叢文娟,魯　靜,項(xiàng)水英,劉自兵

(安徽中醫(yī)藥大學(xué)針灸推拿學(xué)院針灸經(jīng)絡(luò)研究所,合肥　230038;*通訊作者,E-mail:zibingliu@163.com)

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一種復(fù)雜的慢性炎癥性疾病,氣道炎癥尤其是小氣道炎癥和肺實(shí)質(zhì)的病變是COPD的主要病變及發(fā)病原因[1]。COPD的慢性炎癥涉及的炎性細(xì)胞主要為中性粒細(xì)胞、巨噬細(xì)胞、嗜酸性粒細(xì)胞、T-淋巴細(xì)胞和樹(shù)突狀細(xì)胞[2,3]。炎性細(xì)胞在理化因素如香煙煙霧(CS)、脂多糖(LPS)等刺激下,激活機(jī)體相關(guān)轉(zhuǎn)錄因子,使炎癥因子的基因轉(zhuǎn)錄水平表達(dá)增高、大量的炎性因子釋放,在肺及其他組織的炎癥中發(fā)揮著主要作用。COPD的發(fā)生發(fā)展可激活多條炎癥相關(guān)信號(hào)通路,如NF-κB,Notch,JAK-STAT,TGF-Smad,p38MAPK,TLRs信號(hào)通路,這些通路可能成為潛在的COPD研究及治療的靶點(diǎn)。本文就COPD發(fā)病機(jī)制研究中主要炎癥信號(hào)通路做相關(guān)綜述,為COPD相關(guān)信號(hào)通路的探索提供理論基礎(chǔ)。

1　NF-κB信號(hào)通路

核因子-κB(NF-κB)是一種細(xì)胞核轉(zhuǎn)錄因子,最初由Sen和Baltimore[4]報(bào)道提出,已有30多年的歷史,由于其信號(hào)轉(zhuǎn)導(dǎo)的普遍性與復(fù)雜性,至今仍是研究的熱點(diǎn)。NF-κB可以被炎癥因子如白細(xì)胞介素1β(IL-1β)和腫瘤壞死因子α(TNF-α)、生長(zhǎng)因子或趨化因子等激活。NF-κB由兩類(lèi)亞基形成同源或異源二聚體。一類(lèi)亞基包括p65(也稱(chēng)RelA)、RelB和C-Rel;另一類(lèi)亞基包括p50和p52。最常見(jiàn)的NF-κB亞基組成形式為p65/p50或p65/p65。NF-κB未被激活時(shí)和IκB-α形成一個(gè)復(fù)合物,分布在細(xì)胞漿中。在刺激因素存在的情況下,核因子-κB激酶抑制因子(IκB kinase,IKK)會(huì)被激活,導(dǎo)致IκB-α?xí)赟er32和Ser36位點(diǎn)被磷酸化,隨后被泛素-蛋白酶體途徑降解。NF-κB和IκB-α解聚后,其核定位序列暴露,從而被轉(zhuǎn)運(yùn)到細(xì)胞核內(nèi)促進(jìn)NF-κB依賴(lài)的基因轉(zhuǎn)錄。IKK復(fù)合物包括IKKα、IKKβ和IKKγ,其中IKKα和IKKβ是催化亞基,IKKγ是調(diào)節(jié)亞基。IKKβ的Ser177和Ser181和IKKα的Ser176和Ser180被磷酸化修飾后,會(huì)導(dǎo)致IKK的激活。

