一、前言

　　过去二十年对哮喘复杂病理生理学的研究推动了重症哮喘靶向治疗的发展。人们逐渐认识到哮喘是一种异质性疾病，其临床和炎症表型对治疗的反应也不同。最重要的临床表型是基于发病年龄。早发/儿童期发病的哮喘对常见空气过敏原的敏感性高,而晚发/成年型哮喘大多是非过敏的。在哮喘的炎症表型中，2型哮喘的特点是嗜酸性气道炎症，可由过敏原驱动，也可继发于2型先天淋巴细胞 (ILC2) 的激活。ILC2细胞不表达抗原特异性T细胞受体，但对上皮细胞因子有反应，例如胸腺基质淋巴细胞生成素 (TSLP) 和白细胞介素 (IL) 33（图1）。激活后，ILC2细胞可能会产生IL-5（导致嗜酸性粒细胞增多）和IL-13（导致呼出气一氧化氮升高和平滑肌细胞收缩，从而导致支气管高反应性）。

　　多种针对哮喘的细胞因子靶向疗法已被证明可有效治疗重症哮喘。而COPD也包括嗜酸性粒细胞增多的表型。为改善哮喘状况开发的单克隆抗体已在COPD中进行了测试，看看它们是否可为嗜酸性粒细胞表型COPD患者提供类似的治疗益处。本文回顾了现有生物制剂治疗哮喘和COPD的作用机制和功效。

　　图1 重症哮喘和慢性阻塞性肺疾病中的气道炎症

　　Pollens：花粉；Cathepsin：组织蛋白酶；CXCL：C-X-C基序趋化因子；Eosino：嗜酸性粒细胞；IFN-γ：干扰素-γ；IL：白细胞介素；ILC2：先天淋巴细胞2型；MMP：基质金属蛋白酶；Neutro：中性粒细胞；TNF-α：肿瘤坏死因子-α；TSLP：胸腺基质淋巴细胞生成素

　　二、重症哮喘及其靶向疗法

　　1. 重症哮喘表型

　　嗜酸性粒细胞型哮喘的定义是痰液嗜酸性粒细胞计数大于1%-3%，中性粒细胞型哮喘的定义是痰液中性粒细胞计数大于60%-76%。当两种细胞均增加时，为混合粒细胞型哮喘；均低于正常范围时，为少粒细胞型哮喘。

　　2. 重症哮喘的靶向疗法

　　美国食品和药物管理局已批准六种靶向药物用于治疗重症哮喘。（1）抗IgE的奥马珠单抗，是临床上第一个用于治疗重症哮喘的靶向药。可用于对常见过敏原敏感的哮喘患者，这类患者多为早发型哮喘或合并有过敏性鼻炎、慢性鼻窦炎伴鼻息肉或慢性荨麻疹等共存疾病。（2）抗IL-5的甲波利珠单抗，可改善重症嗜酸性粒细胞型哮喘。（3）抗IL-5的瑞替珠单抗，静脉给药后不仅可以显著减少青少年和成人重症哮喘的恶化，还能很好地减少迟发型哮喘患者的病情恶化。（4）抗IL-5受体的贝那利珠单抗，可通过抗体依赖的细胞介导的细胞毒作用来耗尽嗜酸性粒细胞和嗜碱性粒细胞。针对IL-5及其受体的治疗已被发现对成人发病的哮喘和慢性鼻窦炎合并鼻息肉、嗜酸性肺炎或EGPA的患者更有效。（5）抗IL-4受体的度普利尤单抗，是改善儿童或成人重症2型哮喘患者预后的良好选择，支持这种治疗的并存疾病包括特应性皮炎和慢性鼻窦炎合并鼻息肉。（6）抗警报素，如抗TSLP，可阻断上游细胞因子，因此可用于更广泛的重症哮喘患者。

　　综上，应根据患者的特点选择合适的单抗治疗。具体需要结合患者的临床特征、生物标志物和共存疾病等。

　　三、COPD及其靶向疗法

　　1. COPD表型

　　COPD的遗传、临床和炎症表型，如α-1抗胰蛋白酶缺乏症或端粒酶多态、吸烟与不吸烟、小气道疾病和肺气肿，以及频繁恶化或炎症表型如嗜酸性粒细胞型或中性粒细胞型等，这些表型的确立可能会促进靶向治疗的开发。

　　2. COPD的靶向疗法

　　可治疗特征这一概念已被提出，它指的是根据炎症特征使用相同的药物来管理慢性呼吸道疾病，如哮喘和COPD。慢性呼吸道疾病的一个重要的可治疗特征是嗜酸性呼吸道炎症，且已被证实可用于预测ICS和全身皮质类固醇的疗效。然而，几项研究表明，在哮喘中观察到的靶向药物的良好结果不能推广到COPD患者。与重症哮喘相比，COPD患者对生物制剂的反应较差的原因尚不清楚。

　　四、结语

　　对哮喘的免疫学和病理生理学方面的研究进展推动了新治疗方法的开发和重症哮喘患者结局的重大改善。然而目前，靶向治疗还不能很好地改善COPD。

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　　本 期 作 者

　　孟爱宏 主任医师

　　医学博士/主任医师/教授/博士生导师

　　河北医科大学第二医院北院区呼吸与危重症医学科主任

　　孙同欣玮 硕士研究生

　　河北医科大学第二医院

　　本文仅代表作者个人观点

　　仅供医务人员参考

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