p38絲裂原活化蛋白激酶在肺部疾病中的研究進(jìn)展

李丹丹(綜述) 任衛(wèi)英 朱 蕾△(審校)

(1復(fù)旦大學(xué)附屬中山醫(yī)院呼吸內(nèi)科,2老年病科 上海 200032)

絲裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族是真核細(xì)胞進(jìn)化過(guò)程中保守存在的絲氨酸-蘇氨酸蛋白激酶,是介導(dǎo)細(xì)胞反應(yīng)的重要信號(hào)轉(zhuǎn)導(dǎo)系統(tǒng),包括4個(gè)亞型:p38 MAPK、細(xì)胞外調(diào)節(jié)激酶(extracellular signal-regulated kinase,ERK)、ERK5及c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)。多種刺激如細(xì)胞因子、生長(zhǎng)因子、各種應(yīng)激(滲透性、氧化性、熱休克等)可使MAPK中的蘇氨酸和酪氨酸殘基磷酸化而活化MAPK,進(jìn)而調(diào)控細(xì)胞增生、分化、凋亡、壞死等過(guò)程[1]。研究提示p38 MAPK在呼吸系統(tǒng)疾病中起重要作用,現(xiàn)綜述如下。

p38MAPK家族及活化在人類和哺乳動(dòng)物中,p38 MAPK家族包括4個(gè)亞型:p38α、p38β、p38γ 和p38δ[2]。它們?cè)诎被崴骄哂?0%以上的同源序列,都具有蘇氨酸-甘氨酸-酪氨酸(Thr-Gly-Tyr )結(jié)構(gòu)環(huán),但每個(gè)亞型分布具有組織特異性。p38α廣泛分布于多種細(xì)胞類型,p38β主要表達(dá)在肺和腦組織,p38γ則主要在骨骼肌和神經(jīng)系統(tǒng)中,p38δ主要在子宮和胰腺[3]。p38 MAPK有2個(gè)結(jié)構(gòu)域,由135個(gè)氨基酸組成的N端結(jié)構(gòu)域和有225個(gè)氨基酸的C端結(jié)構(gòu)域,主要二級(jí)結(jié)構(gòu)分別為β折疊和α螺旋[2]。p38 MAPK與MAPK家族其他蛋白激酶一樣,通過(guò)三級(jí)激酶級(jí)聯(lián)反應(yīng)傳遞信號(hào):細(xì)胞外刺激激活MAPK激酶激酶(MAP kinase kinase kinase,MKKK),隨后激活MAPK激酶(MAP kinase kinase,MKK),最后Thr180和Tyr182雙位點(diǎn)磷酸化后p38 MAPK活化。p38 MAPK可被上游的多種MKKK激活,如凋亡信號(hào)調(diào)節(jié)激酶1 (apoptosis signal-regulatory kinase 1,ASK1)、轉(zhuǎn)化生長(zhǎng)因子β激活激酶1 (transforming growth factor-β-activated kinase-1,TAK1)、混合性譜系激酶3(mixed lineage kinase 3,MLK3)等,而這些激酶又可被藥物、氧化應(yīng)激[4]、生長(zhǎng)因子[5]、熱應(yīng)激[6]等激活。當(dāng)p38 MAPK活化后作用于下游激酶、轉(zhuǎn)錄因子[7]、細(xì)胞骨架蛋白[8]等,可產(chǎn)生多種效應(yīng),因此其在體內(nèi)作用廣泛。

