組胺及組胺受體的研究進(jìn)展

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)。這與類風(fēng)濕性關(guān)節(jié)炎患者中瘦素水平降低的機(jī)制類似[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還能通過調(diào)節(jié)樹突狀細(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)傷口愈合過程主要是通過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程。通過拮抗體內(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、炎癥等過程[49-52]。研究表明組胺通過上調(diào)H1R和下調(diào)H2R來調(diào)節(jié)基質(zhì)金屬蛋白酶2(matrix metalloproteinase 2, MMP2)的活性[48]。類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)劑可能是通過抑制過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。

參考文獻(xiàn)

1Gutiérrez-Venegas G, Rodríguez-Pérez CE. Toll-like receptor 3 activation

promotes desensitization of histamine response in human gingival fibroblasts: Poly (I︰C) induces histamine receptor desensitization in human gingival fibroblasts[J]. Cell Immunol, 2012, 273(2): 150-157.

2Akdis CA, Blaser K. Histamine in the immune regulation of allergic inflammation[J]. J Allergy Clin Immunol, 2003, 112(1): 15-22.

3Jutel M, Watanabe T, Akdis M, et al. Immune regulation by histamine

[J]. Curr Opin Immunol, 2002, 14(6): 735-740.

4Jutel M, Watanabe T, Klunker S, et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors[J]. Nature, 2001, 413(6854): 420-425.

5Banu Y, Watanabe T. Augmentation of antigen receptor-mediated responses

by histamine H1 receptor signaling[J]. J Exp Med, 1999, 189(4): 673-682.

6Ash AS, Schild HO. Receptors mediating some actions of histamine. 1966[J]. Br J Pharmacol, 1997, 120(4 Suppl): 302-314, discussion 300-301.

7Beghdadi W, Porcherie A, Schneider BS, et al. Inhibition of histamine-

mediated signaling confers significant protection against severe malaria in mouse models of disease[J]. J Exp Med, 2008, 205(2): 395-408.

8Metz M, Doyle E, Bindslev-Jensen C, et al. Effects of antihistamines

on innate immune responses to severe bacterial infection in mice[J]. Int Arch Allergy Immunol, 2011, 155(4): 355-360.

9Glatzer F, Gschwandtner M, Ehling S, et al. Histamine induces proliferation

in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor[J]. J Allergy Clin Immunol, 2013, 132(6): 1358-1367.

10Gschwandtner M, Rossbach K, Dijkstra D, et al. Murine and human

Langerhans cells express a functional histamine H4 receptor: modulation of cell migration and function[J]. Allergy, 2010,65(7): 840-849.

11B?umer W, Wendorff S, Gutzmer R, et al. Histamine H4 receptors modulate dendritic cell migration through skin-immunomodulatory role of histamine[J]. Allergy, 2008, 63(10): 1387-1394.

12Leite-de-Moraes MC, Diem S, Michel ML, et al. Cutting edge: histamine receptor H4 activation positively regulates in vivo IL-4 and IFN-gamma production by invariant NKT cells[J]. J Immunol, 2009, 182(3): 1233-1236.

13Ohsawa Y, Hirasawa N. The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice[J]. Allergy, 2012, 67(8): 1014-1022.

14Hofstra CL, Desai PJ, Thurmond RL, et al. Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells[J]. J Pharmacol Exp Ther, 2003, 305(3): 1212-1221.

15Grzybowska-Kowalczyk A, Wojtecka-Lukasik E, Maslinska D, et al.

Distribution pattern of histamine H4 receptor in human synovial tissue from patients with rheumatoid arthritis[J]. Inflamm Res, 2007, 56 (Suppl 1): S59-S60.

16Adlesic M, Verdrengh M, Bokarewa M, et al. Histamine in rheumatoid

arthritis[J]. Scand J Immunol, 2007, 65(6): 530-537.

17Bokarewa M, Bokarew D, Hultgren O, et al. Leptin consumption in the inflamed joints of patients with rheumatoid arthritis[J]. Ann Rheum Dis,2003, 62(10): 952-956.

18Ma RZ, Gao J, Meeker ND, et al. Identification of Bphs, an autoimmune disease locus, as histamine receptor H1[J]. Science, 2002, 297(5581): 620-623.

19Musio S, Gallo B, Scabeni S, et al. A key regulatory role for histamine in experimental autoimmune encephalomyelitis: disease exacerbation in histidine decarboxylase-deficient mice[J]. J Immunol, 2006, 176(1): 17-26.

20Teuscher C, Subramanian M, Noubade R, et al. Central histamine H3 receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS[J]. Proc Natl Acad Sci U S A, 2007, 104(24): 10146-10151.

