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)胞進化過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)的重要信號轉(zhuǎn)導(dǎo)系統(tǒng),包括4個亞型: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,進而調(diào)控細(xì)胞增生、分化、凋亡、壞死等過程[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物中,p38 MAPK家族包括4個亞型:p38α、p38β、p38γ 和p38δ[2]。它們在氨基酸水平具有60%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個結(jié)構(gòu)域,由135個氨基酸組成的N端結(jié)構(gòu)域和有225個氨基酸的C端結(jié)構(gòu)域,主要二級結(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,通過三級激酶級聯(lián)反應(yīng)傳遞信號: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,如凋亡信號調(diào)節(jié)激酶1 (apoptosis signal-regulatory kinase 1,ASK1)、轉(zhuǎn)化生長因子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受體激動劑。這些藥物并不能延緩COPD的進展及降低死亡率[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和哮喘患者對激素治療不敏感也與p38 MAPK有關(guān)[18,23]。對糖皮質(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,對藥物耐受亦良好[25]。而另一個p38 MAPK抑制劑Losmapimod并沒有顯著改善中重度COPD患者的肺功能或運動耐量[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p38 MAPK抑制劑被批準(zhǔn)進入臨床應(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。發(fā)病機制主要是巨噬細(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)生與進展[35-36]。肺內(nèi)水轉(zhuǎn)運障礙在ARDS發(fā)生中也有重要作用。水主要通過細(xì)胞膜脂質(zhì)雙分子層簡單擴散和細(xì)胞膜上水通道蛋白(aquaporin,AQP)兩條途徑進行轉(zhuǎn)運[37]。p38 MAPK抑制劑能夠下調(diào)AQP4而減輕腸道缺血再灌注導(dǎo)致的肺水腫和病理損傷[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)胞通過抑制p38 MAPK、ERK和RSK信號通路而直接抑制環(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,在中國也有上升趨勢[42]。肺癌的發(fā)生與多種因素有關(guān),其中吸煙是主要的獨立危險因素,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)胞肺癌中顯示出獨特的療效,但是耐藥問題愈加突出,新興的免疫治療仍處于探索研究中[44]。肺癌發(fā)生過程中腫瘤細(xì)胞凋亡異常,p38 MAPK信號通路能夠調(diào)控細(xì)胞凋亡,故一些藥物通過抑制p38 MAPK活化而促進肺癌細(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制之一[49-50]。肺癌對放化療耐藥是目前治療中的棘手問題,有研究顯示p38 MAPK與腫瘤對化療耐藥有關(guān)。對鉑類耐藥的非小細(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)胞對鉑類的敏感性,使癌細(xì)胞凋亡增多[51]。在對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活化能促進腫瘤細(xì)胞凋亡[52]。還有研究發(fā)現(xiàn),TNF-α通過活化p38 MAPK和JNK而提高A549細(xì)胞對放療的敏感性[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過度沉積在肺間質(zhì)和基底膜,最終導(dǎo)致肺實質(zhì)破壞,引起肺功能下降和進行性呼吸困難。其具體發(fā)病機制不明。除了前述p38 MAPK通過調(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還可通過調(diào)控轉(zhuǎn)化生長因子β(transforming growth factor-β,TGF-β)介導(dǎo)的信號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、促進纖維細(xì)胞增生、促進肌成纖維細(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)肺纖維化過程中上皮細(xì)胞損傷與補體系統(tǒng)活化、補體抑制蛋白(complement inhibitory proteins,CIPs) CD46、CD55下降有關(guān),TGF-β通過抑制CD46和CD55表達而損傷上皮細(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脈高壓是以肺血管阻力和肺動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)是肺動脈高壓發(fā)生過程中重要的病理生理改變。特發(fā)性肺動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];肺動脈高壓的動物模型給予p38 MAPK抑制劑后肺動脈高壓能夠逆轉(zhuǎn)[60],肺動脈收縮減輕[61]。

結(jié)語p38 MAPK在人體內(nèi)廣泛表達,多種應(yīng)激和細(xì)胞外信號均可活化p38 MAPK進而調(diào)控細(xì)胞多種生命活動。大量研究已證實p38 MAPK信號通路在呼吸系統(tǒng)疾病中的炎癥反應(yīng)、細(xì)胞增殖與凋亡、腫瘤侵襲等多個方面中起重要作用。盡管目前尚無p38 MAPK抑制劑批準(zhǔn)進入臨床使用,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。

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