Pathophysiological significance of peroxidative stress, neuronal damage, and membrane permeability in acute mountain sickness

1 Department of Physiology, Hypoxia Research Unit, University of Glamorgan, Pontypridd, South Wales, United Kingdom; 2 Departments of Medicine and Radiology, University of Bern, CH-3010 Bern, Switzerland; 3 Clinic for Neurological Rehabilitation Schildautal, D-38723 Seesen, Germany; 4 Department of Medicine, Kantonsspital, Winterthur, Switzerland; and 5 Department of Sports Medicine, University of Heidelberg, D-69115 Heidelberg, Germany Submitted 8 July 2003 ; accepted in final form 27 October 2003 Free radical-mediated changes in vascular permeability and subsequent inflammatory response may be a contributory pathogenetic cofactor responsible for the development of neurological sequelae associated with acute mountain sickness (AMS). To investigate this, 49 subjects were examined at sea level and serially after rapid ascent to 4,559 m. Although the venous concentration of total creatine phosphokinase activity was measured in all subjects, a complementary examination of lipid peroxidation (F 2 -isoprostanes), inflammatory (TNF- , IL-1 , IL-2, IL-6, IL-8, C-reactive protein), and cerebrovascular tissue damage (neuron-specific enolase) biomarkers was confined to a subcohort of 24 subjects. A selective increase ( P < 0.05) in total creatine phosphokinase was observed in subjects diagnosed with AMS at high altitude ( n = 25) compared with apparently healthy controls ( n = 24). However, despite a marked increase in IL-6 and C-reactive protein attributable primarily to subjects developing high-altitude pulmonary edema, subcohort analyses demonstrated no selective differences in F 2 -isoprostanes, neuron-specific enolase, or remaining proinflammatory cytokines due to AMS ( n = 14). The present findings are the first to demonstrate that free radical-mediated neuronal damage of sufficient degree to be detected in the peripheral circulation does not occur and is, therefore, unlikely to be an important, initiating event that is critical for the development of AMS. The pathophysiological significance of increased sarcolemmal membrane permeability and inflammatory response, either as a cause or epiphenomenon of AMS and/or high-altitude pulmonary edema, remains to be elucidated. free radicals; skeletal tissue damage; inflammation; neurological symptoms Address for reprint requests and other correspondence: D. M. Bailey, Reader in Physiology, Hypoxia Research Unit, Dept. of Physiology, School of Applied Sciences, Univ. of Glamorgan, South Wales, UK CF37 1DL (E-mail: dbail