21Sayed BA, Christy AL, Walker ME, et al. Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment?[J]. J Immunol, 2010, 184(12): 6891-6900.

22Somma T, Cinci L, Formicola G, et al. A selective antagonist of histamine H(4) receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1[J]. Br J Pharmacol, 2013, 170(1): 200-213.

23Hartwig C, Munder A, Glage S, et al. The histamine H -receptor (H R) regulates eosinophilic inflammation in ovalbumin-induced experimental allergic asthma in mice[J]. Eur J Immunol, 2014, doi: 10.1002/eji.201445179.

24Yu B, Shao Y, Li P, et al. Copy number variations of the human histamine H4 receptor gene are associated with systemic lupus erythematosus[J]. Br J Dermatol, 2010, 163(5): 935-940.

25Ciebiada M, Kasztalska K, Gorska-Ciebiada M, et al. Histamine type 2 receptor expression on peripheral blood regulatory lymphocytes in patients with allergic rhinitis treated with specific immunotherapy[J]. Am J Rhinol Allergy, 2014, 28(3): e130-e135.

26Baenkler HW, Lux G, Gunthner R, et al. Biopsy histamine in ulcerative

colitis and Crohn's disease[J]. Hepatogastroenterology,1987, 34(6): 289-290.

27Raithel M, Matek M, Baenkler HW, et al. Mucosal histamine content

and histamine secretion in Crohn′s disease, ulcerative colitis and allergic enteropathy[J]. Int Arch Allergy Immunol, 1995, 108(2): 127-133.

28Sander LE, Lorentz A, Sellge G, et al. Selective expression of histamine

receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract[J]. Gut, 2006, 55(4): 498-504.

29Varga C, Horvath K, Berko A, et al. Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat[J]. Eur J Pharmacol, 2005, 522(1-3): 130-138.

30Rajasekaran N, Solomon S, Watanabe T, et al. Histidine decarboxylase

but not histamine receptor 1 or 2 deficiency protects from K/BxN serum-induced arthritis[J]. Int Immunol, 2009, 21(11): 1263-1268.

31Vonakis BM, Sora R, Langdon JM, et al. Inhibition of cytokine gene transcription by the human recombinant histamine-releasing factor in human T lymphocytes[J]. J Immunol, 2003, 171(7): 3742-3750.

32Dy M, Arnould A, Lemoine FM, et al. Hematopoietic progenitors and interleukin-3-dependent cell lines synthesize histamine in response to calcium ionophore[J]. Blood, 1996, 87(8): 3161-3169.

33Gailit J, Marchese MJ, Kew RR, et al. The differentiation and function

of myofibroblasts is regulated by mast cell mediators[J]. J Invest Dermatol, 2001, 117(5): 1113-1119.

34Minami T, Kuroishi T, Ozawa A, et al. Histamine amplifies immune response of gingival fibroblasts[J]. J Dent Res, 2007, 86(11): 1083-1088.

35Gutierrez-Venegas G, Cruz-Arrieta S, Villeda-Navarro M, et al. Histamine

promotes the expression of receptors TLR2 and TLR4 and amplifies sensitivity to lipopolysaccharide and lipoteichoic acid treatment in human gingival fibroblasts[J]. Cell Biol Int, 2011, 35(10): 1009-1017.

36Nakashima K, Roehrich N, Cimasoni G. Osteocalcin, prostaglandin E2 and alkaline phosphatase in gingival crevicular fluid: their relations to periodontal status[J]. J Clin Periodontol, 1994, 21(5): 327-333.

37Van Dyke TE, Serhan CN. Resolution of inflammation: a new paradigm

for the pathogenesis of periodontal diseases[J]. J Dent Res, 2003, 82(2): 82-90.

38鐘斐, 蔣瑾瑾. 組胺及組胺受體對(duì)免疫系統(tǒng)調(diào)節(jié)作用[J]. 中華臨床醫(yī)師雜志, 2013, 7(21): 9753-9755

39Fitzpatrick LA, Buzas E, Gagne TJ, et al. Targeted deletion of histidine

decarboxylase gene in mice increases bone formation and protects against ovariectomy-induced bone loss[J]. Proc Natl Acad Sci U S A, 2003, 100(10): 6027-6032.

40Handley SA, Dube PH, Miller VL. Histamine signaling through the H(2) receptor in the Peyer′s patch is important for controlling Yersinia enterocolitica infection[J]. Proc Natl Acad Sci U S A, 2006, 103(24): 9268-9273.

