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Hypoxia is well known to increase the free radical generation in the body, leading to oxidative stress. In the present study, we have determined whether the increased oxidative stress further upregulates the nuclear transcription factor (NFkB) in the development of pulmonary edema. The rats were exposed to hypobaric hypoxia at 7620 m (280 mm Hg) for different durations, that is, 3 hrs, 6 hrs, 12 hrs, and 24 hrs at 25+/-1 degrees C. The results revealed that exposure of animals to hypobaric hypoxia led to a significant increase in vascular leakage, with time up to 6 hrs (256.38+/-61 rfu/g) as compared with control (143.63+/-60.1 rfu/g). There was a significant increase in reactive oxygen species, lipid peroxidation, and superoxide dismutase levels, with a concurrent decrease in lung glutathione peroxidase activity. There was 13-fold increase in the expression of NFkB level in nuclear fraction of lung homogenates of hypoxic animals over control rats. The DNA binding activity of NFkB was found to be increased significantly (P<0.001) in the lungs of rats exposed to hypoxia as compared with control. Further, we observed a significant increase in proinflammatory cytokines such as IL-1, IL-6, and TNF-alpha with concomitant upregulation of cell adhesion molecules such as ICAM-I, VCAM-I, and P-selectin in the lung of rats exposed to hypoxia as compared with control. Interestingly, pretreatment of animals with curcumin (NFkB blocker) attenuated hypoxia-induced vascular leakage in lungs with concomitant reduction of NFkB levels. The present study therefore reveals the possible involvement of NFkB in the development of pulmonary edema.

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The most frequently reported symptom of exposure to high altitude is loss of body mass and decreased performance which has been attributed to altered protein metabolism affecting skeletal muscles mass. The present study explores the mechanism of chronic hypobaric hypoxia mediated skeletal muscle wasting by evaluating changes in protein turnover and various proteolytic pathways. Male Sprague-Dawley rats weighing about 200 g were exposed to hypobaric hypoxia (7,620 m) for different durations of exposure. Physical performance of rats was measured by treadmill running experiments. Protein synthesis, protein degradation rates were determined by (14)C-Leucine incorporation and tyrosine release, respectively. Chymotrypsin-like enzyme activity of the ubiquitin-proteasome pathway and calpains were studied fluorimetrically as well as using western blots. Declined physical performance by more than 20%, in terms of time taken in exhaustion on treadmill, following chronic hypobaric hypoxia was observed. Compared to 1.5-fold increase in protein synthesis, the increase in protein degradation was much higher (five-folds), which consequently resulted in skeletal muscle mass loss. Myofibrillar protein level declined from 46.79 ± 1.49 mg/g tissue at sea level to 37.36 ± 1.153 (P < 0.05) at high altitude. However, the reduction in sarcoplasmic proteins was less as compared to myofibrillar protein. Upregulation of Ub-proteasome pathway (five-fold over control) and calpains (three-fold) has been found to be important factors for the enhanced protein degradation rate. The study provided strong evidences suggesting that elevated protein turnover rate lead to skeletal muscle atrophy under chronic hypobaric hypoxia via ubiquitin-proteasome pathway and calpains.