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Advances in Clinical Medicine
Vol. 14  No. 04 ( 2024 ), Article ID: 84087 , 8 pages
10.12677/acm.2024.1441031

白细胞介素-6在急性呼吸窘迫综合征中的 生物学作用及治疗研究进展

李雨晴，王导新*

重庆医科大学附属第二医院，呼吸与危重症医学科，重庆

收稿日期：2024年3月8日；录用日期：2024年4月1日；发布日期：2024年4月9日

摘要

急性呼吸窘迫综合征(ARDS)是一种严重急性肺损伤(ALI)的状态，其特征是短时间内弥漫性肺损伤、双侧肺水肿和顽固性低氧血症，目前尚无特异性治疗方法。白细胞介素-6 (IL-6)是一种能与自身受体结合形成复合物并通过信号传导发挥生物学作用的多功能细胞因子，在临床上与ARDS的发生、发展和预后密切相关。现有研究发现ARDS患者循环IL-6水平明显升高，并且与疾病严重程度呈正相关。在脂多糖诱导的急性肺损伤模型中，使用IL-6信号转导抑制剂显著减少了促炎细胞因子的释放。因此，靶向IL-6信号传导可能是治疗ARDS的有效方法。为了更深入理解IL-6在ARDS中的作用，该综述主要对IL-6的生物学特性、IL-6不同受体介导的信号转导机制以及目前靶向IL-6信号治疗的研究进展进行详细阐述，旨在为进一步以IL-6信号通路为靶点的ARDS药物研究提供理论依据。

关键词

急性呼吸窘迫综合征，白细胞介素-6，信号通路

Research Progress on the Biological Role and Treatment of Interleukin-6 in Acute Respiratory Distress Syndrome

Yuqing Li, Daoxin Wang*

Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing

Received: Mar. 8th, 2024; accepted: Apr. 1st, 2024; published: Apr. 9th, 2024

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a state of severe acute lung injury (ALI) characterised by diffuse lung injury in a short period, bilateral pulmonary oedema and refractory hypoxaemia. There is currently no specific treatment for ARDS. Interleukin 6 (IL-6) is a multifunctional cytokine that binds to the receptors to form a complex and exerts biological effects through signaling pathway, which is clinically associated with the onset, development and prognosis of ARDS. Studies have shown that circulating levels of IL-6 are significantly elevated in ARDS patients and correlated with the severity of the disease. A reduction in the release of pro-inflammatory cytokines was observed by inhibiting IL-6 signalling in a lipopolysaccharide-induced acute lung injury model. Therefore, targeting the IL-6 signaling may be an effective approach for ARDS treatment. For a deeper understanding of the role of IL-6 in ARDS, the review elaborated on the biological properties of IL-6, the signalling mechanisms mediated by different receptors and current research progress in IL-6 signaling targeted therapy, which aims to provide a theoretical basis for further drug research targeting the IL-6 signalling pathway.

Keywords:Acute Respiratory Distress Syndrome, Interleukin 6, Signalling Pathway

Copyright © 2024 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

急性呼吸窘迫综合征(acute respiratory distress syndrome, ARDS)是一种以肺部广泛炎症为特征的疾病，其临床表现是短期内快速进行性和严重的低氧血症性呼吸衰竭 [1] ，可由多种肺内因素(如肺炎、肺挫伤、胃内容物误吸等)和肺外因素(如脓毒症、创伤、胰腺炎等)导致肺泡–毛细血管膜损伤，诱发肺血管通透性增加、炎性细胞浸润、肺水肿、透明膜形成等病理变化 [2] 。ARDS患者的短期死亡率高达40% [3] ，目前仍然是全球健康负担的重要因素之一。炎症是ARDS的病理生理学的核心，包括白细胞介素-1 (IL-1)、白细胞介素-6 (IL-6)、肿瘤坏死因子α (TNF-α)和其他介质等在内的细胞因子广泛释放，驱动炎症级联反应，导致患者体内失控的级联炎症反应发生 [4] 。其中，IL-6被认为是一种关键的细胞因子，在炎症的发展中起着重要作用，被认为是ARDS患者的生物标志物 [5] ，肺和血浆中IL-6升高已被证明可预测ARDS患者的不良预后 [6] [7] 。IL-6作为一种多效细胞因子，与ARDS的发生发展息息相关，目前有研究揭示抑制IL-6信号传导似乎有望成为ARDS患者的治疗方法，因此本文综合分析了IL-6的生物学特性、IL-6的信号传导、IL-6与ARDS的关系，以及以IL-6信号传导作为ARDS治疗靶点的潜力，为未来ARDS治疗提供思路和方向。

