Rose Christopher, Ytrebø Lars M, Davies Nathan A, Sen Sambit, Nedredal Geir I, Belanger Mireille, Revhaug Arthur, Jalan Rajiv
Department of Cellular Neuroscience, Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
Hepatology. 2007 Dec;46(6):1883-92. doi: 10.1002/hep.21877.
We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using the molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by portacaval anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups.
The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia requires further investigation.
我们之前在急性肝衰竭（ALF）猪模型中证明，使用分子吸附循环系统（MARS）进行白蛋白透析可减轻颅内压（ICP）升高。这与动脉血氨、脑血流量和炎症的变化无关，从而可以检验其他假设。本研究的目的是确定脑细胞外氨、乳酸、谷氨酰胺、谷氨酸和能量代谢物的变化是否与MARS对ICP的有益作用相关。研究了三个随机分组 [假手术组、ALF组（通过门腔静脉吻合术和肝动脉结扎诱导）和ALF + MARS组]，为期6小时，在血管离断2小时后开始进行4小时的MARS治疗。使用脑微透析技术，发现ALF + MARS组中ALF诱导的脑细胞外氨、乳酸和谷氨酸增加以及细胞外乳酸/丙酮酸和乳酸/葡萄糖比值的增加均显著减轻。脑细胞外氨的百分比变化与ICP的百分比变化相关（r² = 0.511）。与假手术组相比，ALF组脑乳酸脱氢酶活性和复合物IV的线粒体复合物活性增加，而MARS治疗对此无影响。各研究组之间的脑氧消耗量无差异。
在ALF组和MARS治疗组动物中，脑氧消耗量和线粒体复合物酶活性平行变化，这一观察结果表明，MARS治疗组动物脑细胞外氨（和脑细胞外谷氨酸）增加的减轻降低了能量需求并增加了能量供应，从而导致脑细胞外乳酸增加的减轻。MARS降低脑细胞外氨的机制需要进一步研究。
