从呼吸道病毒感染到持续性咳嗽高敏：P2X3/TRP离子通道靶点的神经免疫调控及治疗意义。

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中文摘要

背景： 呼吸道病毒感染日益被认为是持续性气道症状和慢性肺病急性加重的重要驱动因素。感染后咳嗽（PIC），尤其是上呼吸道感染后，是亚急性咳嗽最常见的原因之一，也是一种机制复杂的后遗症，其中咳嗽高敏综合征（CHS）起着核心病理生理作用。除咳嗽频率增加外，PIC患者常表现出喉部感觉异常和对低强度刺激的过度反应，提示气道感觉神经的激活阈值持续降低。在咳嗽高敏的多个促成因素中，P2X3受体和瞬时受体电位（TRP）通道是介导咳嗽反射和感觉神经高敏的关键离子通道靶点，但其临床转化却参差不齐。Gefapixant在纳入难治性或不明原因慢性咳嗽人群的III期试验中降低了客观咳嗽频率，但这些数据提供的是间接而非PIC特异性证据，且其临床效用因味觉障碍而受限。同样，TRPV1拮抗剂可抑制辣椒素诱发的咳嗽，但未能一致改善自发性咳嗽频率，凸显了激发模型与现实世界感染后咳嗽病理之间的脱节。方法：本综述讨论了呼吸道病毒如何通过感觉通路的转录、代谢和神经免疫调控诱导咳嗽高敏。呼吸道合胞病毒、鼻病毒和其他病毒病原体可上调TRPV1、TRPA1和ASIC3表达，而IFN-γ等细胞因子可能通过JAK-STAT和NF-κB信号促进感觉神经元转录重编程。同时，缓激肽、COX/12-LOX代谢物和前列腺素E2等炎症介质可通过激酶依赖性磷酸化使TRP通道敏化，而病毒诱导的上皮ATP释放和CD39/CD73介导的嘌呤能降解受损可能维持P2X3受体的反复激活。持续的外周传入输入可能进一步诱导中枢敏化，这解释了尽管外周靶点被阻断但仍存在残余咳嗽的现象。结果：通过整合病毒免疫发病机制、上皮-神经交互作用和离子通道药理学，本综述提出了一个理解病毒感染后咳嗽高敏作为呼吸道感染神经免疫后遗症的框架。结论：未来研究应优先考虑基于分子内型的分层、PIC特异性随机对照试验、高选择性P2X3拮抗剂的优化以及外周-中枢联合评估策略，以指导更精准的治疗干预。

英文摘要

Respiratory viral infections are increasingly recognized as important drivers of persistent airway symptoms and exacerbations in chronic lung disease. Post-infectious cough (PIC), particularly after upper respiratory tract infection, represents one of the most frequent causes of subacute cough and a mechanistically complex sequela in which cough hypersensitivity syndrome (CHS) plays a central pathophysiological role. Beyond increased cough frequency, patients with PIC frequently exhibit laryngeal sensory abnormalities and exaggerated responses to low-intensity stimuli, suggesting a sustained reduction in the activation threshold of airway sensory nerves. Among several contributors to cough hypersensitivity, P2X3 receptors and transient receptor potential (TRP) channels are key ion-channel targets mediating cough reflexes and sensory nerve hypersensitivity, yet their clinical translation has been heterogeneous. Gefapixant reduced objective cough frequency in phase III trials enrolling refractory or unexplained chronic cough populations, but these data provide indirect rather than PIC-specific evidence, and its clinical utility is limited by dysgeusia. Similarly, TRPV1 antagonists suppress capsaicin-provoked cough but have not consistently improved spontaneous cough frequency, highlighting a disconnect between provocation models and real-world post-infectious cough pathology. This review discusses how respiratory viruses may induce cough hypersensitivity through transcriptional, metabolic, and neuroimmune regulation of sensory pathways. Respiratory syncytial virus, rhinovirus, and other viral pathogens can upregulate TRPV1, TRPA1, and ASIC3 expression, while cytokines such as IFN-γ may promote sensory-neuron transcriptional reprogramming through JAK-STAT and NF-κB signaling. In parallel, inflammatory mediators including bradykinin, COX/12-LOX metabolites, and prostaglandin E2 can sensitize TRP channels through kinase-dependent phosphorylation, whereas virus-induced epithelial ATP release and impaired CD39/CD73-mediated purinergic degradation may sustain repeated P2X3 receptor activation. Persistent peripheral afferent input may further induce central sensitization, explaining residual cough despite peripheral target blockade. By integrating viral immunopathogenesis, epithelial-neural crosstalk, and ion-channel pharmacology, this review proposes a framework for understanding post-viral cough hypersensitivity as a neuroimmune sequela of respiratory infection. Future research should prioritize molecular endotype-based stratification, PIC-specific randomized controlled trials, optimization of highly selective P2X3 antagonists, and combined peripheral-central assessment strategies to guide more precise therapeutic interventions.