脓毒症相关肺损伤/ARDS的研究进展：聚焦miRNA调控机制与巨噬细胞极化

Research Progress in Sepsis-Associated Lung Injury/ARDS: Focus on miRNA Regulatory Mechanisms and Macrophage Polarization

摘要: 脓毒症是感染诱发的宿主反应失调综合征，病程中极易并发多器官功能障碍。肺脏因其丰富的血流灌注、复杂的免疫细胞构成以及脆弱的肺泡–毛细血管屏障，往往最早受到波及，并可进一步发展为脓毒症相关肺损伤(sepsis-associated lung injury, SALI)乃至急性呼吸窘迫综合征(acute respiratory distress syndrome, ARDS)。近年的研究逐渐认识到，SALI/ARDS并非单纯由“炎症过强”所驱动，而是由炎症放大、免疫抑制、屏障破坏、凝血失衡和代谢重编程相互交织形成的动态过程。巨噬细胞位于这一过程的枢纽位置，既参与病原识别、炎症放大和程序性死亡，也决定凋亡细胞清除、炎症消退与组织修复能否顺利完成。与之相对应，microRNA (miRNA)依靠多靶点、网络式的转录后调控，深度介入巨噬细胞极化可塑性、炎性小体激活、焦亡阈值、免疫代谢重塑以及细胞外囊泡介导的细胞间通讯，因此被认为是解释SALI/ARDS生物学异质性的重要分子线索。本文围绕“miRNA–巨噬细胞轴”系统梳理脓毒症相关肺损伤的研究进展，重点讨论其在炎症扩增、程序性死亡、NETs串扰、细胞外miRNA受体识别和肺内免疫微环境重塑中的作用，并结合近年ARDS亚表型、多组学与外泌体递送研究，分析其在早期识别、风险分层、预后评估和靶向干预中的临床转化前景，以期为后续基础研究设计和临床治疗提供参考。

Abstract: Sepsis is a syndrome of dysregulated host responses triggered by infection and is frequently complicated by multiple organ dysfunction during its course. Because of its abundant blood perfusion, complex immune-cell composition, and fragile alveolar-capillary barrier, the lung is often one of the earliest organs to be involved, and may further progress to sepsis-associated lung injury (SALI) and even acute respiratory distress syndrome (ARDS). Recent studies have increasingly recognized that SALI/ARDS is not driven simply by “excessive inflammation”, but rather represents a dynamic process shaped by the interaction of inflammatory amplification, immunosuppression, barrier disruption, coagulation imbalance, and metabolic reprogramming. Macrophages occupy a pivotal position in this process: they participate in pathogen recognition, inflammatory amplification, and programmed cell death, while also determining whether efferocytosis, resolution of inflammation, and tissue repair can proceed effectively. In parallel, microRNAs (miRNAs), through multitarget and network-based post-transcriptional regulation, deeply participate in macrophage polarization plasticity, inflammasome activation, pyroptotic threshold setting, immunometabolic remodeling, and extracellular vesicle-mediated intercellular communication, and are therefore regarded as important molecular clues for explaining the biological heterogeneity of SALI/ARDS. Focusing on the “miRNA-macrophage axis”, this review systematically summarizes recent progress in sepsis-associated lung injury, with particular attention to its roles in inflammatory amplification, programmed cell death, crosstalk with neutrophil extracellular traps, extracellular miRNA receptor recognition, and remodeling of the pulmonary immune microenvironment. Combined with recent advances in ARDS subphenotypes, multi-omics, and exosome-based delivery, we further analyze the clinical translational prospects of this axis in early identification, risk stratification, prognostic evaluation, and targeted intervention, with the aim of providing references for future basic research design and clinical treatment.