Novel therapeutic approaches to hypoxemia and tissue hypoxia

Abstract

Hypoxemia and tissue hypoxia represent central pathophysiological challenges in conditions ranging from high-altitude exposure and pulmonary hypertension to the progression of solid tumors. This habilitation thesis summarizes experimental and translational research aimed at identifying novel therapeutic strategies to restore tissue oxygenation, alleviate microvascular dysregulation, and enhance therapeutic delivery to diffusion-limited tissues. Using rodent models of simulated hypoxia, pharmacological interventions targeting the endothelin pathways, in combination with sympathomimetic or hypertensive agents and targeting of adenosine signaling, were shown to restore exercise capacity independent of blood oxygen content. Clinical pilot studies demonstrated safety and efficacy of drug combinations such as aminophylline with ambrisentan, and theophylline and bambuterol, suggesting translational potential for high-altitude illness and chronic hypoxemic disease. In parallel, intravital microscopy techniques were developed to image and quantify microcirculatory blood flow in the lung and solid tumors, providing unprecedented insights into hypoxia-driven vascular remodeling and perfusion heterogeneity. Investigations into tumor metabolism revealed lactate consumption as a key survival mechanism in hypoxic cancer cells, supporting the “metabolic symbiont” model and offering new avenues for targeting lactate catabolism. Together, these findings highlight that hypoxemia-induced functional impairment is driven less by absolute oxygen shortage than by microvascular and metabolic barriers to oxygen and drug delivery. The work advocates pleiotropic cardiovascular treatments and pro-vascular strategies to improve both systemic oxygen utilization and anticancer therapy. Future directions include optimizing combination drug regimens, refining imaging methodologies, and developing agents that selectively target hypoxic, therapy-resistant tumor fractions.