p38MAPK在慢性阻塞性肺疾病和哮喘中的作用慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)和哮喘是常見(jiàn)的慢性氣道炎癥性疾病,發(fā)病率高,主要治療藥物為糖皮質(zhì)激素、抗膽堿能藥和β受體激動(dòng)劑。這些藥物并不能延緩COPD的進(jìn)展及降低死亡率[9-11]。雖然規(guī)律用藥能夠良好地控制哮喘,但實(shí)際應(yīng)用中由于患者用藥依從性差,哮喘控制率偏低,而且較多難治性哮喘對(duì)于吸入糖皮質(zhì)激素治療反應(yīng)差。研究發(fā)現(xiàn)p38 MAPK在COPD和哮喘的氣道炎癥中起重要作用。COPD患者肺組織中高表達(dá)p38 MAPK及磷酸化的p38 MAPK[12];哮喘患者氣道黏膜下層[13]及哮喘動(dòng)物模型氣道組織[14]p38 MAPK活化明顯增多。當(dāng)氣道上皮細(xì)胞或巨噬細(xì)胞被LPS或香煙刺激后p38 MAPK活化,導(dǎo)致炎癥介質(zhì)IL-8、TNF-α、IL-6及CCL5等釋放[15-18],給予p38 MAPK抑制劑后炎癥因子減少。p38 MAPK還參與介導(dǎo)上呼吸道病毒感染引起的炎癥反應(yīng)[19-20],所以可能在COPD和哮喘的急性加重期起重要作用。p38 MAPK活化與COPD和哮喘的氣道重塑相關(guān)。氣道平滑肌細(xì)胞受到香煙提取物刺激后ERK和p38 MAPK活化明顯,抑制p38 MAPK活化減輕了香煙導(dǎo)致的氣道平滑肌細(xì)胞增生[21];成纖維細(xì)胞受刺激后p38 MAPK、ERK、JNK活化明顯,凋亡增多[22]。另外,COPD和哮喘患者對(duì)激素治療不敏感也與p38 MAPK有關(guān)[18,23]。對(duì)糖皮質(zhì)激素治療不敏感的重癥哮喘患者,其外周血單核細(xì)胞p38 MAPK明顯活化[24];p38 MAPK抑制劑聯(lián)合糖皮質(zhì)激素能夠提高糖皮質(zhì)激素的抑炎效應(yīng),顯著減少肺泡巨噬細(xì)胞分泌TNF-α、IL-6和IL-8[18,23]。鑒于p38 MAPK在氣道炎癥性疾病中的作用,目前有p38 MAPK抑制劑在COPD患者中的臨床研究。中重度COPD患者應(yīng)用p38 MAPK抑制劑PH-797804,6周后FEV1顯著改善,氣急指數(shù)和TDI (transition dyspnoea index)總focal score的基線均有所改善,對(duì)藥物耐受亦良好[25]。而另一個(gè)p38 MAPK抑制劑Losmapimod并沒(méi)有顯著改善中重度COPD患者的肺功能或運(yùn)動(dòng)耐量[26],但在血嗜酸性粒細(xì)胞<2%的亞組中,Losmapimod能夠減少COPD急性發(fā)作次數(shù),15 mg劑量組患者的肺功能明顯改善[27],但新近研究發(fā)現(xiàn)Losmapimod并不能減少這一亞組患者COPD急性發(fā)作次數(shù)[28]。目前尚無(wú)p38 MAPK抑制劑被批準(zhǔn)進(jìn)入臨床應(yīng)用[29]。

