核轉(zhuǎn)錄因子κB對哮喘患兒氣道平滑肌作用機(jī)制的研究進(jìn)展

劉璐， 孫麗平

綜 述

核轉(zhuǎn)錄因子κB對哮喘患兒氣道平滑肌作用機(jī)制的研究進(jìn)展

劉璐， 孫麗平

核轉(zhuǎn)錄因子κB(NF-κB)是一種促進(jìn)轉(zhuǎn)錄的蛋白質(zhì)，可調(diào)節(jié)炎癥介質(zhì)的基因表達(dá)和氣道內(nèi)多種細(xì)胞的功能，是防治哮喘的研究的一個核心環(huán)節(jié)。NF-κB感受刺激而活化后能調(diào)控前炎性因子的生成，參與多種促炎反應(yīng)因子和趨化因子基因的轉(zhuǎn)錄。NF-κB抑制蛋白(IκB)是 NF-κB信號轉(zhuǎn)導(dǎo)途徑成員之一，以無活性形式存在于胞漿中，在外界信刺激下被激活而發(fā)生磷酸化，結(jié)果NF-κB由抑制狀態(tài)被激活。腫瘤壞死因子α刺激IκB激酶α進(jìn)入細(xì)胞核，繼而調(diào)控特定NF-κB應(yīng)答基因的表達(dá)。

哮喘； 氣道平滑肌細(xì)胞； 核轉(zhuǎn)錄因子κB； 兒童

氣道重塑是支氣管哮喘(簡稱哮喘)的特征之一。氣道平滑肌是維持氣道張力的重要組織，而氣道平滑肌細(xì)胞是其效應(yīng)細(xì)胞，過度增殖是導(dǎo)致重塑的主要原因，與炎癥密切相關(guān)。核轉(zhuǎn)錄因子(nuclear transcription factor kappa B，NF-κB)參與多種基因的轉(zhuǎn)錄，是炎癥反應(yīng)發(fā)生的核心環(huán)節(jié)，在發(fā)病過程中占重要角色。目前對于哮喘而言，NF-κB是一個研究熱點。本文通過文獻(xiàn)檢索，從而闡述NF-κB對氣道平滑肌細(xì)胞的作用機(jī)制。

1 NF-κB來源

1986年Sen和Baltimore首次在B細(xì)胞提取物中發(fā)現(xiàn)了能與免疫球蛋白κ輕鏈基因增強(qiáng)子發(fā)生特異結(jié)合和的蛋白，稱其為NF-κB。NF-κB家族是一類可與多種基因啟動子部位的κB位點發(fā)生特異性結(jié)合，促進(jìn)轉(zhuǎn)錄的蛋白質(zhì)總稱，其轉(zhuǎn)錄因子涉及多種細(xì)胞應(yīng)答。NF-κB有5個主要成員，在哺乳動物的細(xì)胞中有RelA(p65)、RelB、c-Rel、p50/p105(NF-κB1)和p52/p100(NF-κB2)，所有成員的N末端均有約300個氨基酸殘基的Rel同源區(qū)，各蛋白成員間可形成不同形式的同源或異源二聚體復(fù)合物[1]。

2 NF-κB與哮喘

哮喘是一種異質(zhì)性疾病，以氣道慢性炎癥和氣道重塑為特征。由多細(xì)胞參與調(diào)控的慢性炎癥導(dǎo)致黏液增多、膠原沉積和氣道平滑肌增生或肥大，致使氣道重構(gòu)，出現(xiàn)氣道高反應(yīng)性，可引起呼吸道通氣受限[2]。臨床上表現(xiàn)為呼吸短促、氣喘、咳嗽、痰液產(chǎn)生。目前，抗炎療法是西醫(yī)主要治療手段，如糖皮質(zhì)激素、白三烯調(diào)節(jié)劑、色甘酸鈉等多種抗炎藥物在臨床廣泛應(yīng)用[3]。因炎癥途徑復(fù)雜，抗炎療法仍無法從根本上解決問題。研究發(fā)現(xiàn)控制炎癥級聯(lián)反應(yīng)的上游是理想的治療策略。誘導(dǎo)痰測驗發(fā)現(xiàn)氣管組織內(nèi)炎癥細(xì)胞隨著NF-κB活化而增加[4-6]。多種因子通過NF-κB調(diào)節(jié)炎癥介質(zhì)的基因表達(dá)，對炎癥細(xì)胞有至關(guān)重要的作用[7-10]。