NF-κB廣泛存在于多種組織細(xì)胞中,參與多種基因的表達(dá)調(diào)控,參與炎癥反應(yīng)、免疫反應(yīng)、細(xì)胞凋亡及腫瘤發(fā)生等多種生物進(jìn)程,在廣泛的炎性系統(tǒng)中起著至關(guān)重要的作用,其信號(hào)通路在肺組織中的異常激活能導(dǎo)致多種肺部疾病的產(chǎn)生,尤其是COPD[5-7]。研究發(fā)現(xiàn),NF-κB蛋白在COPD患者的支氣管活檢標(biāo)本和患者炎癥細(xì)胞中被激活,其表達(dá)水平明顯升高,細(xì)胞質(zhì)中IκBα的DNA水平在吸煙者和COPD患者的肺組織中較健康對(duì)照組明顯降低。CS或LPS刺激細(xì)胞膜后可以增加Toll樣受體4(TLR4)的表達(dá),使IKKα/β磷酸化而激活NF-κB[8],導(dǎo)致炎性增強(qiáng)。在COPD中,NF-κB信號(hào)通路的持續(xù)激活可以生成和激活一種由巨噬細(xì)胞和調(diào)節(jié)性T細(xì)胞組成的促腫瘤的炎性環(huán)境[9],NF-κB對(duì)于氣道中細(xì)胞因子的表達(dá),以及趨化因子和細(xì)胞黏附分子有重要的調(diào)節(jié)作用[6]。在小鼠肺的肺泡和氣道上皮細(xì)胞中,CS暴露增加了RelB和RelA/p65的水平,導(dǎo)致促炎介質(zhì)的增加[10],CS和氧化劑可以激活NF-κB信號(hào)通路,增強(qiáng)基因轉(zhuǎn)錄和增加炎癥介質(zhì)如TNF-α,IL-1β、IL-6、IL-8、環(huán)氧化酶Cox-2等的表達(dá)和釋放,參與氣道炎癥和慢性阻塞性肺病的發(fā)病[11]。而RelB作為促炎基因轉(zhuǎn)錄的抑制劑,可以有效抑制香煙引起的炎性介質(zhì)等的表達(dá)[12]。而在吸煙和不吸煙的COPD患者肺成纖維細(xì)胞和血液樣本中,RelB蛋白表達(dá)明顯降低,減弱了對(duì)Cox-2的抑制,從而加重COPD的炎癥表達(dá)[13]。氣道上皮細(xì)胞中NF-κB信號(hào)通路的激活可以導(dǎo)致過(guò)敏性炎癥,而缺乏NF-κB和IκBα的重組小鼠,其致敏性減弱[14]。因此抑制NF-κB,減少相應(yīng)蛋白的生成,可以緩解COPD的炎性反應(yīng)程度。

2　JAK-STAT信號(hào)通路

JAK-STAT信號(hào)通路是由酪氨酸激酶JAK(Janus kinase)家族及轉(zhuǎn)錄因子STAT(signal transducer and activator of transcription)家族構(gòu)成的酪氨酸蛋白激酶,在COPD相關(guān)研究中,JAK-STAT信號(hào)通路在炎癥反應(yīng)和免疫應(yīng)答中起重要的調(diào)節(jié)作用,JAK-STAT信號(hào)通路不僅參與炎癥反應(yīng),同時(shí)也與細(xì)胞增殖、分化、凋亡以及免疫調(diào)節(jié)等密切相關(guān)[15]。目前發(fā)現(xiàn)有多種細(xì)胞因子如TNF-α、IL-6、IL-1β及趨化因子(CXCL)等通過(guò)與其受體相結(jié)合,與受體耦連的JAKs激酶聚集,導(dǎo)致周?chē)腏AKs互相磷酸化后被激活,激活后的JAKs磷酸化受體上的酪氨酸位點(diǎn)使受體與STATs結(jié)合,從而磷酸化,磷酸化后的STATs家族成員形成二聚體進(jìn)入細(xì)胞核,與核內(nèi)特異的DNA序列結(jié)合參與基因轉(zhuǎn)錄,發(fā)揮其生物學(xué)效應(yīng)[16,17]。

研究表明,在COPD急性加重期過(guò)程中JAK-STAT1/3發(fā)揮著重要作用[18],在COPD患者的肺組織中,STAT3的表達(dá)水平越高,肺部炎癥及肺氣腫的程度越重[19]。STAT3可在炎性介質(zhì)IL-6誘導(dǎo)下過(guò)度表達(dá),引起肺氣腫和肺氣道炎癥的發(fā)生,IL-6誘導(dǎo)的STAT3信號(hào)通路存在于Ⅱ型肺泡上皮細(xì)胞和細(xì)支氣管細(xì)胞中[20]。通過(guò)實(shí)驗(yàn)發(fā)現(xiàn)STAT6的活化促使IL-13表達(dá)水平升高,從而引起氣道上皮杯狀細(xì)胞增生和黏液下腺的肥大,從而認(rèn)為阻斷STAT6可以抑制氣道黏液高分泌,有研究提出阻斷STAT6的活化是治療氣道疾病的新療法[21],減輕COPD的癥狀。這就提示JAK-STAT信號(hào)通路抑制劑的研究可以成為COPD新的治療方法[22]。

