Excercise induced rise in Severity of Altitude Illness

描述(申请者摘要)：数百篇关于急性高山的研究 疾病(AMS)在过去的两个世纪里检验了 呼吸、肺气体交换和液体平衡，但病理生理学 AMS的问题在很大程度上仍未解决。AMS会招致巨大的医疗风险和成本 因为多达5%的病例会发展成危及生命的高海拔 脑水肿(HACE)。AMS本身就是一个严重的公共卫生问题， 在高海拔地区的游客中患病率为15%-65%。这项提案将重点放在 关于脑肿胀的作用，这可能包括脑水和血液的升高 体积，在AMS的病理生理学。该提案使用练习作为一种工具来 比休息时更早出现更严重的AMS症状 研究对象。我们的方法与传统范式背道而驰，许多人遵循 在这一领域，我们正在寻找AMS的病理生理学线索 观察外周反应(肺、肾、血管)。我们的理论基础 对于脑肿胀的关注是：a)AMS的症状主要是 神经学；b)HACE，被认为是严重AMS的终末期，最近 被确认为血管源性水肿，为 AMS的血脑屏障(BBB)通透性；c)新的非侵入性技术 使测量脑水和血容量成为可能；以及d)可用 实验证据和理论论证支持了 脑肿胀在AMS的病理生理学中的作用我们最近展示了这项运动 导致AMS症状严重程度增加3倍以上，动脉血流量下降 运动时的血氧饱和度(SaO2)和轻微的液体滞留。我们也 最近的研究表明，患有AMS的受试者的血浆容量略有下降 与保持游离状态的细胞外水分相比，细胞外水分大幅上升 AMS。在进一步的研究中，磁共振成像显示大多数大脑 当人类上升到高海拔时会膨胀。我们的总体假设是大脑 肿胀导致AMS的症状。我们的方法是应用几个新的和 解决AMS病理生理学问题的创新技术。这些措施包括 测量和操作脑血容量的非侵入性技术， 颅内压、血脑屏障开度、脑脊液容量和选择 AMS患者对低氧的细胞、分子和遗传反应。 我们的三个具体目标是：1)确定脑含水量升高在 2)确定血脑屏障通透性在AMS中的作用； 3)确定选定的细胞、分子和遗传因素的作用 在AMS中。拟议研究的结果将增加我们对 在其他情况下，大脑、脑水分和脑肿胀的作用， 既有与氧气恶化有关的，也有初级的 侮辱是对大脑的伤害。

DESCRIPTION (Applicant's abstract): Many hundreds of studies of acute mountain sickness (AMS) over the past two centuries have examined the role of ventilation, pulmonary gas exchange and fluid balance, yet the pathophysiology of AMS remains largely unsolved. AMS incurs significant medical risks and costs since as many as 5 percent of cases can develop life-threatening high altitude cerebral edema (HACE). AMS itself is a substantial public health problem with a prevalence of 15-65 percent in visitors to high altitude. This proposal focuses on the role of brain swelling, which can include elevated brain water and blood volume, in the pathophysiology of AMS. This proposal uses exercise as a tool to develop more severe symptoms of AMS sooner than would be the case in resting subjects. Our approach departs from the traditional paradigm, followed by many of us in this field, of searching for clues to the pathophysiology of AMS in the observed peripheral responses (pulmonary, renal, vascular). Our rationale for focusing on brain swelling is that a) the symptoms of AMS are largely neurological; b) HACE, considered the end-stage of severe AMS, has recently been identified as a vasogenic edema, opening the door for a role for blood-brain barrier (BBB) permeability in AMS; c) new, noninvasive techniques make measurement of brain water and blood volume possible; and d) available experimental evidence and theoretical arguments support a significant role for brain swelling in the pathophysiology of AMS. We recently showed that exercise caused a more than 3 fold rise in AMS symptom severity, a drop in arterial oxygen saturation (SaO2) during exercise, and slight fluid retention. We also recently showed that subjects ill with AMS had a small drop in plasma volume and a large rise in extracellular water compared to those that remained free of AMS. In further studies, magnetic resonance imaging revealed that most brains swell when humans ascend to high altitude. Our overall hypothesis is that brain swelling causes the symptoms of AMS. Our approach is to apply several new and innovative technologies to solving the pathophysiology of AMS. These include noninvasive techniques to measure and manipulate cerebral blood volume, intracranial pressure, BBB opening, cerebrospinal volumes and selected cellular, molecular and genetic responses to hypoxia in people developing AMS. Our three specific aims are 1) to determine the role of elevated brain water in brain swelling and AMS; 2) to determine the role of BBB permeability in AMS; and 3) to determine the role of select cellular, molecular and genetic factors in AMS. The results from the proposed studies will increase our understanding of the role of the brain, brain water and brain swelling in other conditions, both those associated with oxygen depravation, and those where the primary insult is to the brain.