NF-κB通路從被發(fā)現(xiàn)至今有20年，與多種重要通路聯(lián)系密切、牽涉病種廣。目前多種治療哮喘藥物是通過抑制NF-κB的表達(dá)或阻斷其信號通路的方式來提高抗炎活性[6-7，11-13]。當(dāng)細(xì)胞受到刺激信號后，NF-κB從NF-κB抑制蛋白(inhibitor of NF-κB，IκB)α復(fù)合體中游離后活化進(jìn)入細(xì)胞核，繼而調(diào)控相關(guān)基因的表達(dá)，這個反式過程涉及IKK對IκBα的磷酸催化作用[14]。NF-κB通路是多種誘導(dǎo)物誘導(dǎo)其他基因表達(dá)調(diào)控的途徑[15]。氧化應(yīng)激通過NF-κB通路誘導(dǎo)炎癥基因表達(dá)，從而導(dǎo)致氣道炎癥產(chǎn)生，對生理應(yīng)激反應(yīng)敏感的轉(zhuǎn)錄因子NF-κB，是炎性細(xì)胞因子網(wǎng)絡(luò)中調(diào)節(jié)氣道病理活動的重要參與者。對NF-κB活化響應(yīng)的主要炎癥介質(zhì)有白細(xì)胞介素1β(interleukin-10，IL-1β)、腫瘤壞死因子α(tumor necrosis factor，TNF-α)和Toll樣受體(Toll-like receptors，TLRs)[16]。炎癥中多種信號轉(zhuǎn)導(dǎo)通路匯集于NF-κB/IκBα復(fù)合體，因此將NF-κB定為治療標(biāo)靶，是防治哮喘研究的一個重要環(huán)節(jié)。

3 NF-κB與氣道重塑

氣道上皮細(xì)胞內(nèi)NF-κB活化與哮喘發(fā)病機(jī)制有關(guān)。降低NF-κB過表達(dá)可抑制氣道平滑肌細(xì)胞增殖。NF-κB可以通過調(diào)控免疫和炎癥相關(guān)因子及介質(zhì)之間的級聯(lián)放大瀑布效應(yīng)，從而對炎癥和免疫反應(yīng)起樞紐作用。當(dāng)氣道上皮組織內(nèi)NF-κB通路被激活后，釋放的炎癥介質(zhì)(如IL-1β、TNF-α等)刺激氣道平滑肌細(xì)胞及成纖維細(xì)胞，使之增殖、活化，導(dǎo)致氣道上皮細(xì)胞增生、氣道組織纖維化、氣道重塑[17-18]。

3.1 激活NF-κB對氣道重塑的影響 氣道上皮受氧化應(yīng)激、細(xì)胞因子等多種刺激，可以刺激NF-κB活化，同時也可以作為佐劑誘導(dǎo)抗原特異性致敏。IκB激酶(IKK復(fù)合體)是NF-κB信號轉(zhuǎn)導(dǎo)途徑成員之一，包括IKKα、IKKβ催化亞基和調(diào)調(diào)節(jié)蛋白，研究表明， IKK的表達(dá)能夠證實NF-κB被激活，通過誘導(dǎo)表達(dá)IKK復(fù)合體抑制劑的突變體激活氣道內(nèi)NF-κB后，IKKβ瞬時表達(dá)；而后在卵清蛋白致敏的哮喘小鼠氣道內(nèi)，除氣道反應(yīng)性乙酰甲膽堿、嗜酸性粒細(xì)胞、黏液增多以外，IKKβ表達(dá)活化標(biāo)志物水平顯著升高[19]。

在炎癥環(huán)境中IKKβ對NF-κB的激活是重要因素，與氣道重塑相關(guān)。實驗通過對卵清蛋白致敏小鼠模型腹腔注射IMD-0354(合成的IKKβ抑制劑)，檢測發(fā)現(xiàn)NF-κB的活化被IMD-0354抑制，同時也包括氣道重塑的病理特征，杯狀細(xì)胞增生、上皮下纖維化，膠原沉積，平滑肌肥大，還有嗜酸性粒細(xì)胞數(shù)也明顯目減少。氣道結(jié)構(gòu)改變之所以停止， 是通過IKKβ抑制IL-13、IL-1β的產(chǎn)生致使γ干擾素活化而實現(xiàn)的[20]。

結(jié)合蛋白影響氣道順應(yīng)性、肺反沖和氣道收縮反應(yīng)，對氣道平滑肌起平衡作用，與ankrd1有相互作用關(guān)系?；驒z測表明，NF-κB直接結(jié)合ankrd1啟動子，調(diào)節(jié)ankrd1水平。敲除平滑肌細(xì)胞的結(jié)合蛋白后，可增加Akt、IKK-α、IκBα的磷酸化，導(dǎo)致NF-κB激活，以及氣道平滑肌增生和miR-26a上調(diào)。

