Robert S. Mazzeo’s research while affiliated with University of Colorado Boulder and other places

The human immune system is a complex network of molecular, cellular, and genetic components designed to provide defense against foreign organisms and substances. It is a highly regulated system that is sensitive to a number of extrinsic factors including environmental stress (e.g., heat, cold, microgravity, and hypoxia). The impact that any stressor is likely to have on immune function is dependent on whether the stress is acute or chronic, the severity of the stress, and the individual’s current physiological and emotional state. While the effects of hypoxia on the immune system are evident at almost all levels and so will have potential impact on infectious risks and outcomes, high altitude and hypoxia also affect certain pathogens and their vectors to alter human health at high altitude. We will review how hypoxia affects the innate and adaptive immune systems both positively and negatively, and the central role of hypoxia inducible factor(s) (HIF) in these changes, how the central nervous system (CNS) contributes particularly to the adaptive immune responses at high altitude, and how these responses affect aspects of defense against pathogens, vaccine effectiveness, and immunosurveillance of cancer.

Studies performed over the past decade have yielded new information related to the physiological and metabolic adjustments made in response to both short- and long-term high-altitude exposure. These investigations have examined the potential mechanisms responsible for the alterations observed in such key variables as heart rate, stroke volume, cardiac output, muscle blood flow, substrate utilization and mitochondrial function, both at rest and during exercise of varying intensities. Additionally, the occurrence and mechanisms related to the 'lactate paradox' continues to intrigue investigators. It is apparent that exposure to high altitude is an environmental stressor that elicits a robust sympathoadrenal response that contributes to many of the critical adjustments and adaptations mentioned above. Furthermore, as some of these important physiological adaptations are known to enhance performance, it has become popular to incorporate an aspect of altitude living/training into the training regimens of endurance athletes (e.g. 'live high-train low'). Finally, it is important to note that many factors influence the extent to which individuals adjust and adapt to the stress imposed by exposure to high altitude. Included among these are (i) the degree of hypoxia; (ii) the duration of exposure to hypoxic conditions; (iii) the exercise intensity (absolute vs relative workload); and (iv) the inter-individual variability in adapting to hypoxic environments ('responders' vs 'non-responders').

For more than 60 years, muscle mechanical efficiency has been thought to remain unchanged with acclimatization to high altitude. However, recent work has suggested that muscle mechanical efficiency may in fact be improved upon return from prolonged exposure to high altitude. The purpose of the present work is to resolve this apparent conflict in the literature. In a collaboration between four research centers, we have included data from independent high-altitude studies performed at varying altitudes and including a total of 153 subjects ranging from sea-level (SL) residents to high-altitude natives, and from sedentary to world-class athletes. In study A (n=109), living for 20-22 h/day at 2500 m combined with training between 1250 and 2800 m caused no differences in running economy at fixed speeds despite low typical error measurements. In study B, SL residents (n=8) sojourning for 8 weeks at 4100 m and residents native to this altitude (n=7) performed cycle ergometer exercise in ambient air and in acute normoxia. Muscle oxygen uptake and mechanical efficiency were unchanged between SL and acclimatization and between the two groups. In study C (n=20), during 21 days of exposure to 4300 m altitude, no changes in systemic or leg VO(2) were found during cycle ergometer exercise. However, at the substantially higher altitude of 5260 m decreases in submaximal VO(2) were found in nine subjects with acute hypoxic exposure, as well as after 9 weeks of acclimatization. As VO(2) was already reduced in acute hypoxia this suggests, at least in this condition, that the reduction is not related to anatomical or physiological adaptations to high altitude but to oxygen lack because of severe hypoxia altering substrate utilization. In conclusion, results from several, independent investigations indicate that exercise economy remains unchanged after acclimatization to high altitude.

