p38丝裂原活化蛋白激酶在肺部疾病中的研究进展

李丹丹(综述) 任卫英 朱 蕾△(审校)

(1复旦大学附属中山医院呼吸内科,2老年病科 上海 200032)

丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)家族是真核细胞进化过程中保守存在的丝氨酸-苏氨酸蛋白激酶,是介导细胞反应的重要信号转导系统,包括4个亚型:p38 MAPK、细胞外调节激酶(extracellular signal-regulated kinase,ERK)、ERK5及c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)。多种刺激如细胞因子、生长因子、各种应激(渗透性、氧化性、热休克等)可使MAPK中的苏氨酸和酪氨酸残基磷酸化而活化MAPK,进而调控细胞增生、分化、凋亡、坏死等过程[1]。研究提示p38 MAPK在呼吸系统疾病中起重要作用,现综述如下。

p38MAPK家族及活化在人类和哺乳动物中,p38 MAPK家族包括4个亚型:p38α、p38β、p38γ 和p38δ[2]。它们在氨基酸水平具有60%以上的同源序列,都具有苏氨酸-甘氨酸-酪氨酸(Thr-Gly-Tyr )结构环,但每个亚型分布具有组织特异性。p38α广泛分布于多种细胞类型,p38β主要表达在肺和脑组织,p38γ则主要在骨骼肌和神经系统中,p38δ主要在子宫和胰腺[3]。p38 MAPK有2个结构域,由135个氨基酸组成的N端结构域和有225个氨基酸的C端结构域,主要二级结构分别为β折叠和α螺旋[2]。p38 MAPK与MAPK家族其他蛋白激酶一样,通过三级激酶级联反应传递信号:细胞外刺激激活MAPK激酶激酶(MAP kinase kinase kinase,MKKK),随后激活MAPK激酶(MAP kinase kinase,MKK),最后Thr180和Tyr182双位点磷酸化后p38 MAPK活化。p38 MAPK可被上游的多种MKKK激活,如凋亡信号调节激酶1 (apoptosis signal-regulatory kinase 1,ASK1)、转化生长因子β激活激酶1 (transforming growth factor-β-activated kinase-1,TAK1)、混合性谱系激酶3(mixed lineage kinase 3,MLK3)等,而这些激酶又可被药物、氧化应激[4]、生长因子[5]、热应激[6]等激活。当p38 MAPK活化后作用于下游激酶、转录因子[7]、细胞骨架蛋白[8]等,可产生多种效应,因此其在体内作用广泛。

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)和哮喘是常见的慢性气道炎症性疾病,发病率高,主要治疗药物为糖皮质激素、抗胆碱能药和β受体激动剂。这些药物并不能延缓COPD的进展及降低死亡率[9-11]。虽然规律用药能够良好地控制哮喘,但实际应用中由于患者用药依从性差,哮喘控制率偏低,而且较多难治性哮喘对于吸入糖皮质激素治疗反应差。研究发现p38 MAPK在COPD和哮喘的气道炎症中起重要作用。COPD患者肺组织中高表达p38 MAPK及磷酸化的p38 MAPK[12];哮喘患者气道黏膜下层[13]及哮喘动物模型气道组织[14]p38 MAPK活化明显增多。当气道上皮细胞或巨噬细胞被LPS或香烟刺激后p38 MAPK活化,导致炎症介质IL-8、TNF-α、IL-6及CCL5等释放[15-18],给予p38 MAPK抑制剂后炎症因子减少。p38 MAPK还参与介导上呼吸道病毒感染引起的炎症反应[19-20],所以可能在COPD和哮喘的急性加重期起重要作用。p38 MAPK活化与COPD和哮喘的气道重塑相关。气道平滑肌细胞受到香烟提取物刺激后ERK和p38 MAPK活化明显,抑制p38 MAPK活化减轻了香烟导致的气道平滑肌细胞增生[21];成纤维细胞受刺激后p38 MAPK、ERK、JNK活化明显,凋亡增多[22]。另外,COPD和哮喘患者对激素治疗不敏感也与p38 MAPK有关[18,23]。对糖皮质激素治疗不敏感的重症哮喘患者,其外周血单核细胞p38 MAPK明显活化[24];p38 MAPK抑制剂联合糖皮质激素能够提高糖皮质激素的抑炎效应,显著减少肺泡巨噬细胞分泌TNF-α、IL-6和IL-8[18,23]。鉴于p38 MAPK在气道炎症性疾病中的作用,目前有p38 MAPK抑制剂在COPD患者中的临床研究。中重度COPD患者应用p38 MAPK抑制剂PH-797804,6周后FEV1显著改善,气急指数和TDI (transition dyspnoea index)总focal score的基线均有所改善,对药物耐受亦良好[25]。而另一个p38 MAPK抑制剂Losmapimod并没有显著改善中重度COPD患者的肺功能或运动耐量[26],但在血嗜酸性粒细胞<2%的亚组中,Losmapimod能够减少COPD急性发作次数,15 mg剂量组患者的肺功能明显改善[27],但新近研究发现Losmapimod并不能减少这一亚组患者COPD急性发作次数[28]。目前尚无p38 MAPK抑制剂被批准进入临床应用[29]。