上述證據(jù)表明，NF-κB過表達(dá)對氣道重塑有促進(jìn)作用，因此抑制其表達(dá)，有助于減少炎癥反應(yīng)的發(fā)生，從而抑制氣道重塑。

3.2 抑制NF-κB對氣道重塑的影響 NF-κB是一種轉(zhuǎn)錄因子，通過降低其表達(dá)水平，抑制其活化從而可以改善各種炎癥性疾病，在哮喘的病理生理過程中起著至關(guān)重要的作用[21-22]。

通過抑制NF-κB下游趨化因子和降低Th2反應(yīng)，可降低變應(yīng)性氣道炎癥關(guān)鍵引發(fā)劑(Eotaxin-1和胸腺基質(zhì)淋巴細(xì)胞生成素)和肺部Th2型細(xì)胞因子(IL-4、IL-5和IL-13)以及胸腺淋巴細(xì)胞和脾細(xì)胞中Th2轉(zhuǎn)錄因子結(jié)合蛋白3的表達(dá)，從而發(fā)揮發(fā)揮其抗炎活性[23]。如硫酸鋅可以降低塵螨介導(dǎo)的炎性產(chǎn)物，如IL-6、IL-8、IL-1和氣道平滑肌細(xì)胞的單核細(xì)胞趨化蛋白。動物實驗證明，通過補(bǔ)充不同劑量(6、12、24、96 μmol/L)硫酸鋅而抑制塵螨誘導(dǎo)的細(xì)胞膜外信號調(diào)節(jié)激酶和NF-κB的磷酸化，從而使鋅在氣道平滑肌細(xì)胞才中得以產(chǎn)生抗炎作用[24]。

4 NF-κB在氣道細(xì)胞中的作用

浸潤炎癥細(xì)胞會產(chǎn)生細(xì)胞因子、趨化因子和細(xì)胞黏附分子等一系列炎性介質(zhì)，可調(diào)節(jié)炎癥細(xì)胞、皮細(xì)胞、平滑肌、成纖維細(xì)胞和內(nèi)皮細(xì)胞的功能。NF-κB在調(diào)節(jié)氣管炎癥細(xì)胞基因表達(dá)有著核心作用。

4.1 淋巴細(xì)胞 淋巴細(xì)胞有免疫調(diào)節(jié)的功能。嗜酸粒細(xì)胞性炎癥反應(yīng)促使T淋巴細(xì)胞產(chǎn)生IL-4、IL-5、IL-13，再刺激B淋巴細(xì)胞而產(chǎn)生IgE。非過敏性嗜酸性炎癥由先天淋巴細(xì)胞2和自然殺傷細(xì)胞T共同協(xié)調(diào)[25]。中性粒細(xì)胞性炎癥包括Th1和Th17。Th17細(xì)胞是IL-17A、IL-17F和IL-22的主要來源，在重度哮喘者氣道組織內(nèi)顯著增加[26]。在氣道上皮細(xì)胞和氣道平滑肌細(xì)胞的結(jié)構(gòu)變化中，Th17因子占重要角色[27]。上皮黏蛋白和氣道平滑肌增殖均與NF-κB信號相關(guān)[28-29]。

4.2 嗜酸性粒細(xì)胞 過敏性氣道炎癥以嗜酸性粒細(xì)胞浸潤和激活為特點。嗜酸性粒細(xì)胞對氣道上皮細(xì)胞受NF-κB信號調(diào)控釋放細(xì)胞黏附因子有促進(jìn)作用[30]。過敏原激活NF-κB和其他因子(TNF-α、IL-8等)[31]。NF-κB信號可調(diào)節(jié)TNF-α抗凋亡，對嗜酸性粒細(xì)胞的存亡起重要作用[32]。

4.3 中性粒細(xì)胞 中性粒細(xì)胞性炎癥主要來源于呼吸道黏膜下的中性粒細(xì)胞浸潤。NF-κB是中性粒細(xì)胞產(chǎn)生的IL-8是調(diào)控基因，是重要介導(dǎo)物[33]。Th17和巨噬細(xì)胞分別調(diào)節(jié)中心粒細(xì)胞的應(yīng)答[34-35]。