The following letters are in response to the Point:Counterpoint “The lactate paradox does/does not occur during exercise at high altitude” that appears in this issue. To the Editor : I found the argument put forth by Van Hall ([5][1]) to contain a number of inaccurate and misleading statements

High-altitude anorexia leads to a hormonal response pattern modulated by both hypoxia and caloric restriction (CR). The purpose of this study was to compare altitude-induced neuroendocrine changes with or without energy imbalance and to explore how energy sufficiency alters the endocrine acclimatization process. Twenty-six normal-weight, young men were studied for 3 wk. One group [hypocaloric group (HYPO), n = 9] stayed at sea level and consumed 40% fewer calories than required to maintain body weight. Two other groups were deployed to 4,300 meters (Pikes Peak, CO), where one group (ADQ, n = 7) was adequately fed to maintain body weight and the other [deficient group (DEF), n = 10] had calories restricted as above. HYPO experienced a typical CR-induced reduction in many hormones such as insulin, testosterone, and leptin. At altitude, fasting glucose, insulin, and epinephrine exhibited a muted rise in DEF compared with ADQ. Free thyroxine, thyroid-stimulating hormone, and norepinephrine showed similar patterns between the two altitude groups. Morning cortisol initially rose higher in DEF than ADQ at 4,300 meters, but the difference disappeared by day 5. Testosterone increased in both altitude groups acutely but declined over time in DEF only. Adiponectin and leptin did not change significantly from sea level baseline values in either altitude group regardless of energy intake. These data suggest that hypoxia tends to increase blood hormone concentrations, but anorexia suppresses elements of the endocrine response. Such suppression results in the preservation of energy stores but may sacrifice the facilitation of oxygen delivery and the use of oxygen-efficient fuels.

Contraction-induced injury occurs when a muscle is stretched while activated (lengthening contraction). Exposure to a bout of lengthening contractions results in protection from subsequent lengthening contraction-induced injury as well as an elevation in phosphorylated Akt and p70S6K. Whether Akt or p70S6K is involved in the protection from contraction-induced injury is unclear. To test for a specific role of Akt and/or p70S6K to induce protective adaptations, we used a conditioning protocol of passive stretches that reduces contraction-induced injury with minimal involvement of other cellular responses that have been associated with the Akt signaling pathway, such as increased metabolism, cell growth, and cell death. To determine whether activation of Akt or p70S6K is necessary to induce protective adaptations. Extensor digitorum longus muscles of anesthetized mice were administered 75 lengthening contractions in situ with or without previous exposure to 75 passive stretches 1 h, 24 h, 3 d, or 14 d prior to lengthening contractions. Compared with unconditioned muscles, the deficit in isometric force and number of injured fibers 3 d following lengthening contractions were smaller by half for passive-stretch-conditioned muscles from all time points. Phosphorylation of Akt and p70S6K were analyzed by Western blot 0 or 3 h following either lengthening contractions or passive stretches. Whereas lengthening contractions increased phosphorylation of Akt at 0 h and p70S6K at 3 h, passive stretches did not at any time increase phosphorylation of Akt or p70S6K despite reducing contraction-induced injury. Activation of neither Akt nor p70S6K is necessary to induce adaptations that reduce the severity of contraction-induced injury.

This study tested the hypothesis that antioxidant supplementation would attenuate plasma cytokine (IL-6, tumor necrosis factor (TNF)-alpha), and C-reactive protein (CRP) concentrations at rest and in response to exercise at 4300-m elevation. A total of 17 recreationally trained men were matched and assigned to an antioxidant (N = 9) or placebo (N = 8) group in a double-blinded fashion. At sea level (SL), energy expenditure was controlled and subjects were weight stable. Then, 3 wk before and throughout high altitude (HA), an antioxidant supplement (10,000 IU beta-carotene, 200 IU alpha-tocopherol acetate, 250 mg ascorbic acid, 50 microg selenium, 15 mg zinc) or placebo was given twice daily. At HA, energy expenditure increased approximately 750 kcal.d(-1) and energy intake decreased approximately 550 kcal.d, resulting in a caloric deficit of approximately 1200-1500 kcal.d(-1). At SL and HA day 1 (HA1) and day HA13, subjects exercised at 55% of VO2peak until they expended approximately 1500 kcal. Blood samples were taken at rest, end of exercise, and 2, 4, and 20 h after exercise. No differences were seen between groups in plasma IL-6, CRP, or TNF-alpha at rest or in response to exercise. For both groups, plasma IL-6 concentration was significantly higher at the end of exercise, 2, 4, and 20 h after exercise at HA1 compared with SL and HA13. Plasma CRP concentration was significantly elevated 20 h postexercise for both groups on HA1 compared to SL and HA13. TNF-alpha did not differ at rest or in response to exercise. Plasma IL-6 and CRP concentrations were elevated following exercise at high altitude on day 1, and antioxidant supplementation did not attenuate the rise in plasma IL-6 and CRP concentrations associated with hypoxia, exercise, and caloric deficit.

