2022, Vol. 41文章信息
- 王晶, 李新民, 韩耀巍, 孙丹
- WANG Jing, LI Xinmin, HAN Yaowei, SUN Dan
- 肺炎支原体的致病机制及中药治疗儿童肺炎支原体感染的研究进展
- The pathogenic mechanism of mycoplasma pneumoniae and the progress of traditional Chinese medicine treatment of Mycoplasma pneumoniaeinfection
- 天津中医药大学学报, 2022, 41(4): 513-520
- Journal of Tianjin University of Traditional Chinese Medicine, 2022, 41(4): 513-520
- http://dx.doi.org/10.11656/j.issn.1673-9043.2022.04.20
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文章历史
收稿日期: 2022-03-05
2. 天津中医药大学第一附属医院,天津 300381
2. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
肺炎支原体(MP)是一种无壁自复制病原菌, 体积介于细菌和病毒之间, 主要通过呼吸道传播, 可引起咽炎、支气管炎、肺炎等[1], 此外还可导致多系统肺外并发, 引起心包炎、心肌炎、肝功能障碍、肾炎和脑膜炎、格林-巴利综合征等疾病[2-4]。肺炎支原体肺炎(MPP)是MP感染引起的不典型微生物致病性肺炎, 具有一定的自限性, 但约有18%的MPP患儿需要住院治疗, 其对机体造成的免疫损伤及严重的肺外并发症仍可危及患儿生命[5]。随着近些年难治性MPP和重症MPP病例增多以及临床应用阿奇霉素治疗MPP的不良反应及多重耐药等因素, 使其临床应用受到一定限制[6-7]。
中医药治疗感染性疾病的历史源远流长, 对于支原体感染, 不仅有杀菌抑菌、消除毒素的作用, 还可抑制呼吸道上皮细胞凋亡, 重建防御屏障功能, 调整感染后分子间的生物信号通路传导, 抑制全身炎症反应、调整免疫功能异常及整体机能的失调[8-9]。本课题组致力于儿童肺炎支原体肺炎的临床研究, 探寻支原体致病的多重机制, 如免疫、凝血机制及局部微生态等相关研究, 旨在中西医相结合, 以中医药联合抗生素协同治疗感染性疾病, 减少抗生素单独应用的毒副作用, 增加抗生素疗效, 减少因抗生素耐药导致的抗生素应用的剂量及疗程的增加。故现将肺炎支原体的致病机制、MP耐药现状及近年中医药治疗儿童MPP的研究进展综述如下。
1 MP致病机制 1.1 直接损伤 1.1.1 黏附与膜融合损伤黏附过程是由多种蛋白质及其组分参与的。P1蛋白是黏附的关键[10]。此外, MP还可利用MPN372蛋白与肺表面活性蛋白A结合, 长期稳定的黏附于含有肺表面活性蛋白A受体的靶细胞上, 如肺泡中的巨噬细胞、肺泡上皮细胞及肺内和肺外其他组织细胞[11]。黏附是MP进入人体并引起后续一系列病理反应的第一步也是最为重要的一步[12]。MP黏附于宿主靶细胞, 其细胞膜脂质双分子层易与靶细胞膜发生生物膜融合。膜融可影响细胞间信号传递和细胞因子的产生[13], 同时消耗宿主营养物质, 增加宿主细胞氧耗[14-15]。