2. IL-6概述

2.1. IL-6生理作用及特点

IL-6最初被命名为B细胞刺激因子，其编码基因位于人类第7对染色体上，由Hirano和其同事于1986年首次克隆并报道 [8] 。IL-6的相对分子质量为26 kD，是一种通常以单体形式存在的多功能细胞因子，可由内皮细胞、成纤维细胞、单核细胞/巨噬细胞、T细胞、B细胞等多种细胞类型产生和分泌，其生物活性广泛，主要参与调节炎症、急性期反应、免疫反应、肿瘤发生和造血 [9] 。

2.2. IL-6信号通路

IL-6信号传导与特定的受体相关，通过受体将细胞间信号传递给目标细胞，从而在炎症、免疫、发育、代谢、衰老、癌症等方面发挥作用 [10] [11] [12] [13] 。为了进行信号转导，IL-6必须首先与IL-6受体(IL-6R)结合，然后产生的复合物需与第二种被称为糖蛋白130 (gp130)的蛋白质结合，诱导gp130二聚化，进而激活下游的非受体型酪氨酸蛋白激酶(JAK)和信号转导及转录激活蛋白(STAT)，即通过JAK-STAT途径产生信号转导。IL-6对IL-6R有亲和力，但对gp130没有亲和力，这意味着IL-6必须成为IL-6R复合物的一部分后，才能与gp130结合，进而发生信号传导 [5] 。IL-6R是一种仅由少数细胞类型表达的膜结合受体，最显著的是肝细胞、巨噬细胞、中性粒细胞和一些T细胞亚群，而gp130可由所有细胞类型表达 [14] 。因此在健康状态下，体内存在两种细胞类型：少数表达IL-6R和gp130并天然对IL-6反应的细胞类型，以及表达gp130但不表达IL-6R并因此不能对IL-6反应的细胞类型。目前公认IL-6主要通过三种信号传导方式发挥其生物活性。

2.2.1. 经典信号传导

通过膜结合IL-6R (mIL-6R)的信号传导被称为经典信号传导。胞外IL-6与分子大小为80 kDa的配体结合链IL-6R，即mIL-6R结合，形成IL-6/mIL-6R复合物，随后诱导分子量为130 kDa的信号传导链gp130聚集并与之结合，形成由2个IL-6，2个IL-6R及2个gp130分子构成的异六聚体，该复合体可以激活JAK，后者通过激活STAT形成二聚体进入细胞核调控靶基因转录，即通过JAK-STAT途径产生信号转导 [15] 。在正常情况下，只有少数表达IL-6R的细胞类型可以对IL-6产生反应，因此IL-6经典信号途径表达的范围有限。

2.2.2. 反式信号传导

通过可溶性IL-6R (sIL-6R)的信号传导被称为反式信号传导。在促炎状态下，被激活的关键酶ADAM-17从细胞表面切割IL-6R，并在较小程度上进行选择性剪接，产生可溶性形式受体sIL-6R，其保留了结合配体IL-6的能力。IL-6/sIL-6R复合物能够与普遍表达的gp130结合，故使原本因不表达IL-6R而对细胞因子无反应的细胞可以对IL-6产生反应，并诱导信号传导 [16] 。现有研究认为经典信号传导引起IL-6的生理、抗炎和抗菌活性，而IL-6的促炎作用是通过反式信号传导介导的 [17] 。

2.2.3. 反式呈递

通过树突细胞的膜结合IL-6R从树突细胞呈递到T细胞被称为反式呈递。IL-6与树突状细胞膜上的IL-6结合链(IL-6Ra)结合，并被“呈递”给表达在同源Ｔ细胞表面的gp130同源二聚体，通过树突细胞(产生IL-6信号)和T细胞(接收该信号)的抗原特异性相互作用，导致T细胞具有高度组织破坏性表型 [18] 。

3. IL-6与ARDS的关系

IL-6在机体受到炎症刺激时由各种细胞释放，包括单核细胞、巨噬细胞、成纤维细胞、血管内皮细胞、T淋巴细胞、B淋巴细胞、平滑肌细胞和肿瘤细胞系。除了肿瘤细胞系外，其他细胞在生理状态下通常不表达IL-6，只有在受到脂多糖、病毒、细胞因子、IL-1、TNF-α和INF的刺激时才会高表达。IL-6又进一步介导众多炎症因子释放，引发级联放大的炎症反应，导致毛细血管壁破坏，形成恶性循环。据研究，IL-6已被证明会对肺泡膜造成损害，IL-6通过诱导血管内皮生长因子的产生影响内皮细胞，导致血管通透性增加并诱导肺泡中单核细胞和中性粒细胞的趋化性 [19] 。此外IL-6还可促进免疫细胞的募集和活化，诱导内皮功能障碍，并有助于增加肺泡毛细血管屏障的通透性，导致肺部炎性物质大量渗出，促进ARDS发生及发展 [20] 。目前已经在ARDS动物模型和ARDS患者的血清中均检测到升高的IL-6水平，并且IL-6水平通常与疾病严重程度有关 [21] [22] 。Deme的临床研究揭示，与健康对照组相比，ARDS患者的IL-6水平显著升高，并且非存活者的IL-6水平在疾病发作后数天持续升高 [23] 。尤其在COVID-19 相关的ARDS患者中，大量研究均观察到IL-6显著升高，且其严重程度与IL-6水平的升高呈正相关 [24] [25] 。