41Gutowska-Owsiak D, Selvakumar TA, Salimi M, et al. Histamine enhances keratinocyte-mediated resolution of inflammation by promoting wound healing and response to infection[J]. Clin Exp Dermatol, 2014, 39(2): 187-195.

42Jung SY, Shin SY, Eun YG, et al. Changes of histamine receptors and CC chemokines in nasal epithelial cells and fibroblasts after respiratory syncytial virus infection[J]. Am J Rhinol Allergy, 2013, 27(1): e17-21.

43Ishii M, Iwai M, Harada Y, et al. A role of mast cells for hepatic fibrosis in primary sclerosing cholangitis[J]. Hepatol Res, 2005, 31(3): 127-131.

44Guimaraes JV, Costa FB, Andrade WM, et al. Quantification of mast cells in the uterine cervix of women infected with human immunodeficiency virus[J]. Ann Diagn Pathol, 2011, 15(5): 318-322.

45Williams A, Steffens F, Reinecke C, et al. The Th1/Th2/Th17 cytokine profile of HIV-infected individuals: a multivariate cytokinomics approach[J]. Cytokine, 2013, 61(2): 521-526.

46Pedersen M, Nielsen CM, Permin H. HIV antigen-induced release of histamine from basophils from HIV infected patients. Mechanism and relation to disease progression and immunodeficiency[J]. Allergy, 1991, 46(3): 206-212.

47Shaw JM, Hunt PW, Critchfield JW, et al. Increased frequency of regulatory T cells accompanies increased immune activation in rectal mucosae of HIV-positive noncontrollers[J]. J Virol, 2011, 85(21): 11422-11434.

48Porretti JC, Mohamad NA, Martin GA, et al. Fibroblasts induce epithelial to mesenchymal transition in breast tumor cells which is prevented by fibroblasts treatment with histamine in high concentration[J]. Int J Biochem Cell Biol, 2014, 51: 29-38.

49Garbuzenko E, Berkman N, Puxeddu I, et al. Mast cells induce activation of human lung fibroblasts in vitro[J]. Exp Lung Res,2004, 30(8): 705-721.

50Ikawa Y, Shiba K, Ohki E, et al. Comparative study of histamine H4 receptor expression in human dermal fibroblasts[J]. J Toxicol Sci, 2008, 33(4): 503-508.

51Kohyama T, Yamauchi Y, Takizawa H, et al. Histamine stimulates human lung fibroblast migration[J]. Mol Cell Biochem,2010, 337(1-2): 77-81.

52Kunzmann S, Schmidt-Weber C, Zingg JM, et al. Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: potential role of histamine in airway remodeling[J]. J Allergy Clin Immunol, 2007, 119(6): 1398-1407.

53Asano K, Kanai KI, Suzaki H. Suppressive activity of fexofenadine hydrochloride on metalloproteinase production from nasal fibroblasts in vitro[J]. Clin Exp Allergy, 2004, 34(12): 1890-1898.

54Doyle JL, Haas TL. Differential role of beta-catenin in VEGF and histamine-induced MMP-2 production in microvascular endothelial cells[J]. J Cell Biochem, 2009, 107(2): 272-283.

55Genre F, Valli E, Medina V, et al. Effect of histamine on the expression

of metalloproteinases and cell adhesion in breast cancer cell lines[J]. Inflamm Res, 2009, 58( Suppl 1): 55-56.

56Gschwandtner M, Purwar R, Wittmann M, et al. Histamine upregulates

keratinocyte MMP-9 production via the histamine H1 receptor[J]. J Invest Dermatol,2008, 128(12): 2783-2791.

57Tetlow LC, Woolley DE. Effect of histamine on the production of matrix metalloproteinases-1, -3, -8 and -13, and TNFalpha and PGE(2) by human articular chondrocytes and synovial fibroblasts in vitro: a comparative study[J]. Virchows Arch, 2004, 445(5): 485-490.

58Gschwandtner M, Mommert S, Kother B, et al. The histamine H4 receptor is highly expressed on plasmacytoid dendritic cells in psoriasis and histamine regulates their cytokine production and migration[J]. J Invest Dermatol, 2011, 131(8): 1668-1676.

59Cai WK, Hu J, Li T, et al. Activation of histamine H4 receptors decreases epithelial-to-mesenchymal transition progress by inhibiting transforming growth factor-beta1 signalling pathway in non-small cell lung cancer[J]. Eur J Cancer, 2014, 50(6): 1195-1206.

60Martinel Lamas DJ, Cortina JE, Ventura C, et al. Enhancement of Ionizing Radiation Response by Histamine in Vitro and in Vivo in Human Breast Cancer[J]. Cancer Biol Ther, 2015, 16(1): 137-148.

(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