Nitric Oxide and Oxygen Delivery Among Tibetans

该项目将研究一种新提出的机制，通过这种机制，人类可以适应极端环境中的生活。 藏人在高海拔地区生活了数千年，并已被证明拥有许多适应西藏高原和喜马拉雅山脉生活的能力。 这项拟议的研究旨在验证这样一种假设：西藏高海拔当地人呼出的高水平一氧化氮是在每次呼吸中氧分子较少的环境中提高功能能力的反应，这种情况称为高海拔缺氧。 基于一氧化氮的已知作用，假设肺部高水平的一氧化氮以两种方式起作用。 首先，它可以通过在吸入的空气中提取更大比例的氧气来抵消高海拔缺氧。 其次，它可以通过增加全身的血液流动来改善氧气输送。 最近发现，高海拔地区的藏族人呼出的一氧化氮是海平面地区的藏族人呼出的一氧化氮的两倍多，这需要解释，因为大量的证据表明，在缺氧条件下，一氧化氮的合成较少，而不是更多。 在西藏和安第斯土著高海拔人群中一致发现高肺一氧化氮，这表明了一种适应性的有益功能。 将用91名生活在海拔4200米（~ 14，000 '）的西藏自治区高海拔地区的土著人样本来检验这些假设。研究受试者将是健康、未怀孕、不吸烟、18-55岁的人。 将测量呼出气体中的一氧化氮浓度，预计将有很大的变化，包括比海平面高两到三倍的值。 将通过测量吸入空气（20.9%）和呼出空气（待测量）中氧百分比的差异来检验氧提取量更大的假设。 将通过定量肺和前臂中的血流量来无创地测试更大血流量的假设。 预期结果是呼出的一氧化氮与氧提取、肺血流量、静息时前臂血流量、运动时前臂血流量和呼吸50%氧气（无缺氧应激）时前臂血流量之间存在正相关。 这些发现表明，西藏高原人使用肺中升高的一氧化氮来抵消高海拔缺氧，并向身体组织提供足够的氧气。 肺一氧化氮似乎是理解人类对高海拔和缺氧适应的核心。 一氧化氮生物学的含义解释了西藏高海拔的本地人如何能够达到海平面值的必要的生物过程，需要氧气，如基础代谢和体力工作能力，虽然他们生活在环境中的氧气是严重有限的相对于海平面的环境。 西藏的病例有助于了解一氧化氮生物学的基本知识，因为健康人产生的一氧化氮量在海平面上被认为是病态的。 拟议中的研究为体质人类学的一个中心问题提供了新的知识：人类生物变异的原因和后果。 这项研究的意义在于提高人们对缺氧生活的适应能力的理解。 它直接调查了为什么居住在高海拔环境中的藏族人口具有非常独特的生物学特征，并且对于理解海平面游客对海拔高度的反应也有影响，无论他们是落基山脉的度假者还是在山区服役的军事人员，以及理解导致缺氧的疾病患者的病理生理学。

This project will investigate a newly proposed mechanism by which humans can adapt to life in an extreme environment. Tibetans have lived at high altitudes for millennia and have been demonstrated to possess a number of adaptations for dealing with life on the Tibetan Plateau and in the Himalayan Mountains. The proposed research is designed to test the hypothesis that the high levels of exhaled nitric oxide produced by Tibetan high-altitude natives are responses that improve functional capacity in their environment where there are fewer oxygen molecules in every breath, a situation called high-altitude hypoxia. Based on the known effects of nitric oxide, it is hypothesized that high levels of nitric oxide in the lungs helps in two ways. First, it may offset the high-altitude hypoxia by enabling the extraction of a larger proportion of the oxygen in the inspired air. Second, it may improve oxygen delivery by increasing blood flow throughout the body. The recent finding that high-altitude native Tibetans exhale more than twice as much nitric oxide as sea-level natives at sea level requires explanation because a large body of evidence predicts less, rather than more, synthesis of nitric oxide under hypoxic conditions. The consistent finding of high pulmonary nitric oxide in both Tibetan and Andean indigenous high-altitude populations suggests an adaptive, beneficial function. The hypotheses will be tested with a sample of 91 high-altitude natives of the Tibet Autonomous Region living at 4200m (~ 14,000') altitude. The study participants will be healthy, not pregnant, non-smokers, 18-55 years of age. The concentration of nitric oxide in exhaled breath will be measured and it is expected that there will be a wide range of variation including values two to three times higher than those found at sea level. The hypothesis of greater oxygen extraction will be tested by measuring the difference in the percent of oxygen in inspired air (20.9%) and exhaled air (to be measured). The hypothesis of greater blood flow will be tested noninvasively by quantifying blood flow in the lungs and in the forearm. The anticipated outcome is a positive association between exhaled nitric oxide and oxygen extraction, pulmonary blood flow, forearm blood flow at rest and in response to exercise and in response to breathing 50% oxygen (without the stress of hypoxia). These findings would indicate that Tibetan highlanders use elevated nitric oxide in the lungs to offset high-altitude hypoxia and to deliver adequate oxygen to body tissues. Pulmonary nitric oxide appears central to understanding human adaptation to high altitude and hypoxia. Nitric oxide biology has implications for explaining how Tibetan high-altitude natives can achieve sea-level values for necessary biological processes that require oxygen, such as basal metabolism and physical work capacity, although they live in an environment where ambient oxygen is severely limited relative to sea level. The Tibetan case contributes to basic knowledge of nitric oxide biology because healthy people produce amounts that would be considered pathological at sea level. The proposed research contributes new knowledge to a central question in physical anthropology: the causes and consequences of human biological variation. The significance of the proposed research lies in improving understanding of how people adjust to life with hypoxia. It directly investigates why the Tibetan population inhabiting a stressful, high-altitude environment has very distinctive biological features and also has implications for understanding the responses of sea-level visitors to altitude whether they are vacationers in the Rockies or military personnel serving in mountainous areas, and for understanding the pathophysiology of patients with diseases that cause hypoxia .