p38MAPK在急性呼吸窘迫综合征中的作用急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)由多种肺内外因素导致的急性进行性呼吸衰竭,主要病理特征为肺毛细血管通透性增加、肺水肿、肺内炎性细胞浸润。发病机制主要是巨噬细胞和中性粒细胞在肺内大量聚集及活化,释放了多种趋化因子和炎症介质,引起过度的炎症反应[30-31]。在ARDS中起重要作用的炎性介质(如TNF-α、IL-6、IL-1β),其产生均依赖p38 MAPK信号通路途径[32]。多种抗炎药物如痰热清、泽兰叶黄素等均可通过抑制p38 MAPK磷酸化而抑制炎症反应、减轻肺损伤[33-34]。肺血管内皮细胞和肺泡上皮细胞受损、凋亡增多也是ARDS肺泡-毛细血管通透性增加的重要原因,而p38 MAPK能够调控肺微血管内皮细胞和肺泡上皮细胞的凋亡而影响ARDS的发生与进展[35-36]。肺内水转运障碍在ARDS发生中也有重要作用。水主要通过细胞膜脂质双分子层简单扩散和细胞膜上水通道蛋白(aquaporin,AQP)两条途径进行转运[37]。p38 MAPK抑制剂能够下调AQP4而减轻肠道缺血再灌注导致的肺水肿和病理损伤[38]。骨髓间充质干细胞因具有多向分化潜能、分泌多种蛋白修复血管-内皮屏障而减轻ALI/ARDS[39]。有研究发现骨髓间充质干细胞通过抑制p38 MAPK、ERK和RSK信号通路而直接抑制环氧化酶2和NF-κB,从而减轻炎症[40];另一项研究发现p38 MAPK能够调控骨髓间充质干细胞分泌TNF-βⅠ型和Ⅱ型受体、RAS相关C3肉毒素底物1和2进而影响气道上皮细胞的增生与迁移,起到修复气道的作用[41]。