3　TGF-smad信號(hào)通路

轉(zhuǎn)化生長(zhǎng)因子β(transforming growth factor-β,TGF-β)自1981年被Robert發(fā)現(xiàn)以來(lái),對(duì)其傳導(dǎo)通路一直不清晰,至近年來(lái)發(fā)現(xiàn)細(xì)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)蛋白Smad家族,才清楚了TGF-β信號(hào)的傳導(dǎo)機(jī)制。TGF-β信號(hào)包括依賴(lài)Smad和非依賴(lài)Smad兩條信號(hào)途徑。當(dāng)TGF-β1與轉(zhuǎn)化生長(zhǎng)因子β受體I(TβRI)和受體Ⅱ(TβRⅡ)結(jié)合形成異源四聚體,TβRⅡ磷酸化,而后磷酸化TβRI,導(dǎo)致TβRI具有絲氨酸/蘇氨酸激酶活性,可以磷酸化下游相關(guān)的Smad信號(hào)分子,受體激活型Smads(R-Smads)與Smad4進(jìn)入細(xì)胞核與其他的轉(zhuǎn)錄調(diào)節(jié)分子共同調(diào)節(jié)基因轉(zhuǎn)錄。非依賴(lài)Smad的途徑是不依賴(lài)轉(zhuǎn)錄因子Smad發(fā)揮作用的。TGF-β在肺組織損傷后修復(fù)中起著至關(guān)重要的作用,起著支氣管重塑和誘導(dǎo)纖維細(xì)胞與氣道平滑肌細(xì)胞增殖的作用。TGF-β/Smads信號(hào)通路為多功能性信號(hào)通路,在肺纖維化患者和肺纖維化動(dòng)物模型中特異性增加[23]。TGF-β如TGF-β1/2和骨形成蛋白-6(BMP-6),在細(xì)胞外基質(zhì)成分、肺泡上皮細(xì)胞和成纖維細(xì)胞中發(fā)揮重要作用[24]。其中TGF-β1對(duì)肺和免疫系統(tǒng)具有重要的調(diào)節(jié)作用[25,26]。

研究發(fā)現(xiàn)TGF-β1mRNA在COPD大鼠氣道組織的表達(dá)明顯增多[27],COPD患者肺內(nèi)多種細(xì)胞均發(fā)現(xiàn)TGF-β1的表達(dá)增加,吸煙者和COPD患者中TGF-β1mRNA的水平高于非吸煙者,且TGF-β1mRNA的水平與小氣道阻塞程度和吸煙史呈正相關(guān)[28]。也有研究表明TGF-β1/smad2信號(hào)通路參與COPD炎癥和重構(gòu)的進(jìn)展,炎癥和氧化應(yīng)激在COPD中起重要作用,線粒體氧化應(yīng)激反應(yīng)在氣道氧化應(yīng)激中有重要作用。線粒體靶向抗氧化劑MitoQ通過(guò)抑制TGF-β誘導(dǎo)氣道平滑肌細(xì)胞增殖并減少CXCL8的釋放[29]。Li等[30]實(shí)驗(yàn)研究發(fā)現(xiàn)慢性氣道炎癥、重塑及肺氣腫大鼠肺組織IL-1β、TNF-α、p-NF-κB、p-IκBα、TGF-β1和Smad2表達(dá)高于對(duì)照組,中醫(yī)調(diào)補(bǔ)肺腎的方法能夠降低其表達(dá)水平,其機(jī)制可能與激活NF-κB/TGF-β1/smad2信號(hào)通路相關(guān)。