1.1.2 侵袭损伤MP通常被认为是胞外寄生, 但有研究表明在感染时间和温度适宜的条件下, MP也可入侵和破坏细胞[16]。MP侵入非吞噬细胞内, 存活时长可大于6个月。侵袭过程中, 其在宿主细胞内合成DNA, MP一些特定的酶, 如水解酶、核酸酶、蛋白酶等可向宿主细胞内转移, 降解宿主细胞DNA、干扰氨基酸活性, 损伤宿主细胞[17-18]。
1.1.3 毒力损伤黏附为MP诱导区域细胞毒性作用提供了条件, MP不仅可以通过黏附、辅助蛋白、包膜、侵袭性酶等直接诱导损伤, 还可通过其代谢产物、外毒素、外毒素样物质、脂质分子、LPS、膜脂蛋白等发挥其毒力效应[19]。
1.1.3.1 社区获得性呼吸窘迫综合征毒素(CARDS toxin)CARDS toxin是MP的特异性分子, 也是MP被发现的第一个毒力因子[20]。实验证明, 将纯化的重组CARDS toxin应用于模型动物可以完全复制肺炎支原体疾病的致病特征, 包括: 相关细胞因子的产生、嗜酸性粒细胞的增多、以及其与支气管哮喘相类似的气道高反应性等[21-23]。
1.1.3.2 过氧化氢(H2O2)和超氧化物过氧化氢作为MP的一种毒力因子, 参与MP感染的氧化应激反应。MP黏附于宿主细胞, 其细胞骨架重新排列, 在宿主细胞甘油中合成释放过氧化氢和活性氧, 且MP透过支气管黏膜释放核酸酶和过氧化氢, 导致支气管上皮细胞肿胀、坏死、融合, 微绒毛移动减低、结构变形、摆动终止, 淋巴细胞、浆细胞、单核细胞浸润, 引起肺部损伤[24]。由MP合成的过氧化氢和超氧化物基团, 及宿主细胞产生的内源性毒性氧分子, 增加上皮细胞内氧压, 最终导致氧化应激和细胞死亡[25]。
1.1.3.3 半胱氨酸脱硫酶(HapE)HapE作为MP一种潜在的毒力因子可能与溶血有关。HapE可将半胱氨酸转化为丙氨酸和硫化氢。重组的HapE降解半胱氨酸产生硫化氢使红细胞裂解、破坏导致溶血[26]。不仅如此, 最新研究表明, 肺炎支原体HapE可以改变人支气管上皮细胞的细胞因子的分布和生长。如减少炎症因子的分泌, 特别是促炎细胞因子, 如IL-2、IL-12、IFN-γ、TNF-α, 同时可增加抗炎介质的释放, 如IL-4、IL-6。HapE通过对IL-6分泌的影响, 导致Th1/Th2失衡, 以驱动Th2型细胞反应为主进而影响宿主免疫监测功能, 促进MP逃避宿主的免疫系统清除, 增加了MP慢性感染的风险[27]。
1.1.3.4 Mpn133编码的脂蛋白/脂肽由Mpn133编码的膜结合脂蛋白/脂肽可视为MP的活性物质, 可促使细胞产生ROS[28]。同时具有免疫刺激活性, 其N-末端脂肽部分可与Toll样受体2(TLR2)结合引起一系列免疫反应, 如诱导IL-1β、TNF-α、IL-6在内的促炎因子分泌等。
1.2 免疫损伤除上述直接损伤, MP与宿主间的相互作用导致的炎症反应和免疫损伤机制则更为复杂。宿主免疫反应的特征、强度及宿主免疫能力会极大地影响MP感染导致的呼吸系统疾病的临床结局及肺外并发症的发生率[29]。Shi等[30]发现因血液病使用免疫抑制剂的儿童在感染MP导致肺炎支原体肺炎时比免疫力正常的儿童并发症发生率及严重肺炎支原体肺炎的发生率低。同时免疫抑制剂的应用减少了炎症细胞的募集, 特别是中性粒细胞进入肺组织, 减少了过度炎症通过氧化应激途径参与的氧化-抗氧化失衡而导致的肺损伤。这表明因抗击病原体而激活的免疫应答反应在MP致病机制中扮演了极其重要的角色。
