The Role Of Pulmonary Vascular Endothelial Cell Injury In The Development Of High Altitude Pulmonary Edema

High altitude pulmonary edema(HAPE) is a life-threatening acute mountain sickness of rapid ascents of altitude higher than 3000 m. HAPE typically occurs in the first 2-4 days after arrival at high altitude. It may be over-represented in man compared with women, The cold and people with abnormalities of the cardiopulmonary function may be contributing factors to the development of HAPE. In general, It is considered that hypoxia is the first key step in the development of HAPE, but what are the precise roles of hypoxia in susceptibility to HAPE. The exact mechanisms of HAPE has not been settled yet. In addition, there are several barriers to a better understanding of HAPE: (1) the HAPE is a specific sickness for High altitude, it is difficulty to perform controlled studies in patients with HAPE in remote areas, far from hospital facilities. (2) the lack of a reliable animal model for HAPE, and (3) the invasive studies are not easy to do in patients with HAPE in High altitude.The pulmonary vascular endothelial cells (PVEC) are transparent and are made of smooth platelike cells, covering for inner lining of the blood vessels in the pulmonary circulation. PVEC evolves a lot of physiological and pathological feature of body, for example, existing the physical and metabolic barriers, keeping the vascular wall intact, producing and releasing of some vascular active substances, regulating the pulmonary vascular tone, hemostasis, and thrombosis. In recent year, It has been recognized that the PVEC may have important roles on the development of acute lung injury ( ALI ), the pulmonary vascular endothelial cell injury may be the key step of ALI. ALI is the characteristics of HAPE, We hypothesize that the PVEC play an important role in the development of HAPE, but up to now , little has been known about the relationship of PVEC injury with HAPE.In order to explore the roles of PVEC on the development of HAPE more deeply and completely, we measured the pulmonary haemodynamic changes in HAPE by Swan-Ganz thermistor cathethers, observed the structural and ultrastructural changes of HAPE by microscopy and electron microscopy, determined the number and function of PVEC in patients with HAPE, investigated the relation between the change of endothelium derived factors(EDF) in patients with HAPE and the hypoxic pulmonary hypertension(HPH). The main results and conclusions are as following:1. The PaO2 and SaC>2 of the patients with HAPE significantly decreased compared with healthy high altitude individuals ; The PaCO2 of patients with HAPE was as same as healthy high altitude individuals. It is suggested that the patients with HAPE have severe hypoxemia.2. The important features of haemodynamic changes in HAPE were: (1). Pulmonary arterial pressure was significantly raised compared with control; (2).Pulmonary arterial resistance and cardiac output were significantly raised comprared with control; (3). Pulmonary artery wedge pressures and right atrial pressure were normal; (4). Pulmonary arterial pressure and resistance were induced by oxygen breathing. The normal pulmonary artery wedge pressures with a high cardiac output indicated that HAPE was recognized as a form of noncardiogenic pulmonary edema.3. The well-adapted native Tibetans and immigrant Hans had pulmonary arterial pressures that were similar to sea-level values, it is suggested that high altitude healthy individuals did not exist the hypoxic pulmonary hypertension (HPH); The mPAP of all natives and immigrants was increased while subjects breathed a hypoxic gas mixture. It is suggested that all natives and immigrants existed hypoxic pulmonary pressure response (HPPR); The mPAP of Hans was significantly increased compared with native Tibetans after breathing hypoxic gas mixture, It is suggested that the HPPR of native Tibetans and immigrant Hans showed interspecy variability.4. Some degree of alveolar edema was found in all the pulmonary lobes.The edemawas formed by material of albuminoid appearance, and was rich in cellular elements, the erythrocytes, macrophyages and polynuclears could be seen in the edema. Under electron microscopy, the disruption of capillary endothelial layer was present, the endothelial cells and the alveolar epithelial layer significantly swollen, the intercellular junctions were widened and broken, It is suggested the pathogenesis of HAPE is acute lung injury (ALI). The rich inflammation cells in the alveolar edema suggested that the inflammtory process envolved the development of HAPE. The number of plasma circulating endothelial cell (CEC) in patients with HAPE were significantly higher than those of high altitude individuals, It is suggested that PAEC is severely impaired and dropped in HAPE.5. The level of plasma Endothelin-1 (ET-1) and Thromboxane A2 ( TXA2 ) in HAPE were significantly higher than those of healthy high altitude individuals, but the contents of plasma Nitric oxide ( NO ) and Prostacyclin ( PGI2 ) in HAPE were significantly lower than those of control group; The immunostaining area and color for ET-1 in HAPE were markedly increased as compared with those in controls, the immunostaining area and color for iNOS in HAPE were obviously lowered as compared with those in controls; The mPAP of HAPE was obviously postively correlated to ET-l/NO and TXA2/PGI2 ratio. All of these suggest that the endothelial dysfunction may play an important part in causing the excessive pulmonary hypertension of HAPE through impaired release of relaxing factors(NO, PGI2) and augmented release of vasoconstrictors (ET-1, TXA2).In summary, the abnormal secretion of pulmonary artery endothelium derived relaxing and constricting factors(EDRCF) may play an important role in the developing HPH in patients with HAPE; The accentuated pulmonary hypertension may be the first key step in the development of HAPE; the disruption of capillary endothelial layer was present, the endothelial cells and the alveolar epithelial layer significantly swollen, the intercellular junctions were widened and broken, It is suggested the pathogenesis ofHAPE is a kind of acute lung injury (ALI). The inflammtory process envolved the development of HAPE. The abnormal lung ultrastructural changes were the pathological basis for HAPE as a high-protein, high-permeability type of pulmonary edema.