The effects of a competitive neutrophil elastase (NE) inhibitor, ONO-5046, and a recombinant human superoxide dismutase on leukotriene B4 (LTB4)-induced polymorphonuclear leukocyte (PMN)-mediated increase in microvascular permeability in isolated non-blood-perfused rabbit lungs were studied. Pulmonary microvascular permeability and lung edema were evaluated by use of the fluid filtration coefficient (Kf) and the wet-to-dry lung weight ratio (W/D), respectively. Pulmonary capillary pressure was estimated by the double occlusion technique. NE activity in the perfusate was determined using a spectrophotometric method. The PMNs (2-3 x 10(8) cells) were added into the perfusate in all groups of lungs. Injection of LTB4 (5 micrograms) increased Kf and W/D without affecting pulmonary arterial or capillary pressure. The LTB4-induced lung injury was closely associated with the increase in NE activity in the perfusate. Infusion of ONO-5046 (1 or 10 mg.kg-1 x h-1) inhibited the LTB4-induced increases in Kf, W/D, and perfusate NE activity in a dose-dependent fashion. Infusion of recombinant human superoxide dismutase (80,000 U.kg-1 x h-1) attenuated the LTB4-induced increases in Kf and W/D, although it did not influence the elevation of perfusate NE activity induced by LTB4. These results suggest that both NE and superoxide anion play important roles in the LTB4-induced PMN-mediated increase in pulmonary microvascular permeability.

Yoshimura. Exercise performance of Tibetan and Han adolescents at altitudes of 3,417 and 4,300 m. J. Appl. Physiol. 83(2): 661-667, 1997.-The difference was studied between O 2 transport in lifelong Tibetan adolescents and in newcomer Han adolescents acclimatized to high altitude. We measured minute ventilation, maximal O 2 uptake, maximal cardiac output, and arterial O 2 saturation during maximal exercise, using the incremental exercise technique, at altitudes of 3,417 and 4,300 m. The groups were well matched for age, height, and nutritional status. The Tibetans had been living at the altitudes for a longer period than the Hans (14.5 6 0.2 vs. 7.8 6 0.8 yr at 3,417 m, P , 0.01; and 14.7 6 0.3 vs. 5.3 6 0.7 yr at 4,300 m, P , 0.01, respectively). At rest, Tibetans had significantly greater vital capacity and maximal voluntary ventilation than the Hans at both altitudes. At maximal exercise, Tibetans compared with Hans had higher maximal O 2 uptake (42.2 6 1.7 vs. 36.7 6 1.2 ml · min 21 ·kg 21 at 3,417 m, P , 0.01; and 36.8 6 1.9 vs. 30.0 6 1.4 ml · min 21 ·kg 21 at 4,300 m, P , 0.01, respectively) and greater maximal cardiac output (12.8 6 0.3 vs. 11.4 6 0.2 l/min at 3,417 m, P , 0.01; 11.5 6 0.5 vs. 10.0 6 0.5 l/min at 4,300 m, P , 0.05, respectively). Although the differences in arterial O 2 saturation between Tibetans and Hans were not significant at rest and during mild exercise, the differences became greater with increases in exercise workload at both altitudes. We concluded that exposure to high altitude from birth to adolescence resulted in an efficient O 2 transport and a greater aerobic exercise performance that may reflect a successful adaptation to life at high altitude. cardiac output; maximal oxygen consumption; ventilation; developmental adaptation; genetic adaptation MAXIMAL O 2 UPTAKE (V O 2 max ), an integrated index of the overall functional capacity of the O 2 transport system, invariably decreases with altitude during both acute and chronic exposure to high altitude in lowland adults (31,34). This is due to the reduction of ambient O 2 pressure at high altitude. Although comparative studies of V O 2 max between high altitude natives and lowland residents at high-altitude have been done, the conclusions are controversial (10-13, 30). High-altitude adult natives in either Andean or Himalayan populations have higher exercise performance and maintain better arterial O 2 saturation (Sa O 2 ) during exercise compared with newcomers (17,20,30,38). These characteristics, which are associated with more efficient pulmonary gas exchange (38) and better adaptation to high-altitude stress, are acquired through many generations of lifelong high-altitude exposure. The Tibetans are believed to have lived at high altitude longer than other highaltitude residents. The effects of high-altitude hypoxia on the physiological responses of Tibetan and Han adolescents to exercise have never been reported. Whether the pulmonary adaptations in humans are determined purely by environment or relate to genetic character...

To examine the hypothesis that the pathway of adaptation to high altitude in natives differs considerably from that in newcomers, we measured maximal O2 uptake (VO2max), minute ventilation, anaerobic threshold (AT), blood lactate, and blood gases during maximal exercise in 17 lifelong Tibetan residents and 14 acclimatized Han Chinese newcomers living at the altitude of 4,700 m. The two groups were similar in age, height, and weight, and the subjects were nonathletes. Although VO2max was significantly lower in the Tibetans than in the Hans (30.4 +/- 1.5 vs. 36.0 +/- 1.9 ml.min-1.kg-1 STPD; P < 0.05), at maximal exercise effort the exercise workload was greater (167.7 +/- 4.2 vs. 150.0 +/- 5.9 W; P < 0.05). The mean AT values (in % VO2max) in the Tibetan and Han subjects were 84.1 and 61.6%, respectively (P < 0.01). Minute ventilation at maximal exercise was significantly lower in the Tibetans than in the Hans (68.4 +/- 3.4 vs. 79.7 +/- 4.1 l/min BTPS; P < 0.05), whereas heart rate at maximal effort was equivalent in the two groups. The Tibetans showed lower blood lactate value than did the Hans both before and at the end of exercise. We conclude that the Tibetan natives have higher exercise performance and AT but lower VO2max and blood lactate concentration than do acclimatized Han newcomers. These results may reflect the effects of genetic or peripheral adaptation factors in the Tibetan natives.

Cerebral edema occurs in fatal cases of acute mountain sickness. Dexamethasone, commonly used to treat cerebral edema due to other causes, also reduces the symptoms of acute mountain sickness when given prophylactically. However, the efficacy of dexamethasone in the treatment of established acute mountain sickness remains uncertain. To investigate this question, we exposed six men in a hypobaric chamber to a simulated altitude of 3700 m (barometric pressure, 64 kPa [481 mm Hg]) for 48 hours on two occasions. Acute mountain sickness was diagnosed with use of a symptoms questionnaire, and dexamethasone (4 mg every six hours) or placebo was then given in a randomized, double-blind, crossover fashion. Dexamethasone reduced the symptoms of acute mountain sickness by 63 percent (P less than 0.05), whereas placebo had a minimal effect (reduction by 23 percent; P not significant). In spite of this response, one subject had mild cerebral edema on brain CT after both placebo and dexamethasone. Dexamethasone had no effect on fluid shifts, oxygenation, sleep apnea, urinary catecholamine levels, the appearance of chest radiographs or perfusion scans, serum electrolyte levels, hematologic profiles, or the results of psychometric tests. Dexamethasone treatment was complicated by mild hyperglycemia in all subjects (mean [+/- SE] glucose level, 7.3 +/- 1.3 mmol per liter [132 +/- 23 mg per deciliter]). We conclude that dexamethasone effectively reduces the symptoms of acute mountain sickness. However, it did not improve objective physiologic abnormalities related to exposure to high altitudes. We therefore recommend that dexamethasone be used only when descent is impossible, or to facilitate cooperation in evacuation efforts.

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