1.2.1 体液免疫MP细胞膜上的糖酯抗原诱导宿主产生体液免疫, 抗体应答是抗MP感染的基础。在感染早期, 机体主要靠分泌抑制剂、补体(C1、C2、C3、C4)及吞噬细胞等非特异免疫防御机制抗MP, 大约2周后, 补体水平下降而抗体水平上升[31]。特异性IgA可以保护呼吸道粘膜, 是抗MP的关键。MP感染过程涉及多种特异性和非特异性免疫球蛋白和补体成分参与MP感染的恢复和炎症反应。
1.2.2 细胞免疫MP细胞膜上蛋白抗原参与诱导宿主的细胞免疫, 而细胞免疫的轻度又可直接影响肺损伤的程度[32]。MP感染后, 周血中CD4+T细胞计数减低, CD8+T计数增多, CD4+T/CD8+T比值下降[33-34]。辅助型T淋巴细胞亚群失衡, Th1/Th2比例不平衡向Th2显性表型转变[35-36]。Th2显性促进MP逃避宿主的免疫系统, 为MP持续存在和复制提供了可能。有研究表明肺炎支原体肺炎患儿体内存在Th17/Treg细胞失衡现象, 其与Notch信号通路激活有关[37]。
1.2.3 炎症损伤和免疫抑制炎症因子在MP诱导的炎症反应中起重要的作用。感染早期, TNF-α、IL-1β、IL-6的mRNA表达水平显著升高[38-39]。IL-17被认为是参与MP感染的重要细胞因子。IL-17的过度表达与肺炎的严重程度有关, 肺泡灌洗液中IL-17的水平与肺实变范围大小有关。Fan等[40]在实验中发现MP感染后IL-6、IL-1β、TNF-α、IL-17在肺部感染中形成了一个正反馈循环, 参与了MP感染后细胞免疫反应造成的肺部损伤。与过度炎症损伤伴发的还有MP感染后引起的免疫抑制, 主要表现在引起T细胞亚群失调、B细胞与T细胞的严重破坏。MP感染导致的免疫抑制不利于感染的清除, 同时增加了再次感染的风险。
1.2.4 抗原免疫损伤MP的超抗原成分、抗原变异所产生的毒力及致病性、多组织及组分的交叉抗原反应是MP抗原免疫损伤的基础。抗原变异与毒力的产生及致病性有关[41]。MP膜上的磷酸甘油酶与宿主共享一定的抗原成分, 帮助MP逃避宿主的免疫系统攻击, 为MP长期定植和慢性感染提供条件[42]。此外MP的膜抗原与RBC膜Ⅰ型抗原相似, 在MP感染过程中, 脑、肺、RBC细胞膜、淋巴细胞、心肌细胞自身抗体普遍存在, 交叉反应形成免疫复合物放大自身的免疫反应, 导致多系统免疫损伤[43-44]。
2 肺炎支原体感染的治疗进展及其耐药现状MP对β-内酰胺类、氨基糖苷类、磷霉素类抗生素有天然耐药性。相对于儿童的人群特点, 由于潜在的毒性, 喹诺酮类、四环素类等应予以避免。大环内酯类抗生素特别是阿奇霉素, 因其半衰期更长, 可进行5 d的疗程, 耐受性好, 在国内外均为治疗MPP临床推荐的一线用药[45-46]。由于MP具有易感性和敏感性高突变率[47], 当MP在体外暴露于亚浓度的阿奇霉素时, MP可发生与自然产生的耐药生物体相同的突变, 这表明大环内酯类的广泛应用特别是不合理滥用最终导致了大环内酯类耐药支原体的全球传播。虽然大环内酯类抗菌效果和通过细胞因子抑制免疫反应的特性有关[48]。但一些大环内酯类治疗明显失败的报道又强调出耐大环内酯类MP感染的替代抗生素方案的重要性。日本的指南建议在怀疑耐大环内酯类MP感染时使用妥苏沙星(tosufloxacin)而不是大环内酯类抗生素[49]。
