Role And Mechanism Of CSF Acid-base Imbalance In The Pathogenesis Of High-altitude Brain Disorder

The high-altitude environment influences humans significantly. If plain residents go rapidly to altitude above 3000m elevation, they frequently develop acute pathophysiological reactions, ranging from acute mountain sickness (AMS) to high altitude cerebral edema (HACE). And these reactions endanger the lives of the migrants. Both AMS and HACE are manifestations of the high-altitude brain disorder. Although they have been studied for a century, hypoxia was thought as triggered factor of AMS and HACE and evidence points to a process in the central nervous system,the exact mechanism causing these syndromes is still unknown. The acid-base homeostasis of cerebrospinal fluid (CSF) is of great importance to maintain brain function. Disorders of this homeostasis will necessarily lead to alterations in brain cell function. Researches have shown that pulmonary encephalopathy is closely related to CSF acid-base imbalance. Nevertheless, no literature dealing with the relationship between high-altitude brain disorder and CSF acid-base imbalance is available to date. To provide new approaches for prevention and treatment of high-altitude brain disorder, we reproduced the animal models for high-altitude brain disorder at various altitudes in a simulated fashion and investigated the role of CSF acid-base imbalance in the pathogenesis of high-altitude brain disorder and the relevant mechanisms. Study contents 1. Reproduce the animal models for high-altitude brain disorder: Healthy adult dogs were subjected to simulated altitude elevation to 4500m or 5000 m at a rate of 3m/s for 3d in a large hypobaric chamber. 2. Arterial and CSF acid-base parameters in experimental dogs were monitored at various altitudes, and corresponding characteristics of parameter changes and types of acid-base imbalance were investigated. 3. To study the structural and functional alterations of brain cellular membrane, activity of Na~+, K~+-ATPase and SOD and the content of MDA in canine hippocampal CA1 region were detected at various altitudes. 4. To investigate the role of CSF acid-base imbalance in the pathogenesis of high-altitude brain disorder, expression of AE3 mRNA in canine hippocampal CA1 region at various altitudes was detected using in situ hybridization. 5. To provide new approaches for prevention and treatment of high-altitude brain disorder and to investigate the therapeutic role of CSF acid-base imbalance in the pathogenesis of high-altitude brain disorder, changes of the parameters listed above were observed after the dogs inhaled different air containing 950ml/L O2,30ml/LCO2 and 950ml/L O2+30ml/L CO2 at various altitudes. Results 1. As compared with the plain control group, experimental dogs at a simulated altitude of 4500m for 3d showed the following changes:pHa and CSF pH increased , PaO2,PaCO2,HCO3-and CSF PO2,CSF PCO2,CSF [HCO3-] decreased; the decrement of CSF [HCO3-]was relatively small and increase of CSF pH and CSF [HCO3-] were relatively big.This show the change of respiratory alkalosis and metabolic alkalosis of CSF.These changes were even more apparent at the simulated altitude of 5000m. 2. At the simulated altitude of 4500m and 5000m, dogs'intracranial pressures were 15.48cmH2O and 17.33cmH2O respectively, both significantly higher than that of the plain control group (8.76cmH2O); Brain water contents were 79.24% and 80.67% respectively, both significantly higher than that of the plain control group (74.54%). Microscopic observation on HE stained canine brain tissue revealed brain edema, which was more severe in dogs at 5000m than at 4500m. 3. As compared with the plain control group,at a simulated altitude of 4500m, the activity of Na+, K+-ATPase and SOD decreased significantly and the content of MDA increased significantly in canine hippocampal CA1 region.These changes were even more apparent at the simulated altitude of 5000m. 4. As compared with the plain control group, the results of in situ hybridization indicated that the expression of AE3 mRNA in canine hippocampal CA1 region decreased, which was more evident at 5000m than at 4500m. 5. As compared with the blank control group, dogs at a simulated altitude of 4500m or 5000m showed the following changes:Following inhalation of 30ml/L CO2, ICP,BWC andbrain edema were not ameliorated, pHa and CSF pH were decreased, while HCO3-,PaCO2 and CSF [HCO3-],CSF PCO2 were increased significantly, but SaO2,PaO2 and CSF SO2,CSF PO2 were not changed. Following inhalation of 950ml/L O2,ICP and BWC were significantly decreased,brain edema were mitigated, SaO2,PaO2 and CSF SO2,CSF PO2 were increased, but pHa,PaCO2,HCO3-and CSF pH,CSF [HCO3-],CSF PCO2 were not ameliorated significantly. However, inhalation of 30ml/L CO2 +950ml/L O2 increased PaO2,PaCO2,HCO3-,CSF PO2,CSF PCO2,CSF [HCO3-] ,and decreased pHa,CSF pH,ICP,and BWC,and mitigated brain edema. 6. As compared with the blank control group, dogs at a simulated altitude of 4500m or 5000m showed the following changes:Inhalation of 950ml/L O2 led to obvious decrease in MDA levels and obvious increase in the activity of SOD and Na+,K+-ATPase in hippocampal CA1 region. These changes were exacerbated after inhalation of 30ml/L CO2 +950ml/L O2. Nevertheless, inhalation of 30ml/L CO2 brought no obvious changes. 7. As compared with the blank control group, dogs at a simulated altitude of 4500m or 5000m showed the following changes: Inhalation of 950ml/L O2 or 30ml/L CO2 +950ml/L O2 resulted in increased expression of AE3mRNA in canine hippocampal CA1 region, and the increase was more obvious in the latter than the former. Nevertheless, inhalation of 30ml/L CO2 brought no obvious changes. Conclusions 1. The animal models for high-altitude brain disorder were reproduced successfully. 2. In the hypoxic high-altitude environment, ventilation enhancement acts as the primary response in compensative adaptation of human body. CSF acid-base imbalance is a crucial factor in the pathogenesis of high-altitude brain disorder, whereas PCO2 decrease and alkalosis of CSF may be the key to brain tissue injury. 3. In the hypoxic high-altitude environment, derangement of the oxidation-antioxidation system and increased production of ROS damage the integrity of brain cellular membrane, destroy the blood-brain barrier, increase vasopermeability, thus resulting in brain edema. Reasonably, high-altitude brain disorder may be aggravated due to enhanced oxidative stress. 4. AE3, a major chloridion transporter on neuronal membrane, is downregulated under high-altitude hypoxia or respiratory alkalosis, leading to reduction in Cl-/HCO3-exchange, relative elevation of CSF [HCO3-], and CSF alkalosis. Inhalation of 950ml/L O2 or 30ml/LCO2 +950ml/L O2 resulted in increased expression of AE3 mRNA in canine hippocampal CA1 region, and the increase was more obvious in the latter than the former. This suggests that AE3 may play a certain role in the pathogenesis of high-altitude brain disorder. 5. In the hypoxic high-altitude environment, inhalation of 30ml/L CO2+950ml/L O2 brings more beneficial effects than inhalation of 950ml/L O2, thus the former can be used to prevent and treat high-altitude brain disorder. Nevertheless, inhalation of 30ml/L CO2 brings no obvious effect on high-altitude brain disorder.