p38MAPK在急性呼吸窘迫綜合征中的作用急性呼吸窘迫綜合征(acute respiratory distress syndrome,ARDS)由多種肺內(nèi)外因素導(dǎo)致的急性進(jìn)行性呼吸衰竭,主要病理特征為肺毛細(xì)血管通透性增加、肺水腫、肺內(nèi)炎性細(xì)胞浸潤(rùn)。發(fā)病機(jī)制主要是巨噬細(xì)胞和中性粒細(xì)胞在肺內(nèi)大量聚集及活化,釋放了多種趨化因子和炎癥介質(zhì),引起過(guò)度的炎癥反應(yīng)[30-31]。在ARDS中起重要作用的炎性介質(zhì)(如TNF-α、IL-6、IL-1β),其產(chǎn)生均依賴p38 MAPK信號(hào)通路途徑[32]。多種抗炎藥物如痰熱清、澤蘭葉黃素等均可通過(guò)抑制p38 MAPK磷酸化而抑制炎癥反應(yīng)、減輕肺損傷[33-34]。肺血管內(nèi)皮細(xì)胞和肺泡上皮細(xì)胞受損、凋亡增多也是ARDS肺泡-毛細(xì)血管通透性增加的重要原因,而p38 MAPK能夠調(diào)控肺微血管內(nèi)皮細(xì)胞和肺泡上皮細(xì)胞的凋亡而影響ARDS的發(fā)生與進(jìn)展[35-36]。肺內(nèi)水轉(zhuǎn)運(yùn)障礙在ARDS發(fā)生中也有重要作用。水主要通過(guò)細(xì)胞膜脂質(zhì)雙分子層簡(jiǎn)單擴(kuò)散和細(xì)胞膜上水通道蛋白(aquaporin,AQP)兩條途徑進(jìn)行轉(zhuǎn)運(yùn)[37]。p38 MAPK抑制劑能夠下調(diào)AQP4而減輕腸道缺血再灌注導(dǎo)致的肺水腫和病理?yè)p傷[38]。骨髓間充質(zhì)干細(xì)胞因具有多向分化潛能、分泌多種蛋白修復(fù)血管-內(nèi)皮屏障而減輕ALI/ARDS[39]。有研究發(fā)現(xiàn)骨髓間充質(zhì)干細(xì)胞通過(guò)抑制p38 MAPK、ERK和RSK信號(hào)通路而直接抑制環(huán)氧化酶2和NF-κB,從而減輕炎癥[40];另一項(xiàng)研究發(fā)現(xiàn)p38 MAPK能夠調(diào)控骨髓間充質(zhì)干細(xì)胞分泌TNF-βⅠ型和Ⅱ型受體、RAS相關(guān)C3肉毒素底物1和2進(jìn)而影響氣道上皮細(xì)胞的增生與遷移,起到修復(fù)氣道的作用[41]。

p38MAPK在肺癌中的作用肺癌在世界范圍內(nèi)發(fā)病率及死亡率較高,在中國(guó)也有上升趨勢(shì)[42]。肺癌的發(fā)生與多種因素有關(guān),其中吸煙是主要的獨(dú)立危險(xiǎn)因素,炎癥、大氣污染及遺傳等因素也參與其中[43]。肺癌傳統(tǒng)的治療方法為手術(shù)治療、放化療,其中靶向治療曾在非小細(xì)胞肺癌中顯示出獨(dú)特的療效,但是耐藥問(wèn)題愈加突出,新興的免疫治療仍處于探索研究中[44]。肺癌發(fā)生過(guò)程中腫瘤細(xì)胞凋亡異常,p38 MAPK信號(hào)通路能夠調(diào)控細(xì)胞凋亡,故一些藥物通過(guò)抑制p38 MAPK活化而促進(jìn)肺癌細(xì)胞凋亡、起到抗腫瘤的作用[45-47]。上皮間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transitions,EMT)是腫瘤侵襲和轉(zhuǎn)移中的重要過(guò)程,p38 MAPK能夠調(diào)控EMT而影響肺癌侵襲和轉(zhuǎn)移[48]?；|(zhì)金屬蛋白酶(matrix metalloproteinase,MMP)能夠降解細(xì)胞外基質(zhì)(extracellular matrix,ECM),有利于肺癌侵襲和轉(zhuǎn)移。ERK和p38 MAPK的活化與MMP-2和MMP-9的產(chǎn)生有關(guān),是藥物抑制肺癌侵襲的機(jī)制之一[49-50]。肺癌對(duì)放化療耐藥是目前治療中的棘手問(wèn)題,有研究顯示p38 MAPK與腫瘤對(duì)化療耐藥有關(guān)。對(duì)鉑類耐藥的非小細(xì)胞肺癌細(xì)胞,其侵襲力顯著增加,抑制p38 MAPK活化能夠增加肺癌細(xì)胞對(duì)鉑類的敏感性,使癌細(xì)胞凋亡增多[51]。在對(duì)紫杉醇耐藥的非小細(xì)胞肺癌細(xì)胞中也發(fā)現(xiàn)p38 MAPK和EGFR活化明顯增高,抑制p38 MAPK或EGFR活化能促進(jìn)腫瘤細(xì)胞凋亡[52]。還有研究發(fā)現(xiàn),TNF-α通過(guò)活化p38 MAPK和JNK而提高A549細(xì)胞對(duì)放療的敏感性[53]。