4. 靶向IL-6信号通路治疗ARDS的潜力

4.1. ARDS治疗现状

通过对ARDS药物治疗研究的深入，学者们相继发现了液体疗法 [26] 、他汀类药物 [27] 、皮质类固醇 [28] 等临床干预对部分ARDS亚组患者的预防、治疗、转归有一定作用，但其临床疗效尚需得到临床上多中心、大样本随机对照研究的证实。迄今为止，由于其复杂的发展过程与临床病症，使得该综合征仍没有特定的药物疗法 [29] 。

近几年众多研究发现重症COVID-19患者中IL-6明显升高，以及抗IL-6信号已被证明可降低重症COVID-19住院患者的死亡率，目前被认为是COVID-19危重症患者的标准治疗方法 [30] 。鉴于急性呼吸窘迫综合征的严重程度和炎性本质以及IL-6在引发炎症级联反应中的作用，并考虑到重症COVID-19患者进展为ARDS的易感性，促使人们考虑使用靶向IL-6信号通路的药物抑制该细胞因子的生物学效应，从而抑制ARDS患者体内炎症爆发。随着现代医学进展，IL-6被认为是缓解过度激活的炎症反应的最有潜力的治疗靶点。

4.2. 靶向IL-6/IL-6R

4.2.1. 靶向IL-6R

托珠单抗(Tocilizumab)是全球首个获批上市的靶向IL-6R的人源化单克隆抗体，通过直接结合在IL-6结合表位的方式，阻止IL-6与IL-6R结合，从而抑制经典和反式信号传导 [31] 。托珠单抗最初被开发用于治疗患有系统性慢性炎症性疾病的患者，例如类风湿性关节炎、巨细胞动脉炎、幼年特发性关节炎、成人发病的斯蒂尔病，最近亦建议用于治疗COVID-19相关ARDS，尤其是伴有IL-6明显升高的患者 [32] [33] 。有趣地是，在脂多糖诱导的急性肺损伤模型中，发现使用托珠单抗显著减少了促炎细胞因子的释放 [34] ，这些数据为针对ARDS患者予以IL-6R靶向策略提供了证据。除托珠单抗外，全人源化抗IL-6R单克隆抗体沙利鲁单抗(sarilumab)目前经过临床实验，已经被批准用于治疗类风湿性关节炎 [35] ，进一步扩大了特异性抑制IL-6R介导的炎症的治疗选择。

4.2.2. 靶向IL-6

司妥昔单抗体(Siltuximab)是一种靶向IL-6的人鼠嵌合型单克隆抗体，是FDA批准的首个治疗多中心性Castleman病(MCD)的单克隆抗体，可与IL-6蛋白结合并防止其与IL-6R相互作用 [36] 。目前已经进行了几项随机临床试验来评估司妥昔单抗在新冠肺炎患者中的疗效，结果表明使用司妥昔单抗可显著降低IL-6水平，从而降低细胞因子引起的过度炎症，并改善重症患者的临床结果 [37] 。同样，其他抗IL-6单克隆抗体如Sirukumab、Olokizumab、PF-423691、Elsilimomab、Clazakizumab和Ziltivekimab目前正在进行临床试验阶段，以评估其在不同疾病中的疗效和安全性 [38] 。

值得注意的是，这些IL-6信号传导抑制剂都无法区分经典信号传导和反式信号传导，而是同时阻断这两种途径。尽管sIL-6R介导的IL-6反式信号转导已成为各种疾病状态下IL-6信号转导的病理模式，但通过mIL-6R和信号转导受体gp130的经典信号转导通常被认为具有稳态、保护性和抗炎性 [16] 。因此，干扰经典的IL-6信号传导可能会导致负面作用。

