Ethan Edwards

Background: High-Altitude Pulmonary Edema (HAPE) is a life-threatening condition caused by abnormal pulmonary vasoconstriction in hypoxic environments. Exposure to elevations above 3,000 m is increasing due to growing participation in high-altitude travel and sports, placing a larger population at risk for HAPE.¹ The purpose of this abstract is to summarize current understanding  of HAPE pathophysiology, epidemiology, and treatment strategies, while highlighting limitations in existing therapies. The potential role of pressure-sensitive multivesicular liposomes (PS-MVLs) as a novel drug-delivery solution to these issues will also be outlined.

Methods: A structured literature search was conducted using PubMed and Institute of Electrical and Electronics Engineers Databases. Search terms included “High-Altitude Pulmonary Edema”, “HAPE”, “Pathophysiology”, “HAPE Treatment”, “Nifedipine”, “Acetazolamide”, ”Amlodipine”, “Pulmonary vasoconstriction”, “Multivesicular Liposome”, “Pressure-Sensitive Multivesicular Liposome”, and “Stimuli-Responsive Drug Delivery.” Eligible sources included scientific reviews, clinical trials, and experimental studies.

Results: HAPE is caused by hypoxic exposures at altitudes above 3,000 m.^1,2 Hypoxia induces  exaggerated sympathetic nervous system activation, leading to hypoxic pulmonary vasoconstriction (HPV) and elevated pulmonary artery mean pressures (>25 mmHg). These conditions contribute to endothelial dysfunction and capillary leakage leading to pulmonary edema.^1,2 Acute treatments include immediate descent, supplemental oxygen, and pharmacological agents such as nifedipine, acetazolamide, and amlodipine.^3,4 However, these approaches are limited by delayed administration, lack of targeted delivery, and logistical challenges in remote environments.

Preclinical studies demonstrate that PS-MVLs loaded with amlodipine can selectively target pulmonary capillaries via pressure-mediated vesicle rupture, enabling site-specific drug release. ^5,6 Their low lipid composition facilitates membrane destabilization under elevated pulmonary pressures, allowing drug release at pressures exceeding 25 mmHg. In hypoxia-induced murine HAPE models, PS-MVL-delivered amlodipine displayed greater respiratory function, arterial oxygenation, and reduced histopathologic lung injury compared to free drug formulations.⁶ Additionally, MVL-delivered-quercetin has shown potential in reducing pulmonary fluid accumulation, supporting broader applicability of this platform.⁷

Conclusion: PS-MVLs represent a promising drug delivery strategy for HAPE. This approach potentially enables an immediate pharmacological response to HAPE and reduces the need for repeated prophylactic drug administration. Further research is needed to evaluate safety, scalability, and efficacy in human populations, as well as to assess long-term effects on pulmonary microcirculation.⁶

Works Cited:

1. Cai C, Ni G, Chen L, et al. Altitude hypoxia and hypoxemia: pathogenesis and management. Signal Transduct Target Ther. 2026;11(1):27. doi:10.1038/s41392-025-02531-1
2. Smedley T, Grocott MP. Acute high-altitude illness: a clinically orientated review. Br J Pain. 2013;7(2):85-94. doi:10.1177/2049463713489539
3. Cappuccio FP, Markandu ND, Singer DR, Crane M, Carney C, MacGregor GA. Double-blind comparison between nifedipine and amlodipine for the treatment of essential hypertension. J Hum Hypertens. 1993;7(4):365-368.
4. Mayer L, Lichtblau M, Furian M, et al. Effect of Acetazolamide on Pulmonary Hemodynamics and Right Heart Function in Healthy Adults Going to Altitude: A Randomized Controlled Trial. J Am Heart Assoc. 2025;14(17):e041941. doi:10.1161/JAHA.125.041941
5. Kauscher U, Holme MN, Björnmalm M, Stevens MM. Physical stimuli-responsive vesicles in drug delivery: Beyond liposomes and polymersomes. Adv Drug Deliv Rev. 2019;138:259-275. doi:10.1016/j.addr.2018.10.012
6. Li H, Liu S, Dai W, et al. Pressure-sensitive multivesicular liposomes as a smart drug-delivery system for high-altitude pulmonary edema. J Controlled Release. 2024;365:301-316. doi:10.1016/j.jconrel.2023.11.039
7. Lin L, Shen B, Cui J, et al. Enhancing Quercetin’s Potential: A Nanoliposome Delivery System for High Altitude Pulmonary Edema. Drug Des Devel Ther. 2025;19:9151-9167. doi:10.2147/DDDT.S509270