p38MAPK在肺纖維化中的作用肺纖維化(pulmonary fibrosis,PF)是肺泡上皮細(xì)胞損傷后,成纖維細(xì)胞增生、ECM過(guò)度沉積在肺間質(zhì)和基底膜,最終導(dǎo)致肺實(shí)質(zhì)破壞,引起肺功能下降和進(jìn)行性呼吸困難。其具體發(fā)病機(jī)制不明。除了前述p38 MAPK通過(guò)調(diào)控炎癥反應(yīng)、參與MMP產(chǎn)生、影響ECM降解而影響肺纖維化外,p38 MAPK還可通過(guò)調(diào)控轉(zhuǎn)化生長(zhǎng)因子β(transforming growth factor-β,TGF-β)介導(dǎo)的信號(hào)通路而在肺纖維化中起重要作用。上皮或炎癥細(xì)胞釋放TGF-β后,能夠抑制成纖維細(xì)胞凋亡,導(dǎo)致EMT、促進(jìn)纖維細(xì)胞增生、促進(jìn)肌成纖維細(xì)胞分化、ECM分泌增加[54]。在二氧化硅氣道滴注所致矽肺大鼠模型中,p38 MAPK抑制劑降低了肺泡灌洗液中TGF-β水平,抑制肺組織EMT,減輕了肺間質(zhì)纖維化等病理改變[55]。在體外給予p38 MAPK抑制劑,能夠抑制TGF-β所致肺泡上皮細(xì)胞EMT[56]。還有研究發(fā)現(xiàn)肺纖維化過(guò)程中上皮細(xì)胞損傷與補(bǔ)體系統(tǒng)活化、補(bǔ)體抑制蛋白(complement inhibitory proteins,CIPs) CD46、CD55下降有關(guān),TGF-β通過(guò)抑制CD46和CD55表達(dá)而損傷上皮細(xì)胞,p38 MAPK抑制劑能夠抑制TGF-β途徑介導(dǎo)的補(bǔ)體系統(tǒng)活化而減輕肺泡上皮損傷[57-59]。

p38MAPK在其他肺部疾病中的作用肺動(dòng)脈高壓是以肺血管阻力和肺動(dòng)脈壓力升高為特征的疾病。低氧導(dǎo)致的肺血管收縮和肺血管重構(gòu)是肺動(dòng)脈高壓發(fā)生過(guò)程中重要的病理生理改變。特發(fā)性肺動(dòng)脈高壓患者肺血管壁中磷酸化的p38 MAPK明顯增高[60],低氧和高碳酸下大鼠的肺血管平滑肌細(xì)胞p38 MAPK磷酸化也增加[61];肺動(dòng)脈高壓的動(dòng)物模型給予p38 MAPK抑制劑后肺動(dòng)脈高壓能夠逆轉(zhuǎn)[60],肺動(dòng)脈收縮減輕[61]。

結(jié)語(yǔ)p38 MAPK在人體內(nèi)廣泛表達(dá),多種應(yīng)激和細(xì)胞外信號(hào)均可活化p38 MAPK進(jìn)而調(diào)控細(xì)胞多種生命活動(dòng)。大量研究已證實(shí)p38 MAPK信號(hào)通路在呼吸系統(tǒng)疾病中的炎癥反應(yīng)、細(xì)胞增殖與凋亡、腫瘤侵襲等多個(gè)方面中起重要作用。盡管目前尚無(wú)p38 MAPK抑制劑批準(zhǔn)進(jìn)入臨床使用,但隨著研究的深入,p38 MAPK有望成為治療呼吸系統(tǒng)疾病的新靶點(diǎn)。

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