Targeting Pulmonary and Arterial Chemoreceptors via Inhaled Therapeutics: A Novel Pathway to Blunt Hypoxia-Induced Pulmonary Hypertension?

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.