PULMONARY EPITHELIAL EFFECTS OF HYPOXIA

缺氧对肺上皮的影响

• 批准号: 7607658
• 负责人: NAUSHERWAN K BURKI
• 金额: $ 0.17万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7607658
• 关键词: Acute; Affect; Altitude; Altitude Sickness; Alveolar; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Blood Vessels; Blood-Air Barrier; Breathing; Bronchoalveolar Lavage Fluid; Carbon Dioxide; Cell physiology; Clara cell; Clinical; Computer Retrieval of Information on Scientific Projects Database; Data; Endothelial Cells; Epithelial; Epithelium; Excision; Exposure to; Funding; Grant; Hypoxia; Immune; In Vitro; Institution; Invasive; Liquid substance; Lung; Mechanics; Ozone; Personal Satisfaction; Proteins; Pulmonary Circulation; Pulmonary Edema; Research; Research Personnel; Resources; Sea; Source; Stimulus; Syndrome; United States National Institutes of Health; Vascular Endothelium; alveolar epithelium; human study; human subject; interstitial; man; pulmonary function; relating to nervous system

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Increasing evidence from in vitro animal studies suggests that hypoxia has direct cellular effects on the alveolar epithelium and the alveolocapillary membrane (1). Indirect evidence indicates that this is also likely to be true in man, but there are few studies examining this. The alveolar epithelium and pulmonary vascular endothelium perform crucial functions critical to the overall integrity of the lung, including transfer of fluid and proteins between the alveolar lumen and the interstitial and intravascular spaces, mechanical stability of the lungs, and immune and anti-inflammatory functions. In man, hypoxia-induced damage to some or all of these pulmonary functions can be inferred from some clinical syndromes, such as high altitude pulmonary edema (HAPE), but the mechanism(s) of these actions of hypoxia are unclear (2). It is well established that removal of the hypoxic stimulus relieves acute mountain sickness (3), and recent data indicate an additive effect of supplemental inhaled CO2 with the oxygenation (4). The majority of studies on hypoxia in man have focused on ventilatory neural regulatory mechanisms (5,6,7,8,9) and autonomic nervous control of the pulmonary circulation (2); studies of possible mechanisms of hypoxia-induced lung damage in man have, of necessity been invasive, such as analysis of bronchoalveolar lavage fluid, which itself may alter the milieu being studied (10) and invasive vascular studies (11). There have been no studies specifically evaluating the effects of hypoxia on the pulmonary epithelium in man, partly because until recently there were no available, generally accepted circulating biomarkers of pulmonary epithelial function. Clara cell protein (CC16) is expressed in pulmonary Clara cells and has been shown in animal (12) and human studies (13) to be a sensitive marker of pulmonary epithelial function. Circulating levels of CC16 are altered on exposure to ozone or other noxious stimuli (14, 15). In order to investigate the effects of hypoxia, we performed studies on circulating markers of pulmonary epithelial and endothelial function in normal subjects exposed to hypoxia at sea level and identified changes in circulating levels of these markers. Our hypothesis is that exposure to hypoxia in normal human subjects directly affects pulmonary epithelial and endothelial cell function; in its severe form this may be manifested as pulmonary edema. This effect of hypoxia may be modified by mucosal acidification as would occur with an increase in alveolar CO2.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 来自体外动物研究的越来越多的证据表明，缺氧对肺泡上皮和肺泡毛细血管膜的细胞影响直接影响（1）。 间接证据表明，这在人类中也可能是正确的，但是很少有研究对此进行研究。肺泡上皮和肺血管内皮表现至至关重要的功能，对肺的整体完整性至关重要，包括液体和蛋白质的转移和肺泡腔之间的转移以及肺部和血管内空间之间，肺的机械稳定性，肺的机械稳定性，以及免疫和抗炎功能。在人中，可以从某些临床综合征（例如高海拔肺水肿（HAPE））推断出缺氧引起的某些或所有这些肺功能的损害，但是缺氧这些作用的机制尚不清楚（2）。众所周知，去除低氧刺激可以缓解急性山脉疾病（3），并且最近的数据表明补充吸入的CO2具有氧合作用（4）。 大多数关于人类缺氧的研究集中在通气神经调节机制（5,6,7,8,9）和肺循环的自主神经神经控制上（2）；对缺氧引起的人类肺损伤的可能机制的研究是侵入性的，例如对支气管肺泡灌洗液的分析，这本身可能会改变所研究的环境（10）和侵入性血管研究（11）。尚无专门评估缺氧对人肺上皮的影响的研究，部分原因是直到最近，还没有可用的，普遍接受的肺上皮功能的循环生物标志物。克拉拉细胞蛋白（CC16）在肺克拉拉细胞中表达，并在动物（12）和人类研究（13）中表现为肺上皮功能的敏感标记。 CC16的循环水平随着臭氧或其他有害刺激而改变（14，15）。 为了研究缺氧的影响，我们对暴露于海平面缺氧的正常受试者的肺上皮和内皮功能的循环标记进行了研究，并确定了这些标记物的循环水平的变化。我们的假设是，正常人受试者中缺氧的暴露直接影响肺上皮和内皮细胞功能。以严重的形式，这可能表现为肺水肿。这种缺氧的这种影响可以通过粘膜酸化来改变，因为肺泡二氧化碳的增加所致。