This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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