4　p38 MAPK信號(hào)通路

p38絲裂原活化蛋白激酶(p38 MAPK)是絲裂素活化蛋白激酶(MAPK)的一個(gè)亞型,由Brewster等[31]、Han等[32]于1993年發(fā)現(xiàn)并命名,目前已發(fā)現(xiàn)p38α、p38β、p38γ和p38δ 4個(gè)亞型,其中,p38α廣泛存在于各組織中,并在炎癥細(xì)胞中表達(dá)豐富。在COPD患者中p38 MAPK信號(hào)通路主要介導(dǎo)細(xì)胞外信號(hào)轉(zhuǎn)導(dǎo)到細(xì)胞核,在CS、LPS、氧化應(yīng)激等應(yīng)激條件下活化并參與細(xì)胞的生長(zhǎng)、分化、周期、凋亡、炎癥反應(yīng)等過(guò)程[33],參與了中性粒細(xì)胞、肥大細(xì)胞和嗜酸性粒細(xì)胞的遷移[34],并誘導(dǎo)促炎因子的釋放、細(xì)胞因子的轉(zhuǎn)錄調(diào)控,參與COPD慢性炎癥及氣道重塑的過(guò)程[35]。p38的活性還與肺功能損害及肺泡壁炎癥程度相關(guān)[36]。小氣道的炎癥和重塑是決定COPD嚴(yán)重程度和進(jìn)展的關(guān)鍵因素,p38 MAPK通路由細(xì)胞因子激活,并調(diào)節(jié)炎性細(xì)胞因子的表達(dá),包括CXCL8,MMPs等[37]。在COPD患者氣道及痰液中,p38 MAPK和CXCL8顯著增加。p38 MAPK活化與CXCL8高水平和中性粒細(xì)胞浸潤(rùn)密切相關(guān),且與疾病的嚴(yán)重程度相關(guān)。由此可見(jiàn)p38 MAPK在COPD中的病理發(fā)展過(guò)程中有重要作用[38]。在COPD患者中,CS暴露導(dǎo)致肺成纖維細(xì)胞Stat1-Tyr701及Ser727的磷酸化,并上調(diào)了MAPK信號(hào)通路上各基因的表達(dá),導(dǎo)致肺部炎癥,改變氧化還原反應(yīng),引起肺纖維化[39]。應(yīng)用p38抑制劑,可抑制香煙誘導(dǎo)的肺內(nèi)巨噬細(xì)胞及中性粒細(xì)胞的增加,有效地減少人肺泡巨噬細(xì)胞釋放TNF-α[40],并減輕吸煙COPD模型小鼠的肺內(nèi)炎癥反應(yīng)[41]。在治療COPD時(shí),p38 MAPK在以糖皮質(zhì)激素為主要藥物的治療中起抵抗作用,而使用p38 MAPK抑制劑可通過(guò)調(diào)控基質(zhì)金屬蛋白酶-9(MMP-9)下調(diào)大鼠肺組織中黏蛋白(MUC5AC)的表達(dá),減輕COPD大鼠氣道黏液分泌,因而在降低肺功能損害方面更有優(yōu)勢(shì)[42]。另外,p38MAPK在肺血管收縮中有重要作用,血管緊張素-Ⅱ可引起包括p38MAPK在內(nèi)的MAPK活化,并通過(guò)其磷酸化作用調(diào)節(jié)G蛋白,導(dǎo)致cAMP水平下降、血管阻力增加,造成肺動(dòng)脈高壓。

5　TLRs信號(hào)通路

Toll樣受體(TLRs)屬于Ⅰ型跨膜蛋白受體,是先天性免疫識(shí)別的受體,在各種炎癥刺激的天然免疫中發(fā)揮著重要作用。TLR信號(hào)通路是由TLRs介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)通路,通過(guò)識(shí)別病原相關(guān)分子模式(PAMPs)來(lái)激活天然免疫系統(tǒng),其信號(hào)轉(zhuǎn)導(dǎo)途徑中主要通過(guò)髓樣分化蛋白分子88(MyD88)引起下游炎癥反應(yīng)。目前發(fā)現(xiàn)的TLR家族包括11個(gè)成員,廣泛分布于多種細(xì)胞。目前TLR在免疫反應(yīng)中的作用已得到充分證明,TLR基因多態(tài)性可導(dǎo)致呼吸道炎性疾病的嚴(yán)重程度和易感性發(fā)生劇烈變化。由于吸入空氣的持續(xù)暴露,肺部和呼吸道特別容易受到病原體和過(guò)敏原的影響。氣道上皮作為宿主防御的第一道防線,利用包括TLRs在內(nèi)的多種受體來(lái)檢測(cè)抗原和感染性微生物[43]。通過(guò)外源性病原體相關(guān)的分子模式(PAMPs)和宿主-衍生的損傷相關(guān)的分子模式激活TLRs,有選擇性地誘導(dǎo)炎癥、炎癥細(xì)胞招募和細(xì)胞因子釋放。

