Oxidative stress during high altitude expedition and its influence on vessel tone-modifying mediators

Hypoxia-induced excessive pulmonary vasoconstriction is assumed to be the main cause of life-threatening high altitude pulmonary edema. Decrease of nitric oxide (NO), a potent vasodilator, has been suggested to play a significant role in hypoxia-induced vasoconstriction. To study alterations of prolonged hypobaric hypoxia, serum samples were drawn from 34 healthy mountaineers up to 6865 m during a Swiss research expedition to mount Muztagh Ata (7549 m) in Western China. Comprehensive metabolomics analysis using a mass spectrometry-based targeted aproach revealed a pronounced systemic oxidative stress during high altitude exposure. Detecting more than 390 parameters, a significant increase of lipid peroxidation was shown. Methionine sulfoxid, determined in relation to methionine, furthermore serves as a robust indicator of oxidative stress and showed highly increased values of 30% (mean at 5500m), compared to values of 20% in septic patients. We also found relevant functional impairment of phenylalanine hydroxylase and nitric oxide synthase (NOS), enzymes which both require an oxidation-sensitive co-factor. Consequently, very low levels of NO were found. In addition, significant increase in the serum concentration of vessel tone modifiers such as leukotrienes and prostaglandins were found. This novel and holistic approach extends the mechanistic understanding of hypoxia-related oxidative damage to a biochemical level and unravels underlying biochemical pathways involved in hypoxia-induced pulmonary vasoconstriction. Together, we demonstrate further insight into the molecular pathogenesis of hypoxia-related disorders.