| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 101 === Sudden exposure of non-acclimatized individuals to high altitude can easily lead to high altitude illnesses. High altitude pulmonary edema (HAPE) is the most lethal form of high altitude illness. Although the pathological mechanism of HAPE still requires elucidation, evidence indicates that the major causes of HAPE include hypoxia-induced pulmonary hypertension, increased vascular permeability, and impaired pulmonary transepithelial sodium transport. The present study was designed to investigate the ability of Rhodiola crenulata extract (RCE), an herbal medicine traditionally used as an anti acute mountain sickness remedy, to attenuate hypoxia-induced pulmonary injury. Exposure of animals to hypobaric hypoxia led to a significant increase in pathological indicators for pulmonary edema, including the lung water content, disruption of the alveolar-capillary barrier, and protein-rich fluid in the lungs. In addition, hypobaric hypoxia also increased oxidative stress markers, including reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and myeloperoxidase (MPO) activity. Furthermore, overexpression of plasma endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) in bronchoalveolar lavage fluid (BALF), and hypoxia-inducible factor-1α (HIF-1α) in lung tissue. However, pretreatment with RCE relieved the HAPE findings by curtailing all of the hypoxia-induced lung injury parameters. These findings suggest that RCE confers effective protection for maintaining the integrity of the alveolar-capillary barrier by alleviating the elevated ET-1 and VEGF levels; it does so by reducing hypoxia-induced oxidative stress. Furthermore, A549 cells were also used to examine the effects of RCE, salidroside, or tyrosol on hypoxia-mediated Na,K-ATPase endocytosis that contributes to an important part of impaired pulmonary sodium transport. Our results showed that Rhodiola products significantly prevented Na,K-ATPase endocytosis from hypoxic insults via the inhibition of ROS-AMPK-PKCζ pathway in both A549 cells and rodent model, respectively. Our study is the first to offer substantial evidence to support the efficacy of Rhodiola products against hypoxia-associated Na,K-ATPase endocytosis and clarify the ethnopharmacological relevance of Rhodiola crenulata as a popular folk medicine for high altitude illness.
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