3 中医药治疗MP感染及其作用机制研究 3.1 中医药治疗MP感染的特色 3.1.1 中医辨治特色从中医辨证论治的角度上看, MPP的病机特点可总结为"热、毒、痰、瘀、虚"五个方面, 而相较于其他病原菌所致的肺炎又有"病初肺闭尤甚"、"瘀热贯穿病程始终"的疾病特点[50-52]。故在治疗时要以辨证论治为基本中医理论, 以MPP 5方面病机特点为抓手, 以早期诊断, 诊断后及时用药为原则, 在宣肺清热等肺炎基本治疗方法基础上, 善用化瘀通络法, 以中医药与抗生素协同应用, 不仅可以提高治疗儿童MPP的总体疗效、缓解主要临床症状、还可以减少抗生素用量及其产生的不良反应。如别江丽[53]在治疗MPP风热闭肺证时应用程氏咳嗽方联合阿奇霉素, 其愈显率高于单纯使用阿奇霉素治疗组, 而在咳嗽、咳痰、咽红咽痛、鼻塞流涕、大便性状改善等主要临床症状的缓解方面均表现较好, 且未见明显不良反应。张克青等[54]应用豁痰活血方联合阿奇霉素和基础治疗方法治疗MPP, 发现其退热时间、咳嗽咳痰好转时间、啰音消失时间以及炎症吸收时间均明显短于单用阿奇霉素组(P<0.05)。吕蓉蓉等[55]应用理肺通络方联合阿奇霉素在治疗痰热闭肺证、阴虚肺热证及肺脾气虚证方面均优于单独使用阿奇霉素治疗。沈毅韵等[56]应用清肺通络方作为静滴阿奇霉素后的口服序贯用药, 与单纯应用阿奇霉素组相较不仅减少了抗生素用量, 还能缓解患儿咳嗽咯痰等症状, 更好促进MP-IgM抗体转阴, 抑制炎症反应及过度炎症反应引起的肺外并发症。
3.1.2 中医"辨体论治"MPP从"辨体论治""因质制宜""治病求本"的角度出发, MPP是否易发、其发病特点、证候特点、兼夹变证等均与小儿体质因素关系密切[57]。"治病求本"是中医治疗疾病的特色和优势, "知病所由而直取之, 乃为善治", 而"辨体论治"和"因质制宜"又是"治病求本"的具体体现。"因质制宜"体现在MPP的治疗上对于素体阴虚者, 遣方用药中可适当加入沙参、麦冬等滋润之品; 阳虚者, 注意健脾益气, 可加茯苓、白术之类; 痰湿体质者可酌加苦温燥湿之清半夏、陈皮、厚朴之品; 内热体质者注意苦寒清热和甘寒清润之品的应用如: 大黄、黄芩、生地、玄参等。平和体质虽用药拘束较少, 但也应注意时时顾护脾胃, 以免攻伐太过损伤正气[58]。
3.1.3 内外合治MPP从"内外合治"的角度上看, 在治疗MPP是辅以有中医特色的外治法, 可缩短病, 程改善症状, 提高治疗有效率。陈弘韬[59]在阿奇霉素治疗基础上合用风热方配合肺炎贴, 与单纯应用阿奇霉素作比较, 发现分别对两组患儿在发热、咳嗽、肺部啰音消失时间进行对比, 均具有显著性差异(P<0.01)。余德钊等[60]应用中药外治法联合大桑菊合剂口服与单纯应用阿奇霉素组相较, 可明显改善MPP患儿的临床症状与体征, 缩短病程, 提高疗效, 同时能够缩短阿奇霉素的疗程, 减少不良反应。黄晓琳[61]应用蒿芩麻杏石甘汤加敷背散外敷与阿奇霉口服治疗组比较可缩短患儿发热时间, 缓解咳嗽痰壅, 促进肺部啰音吸收, 改善食欲且无明显不良反应。
3.2 中医药抗MP感染的作用机制 3.2.1 抑制感染后炎症反应MP侵入宿主后, 通过粘附与膜融合作用, 可以导致肺上皮细胞损伤、纤毛倒伏, 炎症细胞与炎症因子浸润, 引发局部炎症反应。Yang等[62]应用清肺合剂(黄芩、金银花、连翘、玄参、生地黄、牡丹皮、麻黄、杏仁、当归、桃仁、姜黄、党参、白术、甘草等)联合阿奇霉素干预MP感染模型小鼠, 在电镜下观察小鼠毛细血管基底膜比单纯应用阿奇霉素薄, 说明清肺合剂联用阿奇霉素可保护肺上皮细胞并有效抑制感染后的炎症反应。Jiang等[63]等通过动物实验发现清肺通络方(桑白皮、地骨皮、桃仁、杏仁、苏子、葶苈子、蝉衣、地龙、平地木、甘草等)可以抑制JNK、ERK和NF-κB的磷酸化激活, 从而抑制MP感染后的炎症反应。Xiao等[64]通过体外实验证明清肺通络方可有效缓解MPP诱发的过敏性炎症反应, 有效地抑制炎症因子和血管内皮生长因子(VEGF)的释放。Liu等[65]发现存在于金丝桃和山楂中的黄酮类化合物--金丝桃苷可显著降低MP诱导的IL-8、TNF-α的产生, 以剂量依赖的方式促进宿主细胞增殖, 通过抑制感染细胞中趋化因子配体5(CCL5)从而抑制MP感染后的炎症反应。
