Excercise induced rise in Severity of Altitude Illness

运动导致高原病严重程度上升

• 批准号: 6603945
• 负责人: ROBERT C ROACH
• 金额: $ 2.47万
• 依托单位: NEW MEXICO RESONANCE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-10 至 2003-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603945
• 关键词: altitude; blood brain barrier; brain edema; cerebral ischemia /hypoxia; cerebrospinal fluid; clinical research; dysbarism; exercise; human subject; membrane permeability; neurogenetics

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.

描述（申请人摘要）：数百项关于急性山 在过去的两个世纪里，疾病（AMS）已经研究了 通气，肺气体交换和液体平衡，但病理生理学 AMS在很大程度上仍未解决。医疗辅助队会带来重大的医疗风险和成本 因为多达5%的病例可能发展为危及生命的高海拔 脑水肿（HACE）。AMS本身是一个重大的公共卫生问题， 在高海拔地区的游客中患病率为15- 65%。该提案重点 对脑肿胀的作用，其中可包括脑水和血的升高 卷，在AMS的病理生理学。该提案将锻炼作为一种工具， 与休息时相比，更早出现更严重的AMS症状 科目我们的方法不同于传统的模式， 我们在这一领域，寻找线索的病理生理学的AMS， 观察到的外周反应（肺、肾、血管）。我们的理据 关注脑肿胀的原因是a）AMS的症状主要是 B）HACE，被认为是严重AMS的终末期，最近 被确定为血管源性水肿，打开了一扇大门， AMS的血脑屏障（BBB）通透性; c）新的非侵入性技术 使脑水和血容量的测量成为可能;以及d）可用 实验证据和理论论据支持了一个重要的作用， 脑肿胀在AMS的病理生理学。我们最近发现， 导致AMS症状严重程度增加3倍以上，动脉粥样硬化指数下降， 运动时的血氧饱和度（SaO 2）和轻微的液体潴留。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， 与那些没有水的细胞相比， AMS。在进一步的研究中，磁共振成像显示， 当人类上升到高海拔时会膨胀我们的总体假设是 肿胀导致AMS的症状。我们的方法是应用几个新的和 解决AMS病理生理学的创新技术。这些包括 测量和操纵脑血容量的非侵入性技术， 颅内压、血脑屏障开放度、脑脊液容量和选择的 细胞，分子和遗传反应缺氧的人发展AMS。 我们的三个具体目标是：1）确定脑水升高的作用， 2）探讨血脑屏障通透性在AMS中的作用; 和3）确定选择的细胞、分子和遗传因素的作用 在AMS。拟议研究的结果将增加我们对 的作用，脑水和脑肿胀在其他条件下， 这两种情况都与氧气恶化有关， 这是对大脑的侮辱。