Flower Luke, Vozza Emilio G, Bryant Clare E, Summers Charlotte
Victor Phillip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK
Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Thorax. 2025 Mar 18;80(4):255-263. doi: 10.1136/thorax-2024-222596.
Acute respiratory distress syndrome (ARDS) is present in >10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis. The dominant pathways through which IL-1β and IL-18 are believed to be elaborated are multimeric protein structures called inflammasomes that consist of sensor proteins, adaptor proteins and an effector enzyme. The inflammasome's initial activation depends on one of a variety of damage-associated (DAMP) or pathogen-associated (PAMP) molecular patterns. However, once activated, a common downstream inflammatory pathway is initiated regardless of the specific DAMP or PAMP involved. Several inflammasomes exist in humans. The nucleotide-binding domain leucine-rich repeat (NLR) family, pyrin domain-containing 3 (NLRP3), inflammasome is the best described in the context of ARDS and is known to be activated in both infective and sterile cases. The NLR family, caspase activation and recruitment domain-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have also been implicated in various ARDS settings, as have inflammasome-independent pathways. Further work is required to understand human biology as much of our knowledge is extrapolated from rodent experimental models. Experimental lung injury models have demonstrated beneficial responses to inflammasome, IL-1β and IL-18 blockade. However, findings have yet to be successfully translated into humans with ARDS, likely due to an underappreciation of the central role of the neutrophil inflammasome. A thorough understanding of inflammasome pathways is vital for critical care clinicians and researchers and for the development of beneficial therapies. In this review, we describe the central role of the inflammasome in the development of ARDS and its potential for immunomodulation, highlighting key areas for future research.
急性呼吸窘迫综合征（ARDS）在所有入住重症监护病房的患者中占比超过10%，且与严重的发病率和死亡率相关。尽管自首次描述以来已过去半个多世纪，但尚未开发出有效的药物治疗方法，在改善临床结局方面也进展甚微。中性粒细胞是ARDS的主要驱动因素，其启动及随后异常的下游功能，包括白细胞介素（IL）-1β和IL-18的分泌，是该疾病发病机制的核心。人们认为IL-1β和IL-18产生的主要途径是一种称为炎性小体的多聚体蛋白结构，它由传感蛋白、衔接蛋白和一种效应酶组成。炎性小体的初始激活取决于多种损伤相关（DAMP）或病原体相关（PAMP）分子模式中的一种。然而，一旦激活，无论涉及的具体DAMP或PAMP是什么，都会启动一条共同的下游炎症途径。人类体内存在多种炎性小体。核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体在ARDS背景下的描述最为详尽，已知在感染性和非感染性病例中均可被激活。含半胱天冬酶激活和募集结构域的NLR家族成员4（NLRC4）炎性小体和黑色素瘤缺乏因子2（AIM2）炎性小体也与各种ARDS情况有关，炎性小体非依赖途径亦是如此。由于我们的许多知识是从啮齿动物实验模型推断而来，因此需要进一步开展研究以了解人类生物学特性。实验性肺损伤模型已证明对炎性小体、IL-1β和IL-18阻断有有益反应。然而，这些发现尚未成功转化用于ARDS患者，这可能是因为对中性粒细胞炎性小体的核心作用认识不足。深入了解炎性小体途径对于重症监护临床医生和研究人员以及开发有益疗法至关重要。在本综述中，我们描述了炎性小体在ARDS发生发展中的核心作用及其免疫调节潜力，强调了未来研究的关键领域。