p38MAPK在肺癌中的作用肺癌在世界范围内发病率及死亡率较高,在中国也有上升趋势[42]。肺癌的发生与多种因素有关,其中吸烟是主要的独立危险因素,炎症、大气污染及遗传等因素也参与其中[43]。肺癌传统的治疗方法为手术治疗、放化疗,其中靶向治疗曾在非小细胞肺癌中显示出独特的疗效,但是耐药问题愈加突出,新兴的免疫治疗仍处于探索研究中[44]。肺癌发生过程中肿瘤细胞凋亡异常,p38 MAPK信号通路能够调控细胞凋亡,故一些药物通过抑制p38 MAPK活化而促进肺癌细胞凋亡、起到抗肿瘤的作用[45-47]。上皮间质转化(epithelial-mesenchymal transitions,EMT)是肿瘤侵袭和转移中的重要过程,p38 MAPK能够调控EMT而影响肺癌侵袭和转移[48]。基质金属蛋白酶(matrix metalloproteinase,MMP)能够降解细胞外基质(extracellular matrix,ECM),有利于肺癌侵袭和转移。ERK和p38 MAPK的活化与MMP-2和MMP-9的产生有关,是药物抑制肺癌侵袭的机制之一[49-50]。肺癌对放化疗耐药是目前治疗中的棘手问题,有研究显示p38 MAPK与肿瘤对化疗耐药有关。对铂类耐药的非小细胞肺癌细胞,其侵袭力显著增加,抑制p38 MAPK活化能够增加肺癌细胞对铂类的敏感性,使癌细胞凋亡增多[51]。在对紫杉醇耐药的非小细胞肺癌细胞中也发现p38 MAPK和EGFR活化明显增高,抑制p38 MAPK或EGFR活化能促进肿瘤细胞凋亡[52]。还有研究发现,TNF-α通过活化p38 MAPK和JNK而提高A549细胞对放疗的敏感性[53]。

p38MAPK在肺纤维化中的作用肺纤维化(pulmonary fibrosis,PF)是肺泡上皮细胞损伤后,成纤维细胞增生、ECM过度沉积在肺间质和基底膜,最终导致肺实质破坏,引起肺功能下降和进行性呼吸困难。其具体发病机制不明。除了前述p38 MAPK通过调控炎症反应、参与MMP产生、影响ECM降解而影响肺纤维化外,p38 MAPK还可通过调控转化生长因子β(transforming growth factor-β,TGF-β)介导的信号通路而在肺纤维化中起重要作用。上皮或炎症细胞释放TGF-β后,能够抑制成纤维细胞凋亡,导致EMT、促进纤维细胞增生、促进肌成纤维细胞分化、ECM分泌增加[54]。在二氧化硅气道滴注所致矽肺大鼠模型中,p38 MAPK抑制剂降低了肺泡灌洗液中TGF-β水平,抑制肺组织EMT,减轻了肺间质纤维化等病理改变[55]。在体外给予p38 MAPK抑制剂,能够抑制TGF-β所致肺泡上皮细胞EMT[56]。还有研究发现肺纤维化过程中上皮细胞损伤与补体系统活化、补体抑制蛋白(complement inhibitory proteins,CIPs) CD46、CD55下降有关,TGF-β通过抑制CD46和CD55表达而损伤上皮细胞,p38 MAPK抑制剂能够抑制TGF-β途径介导的补体系统活化而减轻肺泡上皮损伤[57-59]。

p38MAPK在其他肺部疾病中的作用肺动脉高压是以肺血管阻力和肺动脉压力升高为特征的疾病。低氧导致的肺血管收缩和肺血管重构是肺动脉高压发生过程中重要的病理生理改变。特发性肺动脉高压患者肺血管壁中磷酸化的p38 MAPK明显增高[60],低氧和高碳酸下大鼠的肺血管平滑肌细胞p38 MAPK磷酸化也增加[61];肺动脉高压的动物模型给予p38 MAPK抑制剂后肺动脉高压能够逆转[60],肺动脉收缩减轻[61]。

结语p38 MAPK在人体内广泛表达,多种应激和细胞外信号均可活化p38 MAPK进而调控细胞多种生命活动。大量研究已证实p38 MAPK信号通路在呼吸系统疾病中的炎症反应、细胞增殖与凋亡、肿瘤侵袭等多个方面中起重要作用。尽管目前尚无p38 MAPK抑制剂批准进入临床使用,但随着研究的深入,p38 MAPK有望成为治疗呼吸系统疾病的新靶点。

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