3.2.2 双向调节免疫反应王征军等[66]以穿心莲内酯磺化物辅助治疗MPP, 治疗后CD3+、CD4+、CD8+及IgA、IgG、IgM水平较单用阿奇霉素改善幅度大, 差异有统计学意义(P<0.05)。实验证实脱水穿心莲内酯可直接破坏MP内毒素结构, 从而抑制由内毒素诱导产生的细胞因子活性, 同时促进淋巴细胞CD3+、CD4+及免疫球蛋白IgA、IgG、IgM的增殖活化, 抑制淋巴细胞CD8+水平, 从而双向调节机体的免疫反应。这与孙洪华等[67]的临床研究结果一致。Chen等[68]在动物实验中证实, 桑根白皮素作为有力的抗炎剂可以抑制IL-6、TNF-α、IL-1β等促炎因子的诱导、活化, 同时升高抑炎因子IL-10的水平, 进而通过抑制Wnt/β-catenin的表达和NF-κB的活动形式显著减轻小鼠MPP的肺部炎症反应。
3.2.3 改善感染后微循环障碍MP感染后可导致血管内皮的损伤和微循环障碍。机体的高凝状态有进一步加重了MP感染病情。李茜梅等[69]认为麻黄碱、甘草酸等物质有助于抑制病原微生物繁殖, 减轻过度炎症反应, 改善毛细血管通透性, 减少血管内皮损伤, 改善MP感染后的血液高凝状态。方琼杰等[70]应用清肺止痉活血法治疗小儿MPP, 通过对血小板、凝血因子、D-二聚体的影响, 改善MP感染后的高凝状态, 其方应用的活血化瘀药可通过开放毛细血管、扩张微动脉等途径, 使微循环血流量增多、血流速度加快, 从而消除微循环障碍时的血液瘀滞。
3.2.4 修复肺组织损伤Yang等[62]认为清肺合剂在MPP肺损伤恢复期可以调节免疫、延缓肺纤维化、保护肺血管内皮细胞, 有利于MP感染的恢复。Lin等[71]通过动物实验证实, 柚皮素(NRG, 清肺通络方的主要成分)通过抑制炎症细胞因子表达和肺纤维化从而减轻MPP诱导的小鼠肺损伤。NRG抑制了MP诱导的自噬相关蛋白IC3、Beclin-1的表达, 而增强了MP诱导的P62对自噬的抑制作用。NRG通过抑制自噬介导的肺部炎症和纤维化对MP感染后气道重塑起保护作用。此外, 桔梗总皂苷和桔梗皂苷D通过下调TGF-β表达, 恢复支气管上皮细胞功能, 增加肺组织表面活性物质A的合成与分泌, 减轻MP感染所致的大鼠肺部炎症反应, 对肺组织有一定的修复功能[72]。
4 小结综上, MP致病机制较为复杂, 各致病机制及其相互作用尚不十分明确, 而免疫损伤仍被认为是主要的致病机制。随着难治病例的大量出现及抗生素不合理应用导致的临床耐药病例的增多和菌群失调、二重感染等不良反应的出现, 使大环内酯类抗生素治疗MP感染受到挑战。中药治疗MP感染具有一定的特色, 特别是从整体出发抓住MPP的病机关键, 从"闭"与"瘀"入手, 提高了治疗MPP的疗效。随着基础实验的不断开展, 中医药治疗MP感染机制逐渐得以揭示。但现在的研究仍有不足之处, 如实验设计不够系统、严谨, 实验周期长, 无法全面的阐明治疗效果及机制。再者缺少多中心临床试验研究, 单一中心研究结果缺乏代表性等。因此, 中医药治疗MP感染的机制仍需进一步深入挖掘与讨论, 并在基础研究和临床试验中不断加以验证。
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