中性粒细胞胞外诱捕网介导的急性缺血性卒中替奈普酶抵抗机制与昼夜节律干预策略的研究进展
Mechanisms of NETs-Mediated Tenecteplase Resistance in Acute Ischemic Stroke and Advances in Chronotherapeutic Strategies
DOI: 10.12677/acm.2026.163943, PDF,   
作者: 杨尚松, 黄小凤：右江民族医学院研究生学院，广西 百色；李登星*：右江民族医学院附属西南医院(百色市人民医院)神经内科，广西 百色
关键词: 急性缺血性卒中；替奈普酶；中性粒细胞胞外诱捕网；溶栓抵抗；昼夜节律；Acute Ischemic Stroke； Tenecteplase； Neutrophil Extracellular Traps； Thrombolytic Resistance； Circadian Rhythm
摘要: 急性缺血性卒中(Acute Ischemic Stroke, AIS)的药物再灌注治疗正处于从传统的阿替普酶(rt-PA)向替奈普酶(Tenecteplase, TNK)转变的关键时期。尽管TNK凭借其经过分子工程改良的纤维蛋白特异性和药代动力学特性，展现出优于前一代药物的潜能，但在临床实践中仍然有部分患者表现出显著的“溶栓抵抗”。近年来的研究发现，血栓内部不仅包含纤维蛋白网，还富含一种被称为“免疫血栓”骨架的中性粒细胞胞外诱捕网(Neutrophil Extracellular Traps, NETs)。这种由DNA与蛋白酶交织而成的网状结构，在物理层面阻碍了溶栓药物的渗透，并通过生化机制降低了TNK的药效。最新的时间生物学研究显示，中性粒细胞活化及NETs分泌受Bmal1/CXCR4等多种生物钟基因调控，周期具有明显昼夜波动趋势，说明卒中的严重程度和治疗效果可能具有时间依赖性。本文旨在系统梳理NETs导致TNK溶栓抵抗的生物学机制，阐述免疫系统的昼夜节律对血栓病理的影响，并探讨利用DNase-1进行辅助溶栓及基于时间维度的精准治疗策略，为提升AIS的临床再通率提供理论参考。
Abstract: Pharmacological reperfusion therapy for Acute Ischemic Stroke (AIS) is currently undergoing a pivotal transition from the traditional alteplase (rt-PA) to tenecteplase (TNK). Although TNK exhibits superior potential compared to its predecessor—owing to its bioengineered fibrin specificity and optimized pharmacokinetics—a significant subset of patients still manifests “thrombolysis resistance” in clinical practice. Recent investigations have revealed that thrombi are composed not only of a fibrin mesh but are also enriched with Neutrophil Extracellular Traps (NETs), which serve as the scaffold of “immunothrombosis.” This meshwork, interwoven with DNA and proteases, physically impedes the penetration of thrombolytic agents and biochemically attenuates the efficacy of TNK. Emerging chronobiological research indicates that neutrophil activation and NETs secretion are governed by various circadian clock genes, such as Bmal1 and CXCR4, exhibiting distinct diurnal oscillations. This suggests that the severity of stroke and therapeutic responsiveness may be time-dependent. This review aims to systematically elucidate the biological mechanisms by which NETs induce TNK resistance, describe the impact of immune circadian rhythms on thrombus pathology, and explore adjuvant thrombolytic approaches using DNase-1 as well as chronotherapy-based precision medicine strategies. Ultimately, this work seeks to provide a theoretical reference for enhancing clinical recanalization rates in AIS.
文章引用：杨尚松, 黄小凤, 李登星. 中性粒细胞胞外诱捕网介导的急性缺血性卒中替奈普酶抵抗机制与昼夜节律干预策略的研究进展[J]. 临床医学进展, 2026, 16(3): 1598-1606. https://doi.org/10.12677/acm.2026.163943

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