通过吸入性治疗靶向肺部和动脉化学感受器：缓解缺氧诱导的肺动脉高压的新途径？

文献信息

中文摘要

背景： 与阻塞性睡眠呼吸暂停（OSA）和高海拔暴露相关的第3组缺氧诱导的肺动脉高压（HPH）以适应性不良的化学反射表型为特征，表现为肺内和动脉氧传感器高反应性。目前，非选择性全身性血管扩张剂治疗通常无法逆转血管重塑，并带来全身性低血压和通气-灌注不匹配恶化的风险。
目的： 提出一种概念性治疗方法，将HPH治疗从非特异性血管扩张转向精准靶向的吸入性化学传感器调节。
方法： 对PubMed和Scopus数据库（2015年1月至2026年9月）进行了全面文献检索，以识别评估HPH自主神经和分子机制的原始临床前和临床研究、系统综述和指南，同时结合靶向肺部药物递送系统的进展。
结果： 此处综合的临床前证据支持靶向特定分子通路，如氧敏感性K+通道、线粒体活性氧（ROS）和缺氧诱导因子（HIFs），并使用新型雾化纳米载体在肺-颈动脉轴原位成功重新调谐这些过度活跃的传感器。这种局部干预理论上可正常化肺血管阻力并减弱交感神经过度驱动，同时显著减少与传统口服血管扩张剂相关的脱靶全身效应。
局限性： 临床转化的主要障碍包括缺乏非侵入性化学反射生物标志物，以及在急性缺氧期间 undesirable 地覆盖人体必需的、维持生命的缺氧通气驱动的高风险。
结论： 局部吸入性传感器调节是一种有前景的转化方法，可减轻缺氧诱导的自主神经和血管功能障碍，前提是未来的早期临床试验优先考虑严格的安全性监测和整合的自主神经终点。

英文摘要

BACKGROUND: Group-3 hypoxia-induced pulmonary hypertension (HPH) associated with obstructive sleep apnea (OSA) and high-altitude exposure is characterized by a maladaptive chemoreflex phenotype with hyper-reactive intrapulmonary and arterial oxygen sensors. At present, non-selective systemic vasodilator therapy often cannot reverse vascular remodeling and carries the risk for systemic hypotension and worsening of ventilation-perfusion mismatch.
OBJECTIVE: To suggest a conceptual therapeutic approach to transfer HPH treatment from nonspecific vasodilation to precision-targeted inhaled chemosensor modulation.
METHODS: A comprehensive literature search of the PubMed and Scopus databases (January 2015- September 2026) was performed to identify original preclinical and clinical studies, systematic reviews, and guidelines evaluating the autonomic and molecular mechanisms of HPH, in parallel with advances in targeted pulmonary delivery systems for drugs.
RESULTS: The preclinical evidence synthesized here supports targeting of specific molecular pathways such as oxygen-sensitive K+ channels, mitochondrial reactive oxygen species (ROS) and hypoxia-inducible factors (HIFs) with novel aerosolized nanocarriers to successfully retune these hyperactive sensors in situ at the lung-to-carotid axis. This localized intervention theoretically normalizes pulmonary vascular resistance and attenuates sympathetic overdrive while dramatically reducing the off-target systemic effects associated with traditional oral vasodilators.
LIMITATIONS: Major barriers to clinical translation include the absence of non-invasive chemoreflex biomarkers and the high risk of undesirably overriding the body's essential, life-sustaining hypoxic ventilatory drive during acute hypoxia.
CONCLUSION: Localized, inhaled sensor modulation is a promising translational approach to mitigate hypoxia-induced autonomic and vascular dysfunction, assuming future early-phase clinical trials prioritize stringent safety monitoring and integrated autonomic endpoints.