中基質(zhì)金屬蛋白酶基因和蛋白的表達(dá)來(lái)影響腫瘤細(xì)胞的侵襲力[53-57]。此外，上述研究還證實(shí)成纖維細(xì)胞的遷移與組胺的表達(dá)存在劑量依賴(lài)性，高劑量的組胺可能抑制成纖維細(xì)胞的遷移活性，同時(shí)避免由成纖維細(xì)胞誘導(dǎo)的腫瘤細(xì)胞EMT。有證據(jù)表明組胺對(duì)肺纖維化成纖維細(xì)胞的遷移能力和炎癥組織中免疫細(xì)胞的功能也具有重要影響[51, 58]。

Cai等[59]從體外和體內(nèi)試驗(yàn)探討了H4R激動(dòng)劑和拮抗劑對(duì)非小細(xì)胞肺癌(non-small cell lung cancer, NSCLC)EMT進(jìn)程的影響。其結(jié)果顯示H4R受體的激活是通過(guò)TGF-β信號(hào)通路下調(diào)細(xì)胞內(nèi)cAMP和抑制NSCLC中EMT的進(jìn)程發(fā)揮作用。由此推測(cè)H4R受體可能是NSCLC治療的新的治療靶點(diǎn)。

Martinel等[60]通過(guò)將H1R和H4R激動(dòng)劑作用于受γ輻射的乳腺癌細(xì)胞，發(fā)現(xiàn)組胺增加了乳腺癌細(xì)胞的放射敏感性。這里組胺及其受體激動(dòng)劑可能是通過(guò)抑制過(guò)氧化氫酶和超氧化物歧化酶的活性增加了活性氧的釋放，從而增加了輻射誘導(dǎo)的DNA氧化損傷，DNA雙鏈斷裂，細(xì)胞凋亡和衰老。因此，組胺可以作為一個(gè)潛在提高腫瘤放療療效的輔助藥物。

組胺及其受體的相互作用不僅參與調(diào)節(jié)了機(jī)體的許多重要的生理過(guò)程： 如神經(jīng)內(nèi)分泌調(diào)節(jié)、學(xué)習(xí)記憶、體溫調(diào)節(jié)、胃腸循環(huán)調(diào)節(jié)等，還參與了許多病理過(guò)程： 如炎癥反應(yīng)、變態(tài)反應(yīng)、腫瘤性疾病。組胺是研究較為廣泛的自體活性物質(zhì)之一，充分了解組胺及其受體的相互作用，有利于許多疾病的臨床治療。第一代和第二代H1R拮抗劑一直是變應(yīng)性鼻炎治療的一線藥物。選擇性H2R激動(dòng)劑可能有助于減輕自身免疫性疾病及超敏反應(yīng)的臨床癥狀，而選擇性H1R、H2R及H4R拮抗劑有利于腫瘤及炎癥性疾病的治療。盡管組胺在臨床的應(yīng)用已逐漸減少，但其受體激動(dòng)和阻斷藥物在臨床上卻有重大價(jià)值，因此組胺及其受體的相互作用機(jī)制值得進(jìn)一步深入研究和探討。

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(本文編輯：黃紅稷)

馮小倩，武曦，譚穎徽. 組胺及組胺受體的研究進(jìn)展[J/CD]. 中華肺部疾病雜志： 電子版， 2015， 8(2)： 234-237.

·綜述·

收稿日期：(2014-12-05)

文獻(xiàn)標(biāo)識(shí)碼：中圖法分類(lèi)號(hào)： R563 A

通訊作者：譚穎徽， Email: tanyh1962@outlook.com

基金項(xiàng)目：國(guó)家自然科學(xué)基金(81170934)

DOI：10.3877/cma.j.issn.1674-6902.2015.02.023