呼吸道上皮包含無(wú)數(shù)的TLR,參與激活免疫反應(yīng),包括TLR2、TLR4和TLR9在內(nèi)的幾個(gè)TLR參與了COPD的發(fā)病機(jī)制,特別是TLR2和TLR4被認(rèn)為是維持COPD炎癥反應(yīng)的主要TLRs,也是誘導(dǎo)機(jī)體對(duì)呼吸系統(tǒng)中微生物入侵的免疫應(yīng)答的主要介質(zhì)[44]。吸煙暴露與TLR4和TLR9基因表達(dá)的增加以及細(xì)胞因子過(guò)度生產(chǎn)之間存在著高度的相關(guān)性[46],TLR4和TLR9均已被證明有助于釋放CD8+T細(xì)胞的IL-8[45],通過(guò)IL-8的上調(diào),TLR9可以通過(guò)啟動(dòng)中性粒細(xì)胞的招募來(lái)引起炎癥反應(yīng)[45,46],TLR4缺乏促進(jìn)肺氣腫[47],缺乏TLR4表達(dá)的小鼠更容易受到氧化應(yīng)激的影響,原因是NADPH氧化酶(Nox)3的上調(diào)[48,49]。TLR4作為Nox3的抑制因子,可以調(diào)控ROS的釋放,在TLR4缺失的情況下,ROS可能達(dá)到有害水平,最終導(dǎo)致細(xì)胞凋亡和肺氣腫。TLRs與COPD的惡化相關(guān),研究表明,MyD88與TLR4協(xié)同作用于IL激酶,并上調(diào)IL的表達(dá)[50],MyD88、TLR4和IL-1受體1(IL1R1)之間的相互作用可導(dǎo)致COPD患者急性肺部炎癥。此外,由于吸煙導(dǎo)致的中性粒細(xì)胞的招募依賴(lài)于TLR4/MyD88/IL1R1信號(hào)[50,51],COPD患者在CD8+T細(xì)胞上的TLR1和TLR2表達(dá)增加,可能導(dǎo)致肺損傷和肺泡破壞[52]。Di Stefano等[53]研究發(fā)現(xiàn),在COPD急性加重期和穩(wěn)定期,TLR4和核苷酸結(jié)合寡聚域蛋白(NOD1)在支氣管黏膜上表達(dá)增強(qiáng),支氣管上皮中CD4+和CD8+細(xì)胞中TLR4、NOD1的表達(dá)量與氣道阻塞呈正相關(guān),參與COPD氣道炎癥的發(fā)生發(fā)展,提示TLR可能是治療慢阻肺的潛在治療靶點(diǎn)。

6　Notch信號(hào)通路

Notch信號(hào)通路廣泛存在于多種組織和免疫細(xì)胞中,是一條高度保守的信號(hào)轉(zhuǎn)導(dǎo)途徑,Notch信號(hào)通路由細(xì)胞外配體、跨膜受體、DNA結(jié)合蛋白及靶基因四部分組成。Notch信號(hào)在協(xié)調(diào)肺發(fā)育過(guò)程中表達(dá)明顯,在調(diào)控肺泡上皮、肺血管的生成和發(fā)育中起關(guān)鍵作用[54],且Notch家族中各種不同的受體和配體以及多種調(diào)節(jié)因子的相互作用,能夠在肺發(fā)育的過(guò)程中起到不同的作用[55,56]。近年來(lái)發(fā)現(xiàn)COPD的發(fā)生發(fā)展與免疫紊亂密切相關(guān),且與T淋巴細(xì)胞失衡有關(guān),而Notch信號(hào)在適應(yīng)性調(diào)節(jié)及獲得性免疫中發(fā)揮著主要作用[56]。最近進(jìn)行的研究表明,Notch受體、配體及下游分子在成人支氣管活檢及肺組織活檢標(biāo)本上皮細(xì)胞中廣泛表達(dá),且在成人吸煙者和吸煙的COPD患者的標(biāo)本中Notch受體和配體(如Notch3,DLL1,Hes)中是下調(diào)的[57]。Notch信號(hào)通路在顆粒物質(zhì)的誘導(dǎo)下過(guò)度激活,并能加劇COPD的免疫紊亂,導(dǎo)致T淋巴細(xì)胞亞群(如Th1,Th17等促炎性細(xì)胞增多)失衡,Notch1信號(hào)及其下游的Hes1 mRNA和蛋白水平增加[58]。CS暴露能夠啟動(dòng)肺淋巴組織中的Notch信號(hào)[58],CS暴露下,Notch信號(hào)在肺淋巴組織中被激活,Notch配體和受體表達(dá)水平升高,尤其是Notch3[59]。因此抑制Notch信號(hào)通路的激活可以減輕COPD的免疫紊亂[57]。

7　結(jié)語(yǔ)

目前,關(guān)于COPD相關(guān)信號(hào)通路的研究并未完全闡明,以信號(hào)通路為靶點(diǎn)的治療方興未艾,關(guān)于信號(hào)機(jī)制在致病因素和治療中的研究也日益豐富。雖然人們已經(jīng)認(rèn)識(shí)到信號(hào)轉(zhuǎn)導(dǎo)在COPD發(fā)病機(jī)制中起著至關(guān)重要的作用,但具體的分子機(jī)制還不是很清楚?，F(xiàn)有研究資料表明,在COPD發(fā)病機(jī)制中,針對(duì)不同的信號(hào)通路,對(duì)細(xì)胞因子和緊密連接的網(wǎng)絡(luò)途徑進(jìn)行干預(yù)和治療,為COPD的治療提供新的策略,很有可能為COPD的臨床治療開(kāi)辟新的途徑。

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