Purpose: This study tested the hypothesis that antioxidant supplementation would attenuate plasma cytokine (IL-6, tumor necrosis factor (TNF)-α), and C-reactive protein (CRP) concentrations at rest and in response to exercise at 4300-m elevation. Methods: A total of 17 recreationally trained men were matched and assigned to an antioxidant (N = 9) or placebo (N = 8) group in a double-blinded fashion. At sea level (SL), energy expenditure was controlled and subjects were weight stable. Then, 3 wk before and throughout high altitude (HA), an antioxidant supplement (10,000 IU β-carotene, 200 IU α-tocopherol acetate, 250 mg ascorbic acid, 50 2g selenium, 15 mg zinc) or placebo was given twice daily. At HA, energy expenditure increased approximately 750 kcald-1 and energy intake decreased approximately 550 kcald-1, resulting in a caloric deficit of approximately 1200–1500 kcald-1. At SL and HA day 1 (HA1) and day HA13, subjects exercised at 55% of VO2peak until they expended approximately 1500 kcal. Blood samples were taken at rest, end of exercise, and 2, 4, and 20 h after exercise. Results: No differences were seen between groups in plasma IL-6, CRP, or TNF-! at rest or in response to exercise. For both groups, plasma IL-6 concentration was significantly higher at the end of exercise, 2, 4, and 20 h after exercise at HA1 compared with SL and HA13. Plasma CRP concentration was significantly elevated 20 h postexercise for both groups on HA1 compared to SL and HA13. TNF-α did not differ at rest or in response to exercise. Conclusion: Plasma IL-6 and CRP concentrations were elevated following exercise at high altitude on day 1, and antioxidant supplementation did not attenuate the rise in plasma IL-6 and CRP concentrations associated with hypoxia, exercise, and caloric deficit.

Little is known with regard to how acute and chronic high altitude exposure effects immune function. Hypoxia is an environmental stressor that is known to elicit alterations in both the autonomic nervous system and endocrine function. Alterations in these systems can have an immediate as well as a longer lasting impact on immune function. Studies from the summit of Pikes Peak (4300 m) have indicated a strong alpha- & beta-adrenergic component in the regulation of immune function at altitude that can persist weeks after initial exposure. Specifically, interleukin (IL)-6 is elevated with acute altitude exposure primarily mediated via beta-adrenergic stimulation and remains elevated for several weeks as a result of alpha-adrenergic activation. When the added stress of physical exercise is combined with that of hypoxia, a more pronounced impact on immune function is observed compared to that of either exercise or hypoxia alone. A popular training paradigm currently employed by endurance athletes to enhance performance involves living at high altitude while training at low altitude. The concept entails incorporating the physiologic and metabolic adaptations associated with chronic high altitude exposure (increase in RBC, mitochondrial oxidative capacity, capillary density, etc) while training at a lower altitude allowing for the maintenance of a high absolute training intensity. Others have demonstrated that a short-term application (18 days) of the live high-train low paradigm results in suppression of the mucosal immune system as indicated by a cumulative decline in salivary IgA levels. Taken together, the majority of evidence suggests a potential additive effect of combined hypoxia and exercise in transiently suppressing immune function, at least in the short-term. Implications for the athletes and training are addressed.