4.4 上皮細(xì)胞 氣道上皮組織直接與空氣接觸，是保護(hù)組織免受外界侵害的生理屏障，其中上皮細(xì)胞起關(guān)鍵作用。受NF-κB調(diào)節(jié)產(chǎn)生免疫或炎癥介質(zhì)，這些介質(zhì)可復(fù)原炎癥細(xì)胞，從而影響上皮功能。通過Th2應(yīng)答，上皮細(xì)胞可產(chǎn)生胸腺基質(zhì)淋巴細(xì)胞生成素[36]。黏蛋白過度增殖來源于上皮細(xì)胞，Toll樣受體4和NF-κB對其有調(diào)控作用[37]。

4.5 氣道平滑肌細(xì)胞 氣道平滑肌持續(xù)收縮與氣管痙攣有關(guān)，同時也參與氣道重構(gòu)，致使氣管阻塞[38-40]。氣道平滑肌細(xì)胞所產(chǎn)生生長因子、細(xì)胞因子和其他炎癥介質(zhì)，與阻塞性呼吸道疾病的炎癥有密切聯(lián)系。通過刺激炎癥因子和生長因子的表達(dá)，可產(chǎn)生炎癥細(xì)胞和上皮細(xì)胞[41]。NF-κB被凝血酶和IL-1α激活，從而調(diào)節(jié)與哮喘相關(guān)的基因。

5 NF-κB作為治療的靶標(biāo)

NF-κB是多種炎性反應(yīng)的通路，可以作為抗炎治療的重要靶點。目前GINA推薦的治療或控制哮喘的一線基礎(chǔ)藥物——糖皮質(zhì)激素，則是NF-κB活化抑制劑，糖皮質(zhì)激素受體和NF-κB可能在功能上互為轉(zhuǎn)錄拮抗因子GC可直接結(jié)合IκB-α基因啟動子上的GC結(jié)合位點，活化IκB-α基因的啟動子，促使IκB-α表達(dá)的上調(diào)，進(jìn)而抑制NF-κB依賴的基因轉(zhuǎn)錄[42-43]。已使用多年的哮喘控制類藥物——長效β2受體激動劑，實驗表明通過抑制NF-κB信號可降低小鼠模型中TNF-α、IL-1、IL-6等促炎因子的表達(dá)[44]。除此之外，多種中藥成分也具有相似作用，如在卵清蛋白致敏小鼠肺組織樣本中檢測到黃芪提取物能抑制NF-κB表達(dá)。雷公藤甲素通過抑制NF-κB表達(dá)，從而抑制哮喘小鼠氣道杯狀細(xì)胞增生[45]。說明通過抑制NF-κB活化對治療哮喘有效。

綜上所述，NF-κB與多細(xì)胞聯(lián)系緊密，對哮喘相關(guān)的因子表達(dá)起重要調(diào)控作用，參與氣道重塑整個環(huán)節(jié)。因此，NF-κB可以作為治療哮喘的目標(biāo)。

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(本文編輯：劉穎)

Mechanism of action of nuclear transcription factor kappa B in airway smooth muscle in asthmatic children

LIULu，SUNLiping.
ChangchunUniversityofTraditionalChineseMedicine，Changchun130117，China

Nuclear factor kappa B is a transcription-promoting protein, which regulates the gene expression of inflammatory mediators and function of many kinds of cells in airway. It is a core element in the research of asthma prevention and treatment. NF-kappa B can regulate the production of proinflammatory factors after activation,and participates in the transcription of a variety of proinflammatory and chemokine genes. I kappa B is one of the NF- kappa B signal pathways and is inactive in the cytoplasm. The phosphorylation arises after I kappa B is activated by external stimuli, and then NF- kappa B is activated. Tumor necrosis factor α stimulates I kappa B kinase α to enter into the nucleus, which then regulate the expression of specific NF-kappa B response gene.

Asthma； Airway smooth muscle； Nuclear transcription factor kappa B; Children

國家自然基金面上資助項目(81473729)；吉林省科技廳自然科學(xué)基金項目(20150101209JC)

130117 長春，長春中醫(yī)藥大學(xué)2014級中醫(yī)兒科學(xué)專業(yè)研究生(劉璐)；130021 長春，長春中醫(yī)藥大學(xué)附屬醫(yī)院兒科(孫麗平)

劉璐(1983-)，男，長春中醫(yī)藥大學(xué)2014級博士研究生在讀。研究方向：中醫(yī)藥防治小兒肺系疾病的基礎(chǔ)研究

孫麗平，E-mail：slpwzt7063@163.com

10.3969/j.issn.1674-3865.2017.02.005

R725.6

A

1674-3865(2017)02-0106-04

2016-10-29)