4.3. 靶向IL-6 反式信号

可溶性gp130 (sgp130)可中和IL-6/sIL-6R复合体以终止IL-6信号通路的传导，在此基础上研发了一种sgp130Fc融合蛋白(Olamkicept)，是由gp130的细胞外区域和人IgG1抗体的Fc部分组成的融合蛋白，可以选择性阻断由sIL-6R介导的促炎信号通路，是反式信号通路特异性抑制剂，在各种临床前疾病模型中显示出治疗潜力 [16] 。Olamkicept在溃疡性结肠炎的前瞻性IIb期临床研究中已经取得了有希望的结果，其招募了91例对常规治疗反应不足的中度至重度溃疡性结肠炎患者，结果显示Olamkicept在临床反应、临床缓解和粘膜愈合方面均显示出剂量依赖性的高疗效(NCT03235752) [39] 。

在ARDS动物模型中亦发现抑制gp130可能通过JAK1/STAT3信号通路调节炎症反应和细胞凋亡，从而减轻ARDS，目前被认为是ARDS诊断和治疗的一个有价值的靶点 [40] 。sgp130Fc通过与IL-6/sIL-6R复合体结合而阻止复合体与细胞膜上的gp130受体结合，选择性抑制反式信号通路并保留了经典信号的抗炎作用，故不会损害人体对细菌感染的防御 [41] 。因此sgp130Fc预计比非特异性的抗IL-6/IL-6R单克隆抗体具有更好的治疗效果。

4.4. ADAM17

解联蛋白和金属蛋白酶17 (ADAM17)，也称为肿瘤坏死因子α转化酶(TACE)，是一种I型跨膜细胞表面金属蛋白酶，广泛表达于各种组织和细胞类型中，是细胞膜上非常重要的脱落酶 [42] 。目前已经报道过的ADAM17底物超过80多种，包括IL-6R、TNFα、ACE2等，其作用涉及炎症、免疫、癌症、心血管疾病等多种病理过程 [43] 。其中IL-6R可以通过ADAM17以蛋白水解的方式从细胞膜上裂解，生成可溶性形式的sIL-6R，而IL-6的促炎功能正是与sIL-6R介导的反式信号传导相关。因此抑制ADAM17被认为是治疗炎症的一个重要靶点。ADAM17蛋白由N末端序列前结构域、催化结构域、解联蛋白结构域、富含半胱氨酸的近膜结构域、单跨膜结构域和C端胞浆结构域组成 [44] 。重组前结构域蛋白(A17pro)已被开发为多种炎症疾病模型(例如ADAM17介导的脓毒症、类风湿关节炎、炎症性肠病等)的ADAM17特异性抑制剂，并且显示出显著的治疗效果而没有毒性 [45] 。

ADAM17在促进肺部炎症反应失调方面发挥着重要作用 [46] ，包括冠状病毒肺炎-19相关的肺部炎症。根据冠状病毒肺炎‐19小鼠模型，ADAM17抑制通过减弱细胞因子风暴和中性粒细胞向肺部的浸润来改善肺部炎症 [47] 。虽然大量的临床前数据表明，靶向ADAM17对于许多炎症性疾病是一种有吸引力的治疗方法，但目前尚未转化为针对ARDS的广泛临床实施，需要未来临床实验的进一步研究。

5. 总结

IL-6作为一种多效细胞因子，因其在多种炎症性疾病中的特异性作用而被广泛研究。IL-6在不同环境下通过mIL-6R介导的经典信号传导，sIL-6R介导的反式信号传导，树突细胞的膜结合IL-6Ra介导的反式呈递，发挥不同的生物效应。其中IL-6促炎功能与sIL-6R介导的反式信号传导密切相关，导致肺泡膜损害、内皮细胞功能障碍、肺部炎症爆发、炎症反应级联放大等，均促进ARDS的发生和发展。所以，通过阻断IL-6/sIL-6R/gp130这一途径抑制IL-6的促炎信号传导，有希望成为治疗ARDS的药物靶点，尤其是目前阻断IL-6或IL-6R的单克隆抗体治疗已被广泛批准用于新型冠状病毒肺炎导致的ARDS患者。但是阻断IL-6或IL-6R的单克隆抗体均同时阻断了经典信号传导，抑制了其一定的抗炎和保护作用。根据目前临床研究工作基础，特异性靶向反式信号以及sIL-6R切割时的关键酶ADAM17的治疗已经显示出吸引力，未来这一方向的深入研究将有助于针对ARDS特异性阻断反式信号通路的靶向治疗。

文章引用

李雨晴,王导新. 白细胞介素-6在急性呼吸窘迫综合征中的生物学作用及治疗研究进展
Research Progress on the Biological Role and Treatment of Interleukin-6 in Acute Respiratory Distress Syndrome[J]. 临床医学进展, 2024, 14(04): 364-371. https://doi.org/10.12677/acm.2024.1441031

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