Yokohama S, Yoneda M, Nakamura K, Makino I
Second Department of Medicine, Asahikawa Medical College, Asahikawa 078, Japan.
Am J Physiol. 1999 Mar;276(3):G622-8. doi: 10.1152/ajpgi.1999.276.3.G622.
Central neuropeptides play important roles in many instances of physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Stressors and sympathetic nerve activation are reported to exacerbate experimental liver injury. Some stressors are known to stimulate corticotropin-releasing factor (CRF) synthesis in the central nervous system and induce activation of sympathetic nerves in animal models. The effect of intracisternal CRF on carbon tetrachloride (CCl4)-induced acute liver injury was examined in rats. Intracisternal injection of CRF dose dependently enhanced elevation of the serum alanine aminotransferase (ALT) level induced by CCl4. Elevations of serum aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels by CCl4 were also enhanced by intracisternal CRF injection. Intracisternal injection of CRF also aggravated CCl4-induced hepatic histological changes. Intracisternal CRF injection alone did not modify the serum ALT level. Intravenous administration of CRF did not influence CCl4-induced acute liver injury. The aggravating effect of central CRF on CCl4-induced acute liver injury was abolished by denervation of hepatic plexus with phenol and by denervation of noradrenergic fibers with 6-hydroxydopamine treatment but not by hepatic branch vagotomy or atropine treatment. These results suggest that CRF acts in the brain to exacerbate acute liver injury through the sympathetic-noradrenergic pathways.
中枢神经肽在许多由自主神经系统介导的生理和病理生理调节过程中发挥着重要作用。就肝胆系统而言，几种神经肽在大脑中发挥作用，调节胆汁分泌、肝血流量和肝脏增殖。据报道，应激源和交感神经激活会加重实验性肝损伤。已知一些应激源会刺激中枢神经系统中促肾上腺皮质激素释放因子（CRF）的合成，并在动物模型中诱导交感神经激活。本研究在大鼠中检测了脑池内注射CRF对四氯化碳（CCl4）诱导的急性肝损伤的影响。脑池内注射CRF剂量依赖性地增强了CCl4诱导的血清丙氨酸氨基转移酶（ALT）水平的升高。脑池内注射CRF也增强了CCl4引起的血清天冬氨酸氨基转移酶、碱性磷酸酶和总胆红素水平的升高。脑池内注射CRF还加重了CCl4诱导的肝脏组织学变化。单独脑池内注射CRF并未改变血清ALT水平。静脉注射CRF对CCl4诱导的急性肝损伤没有影响。用苯酚去神经支配肝丛和用6-羟基多巴胺处理去神经支配去甲肾上腺素能纤维可消除中枢CRF对CCl4诱导的急性肝损伤的加重作用，但肝支迷走神经切断术或阿托品处理则不能消除。这些结果表明，CRF在大脑中通过交感-去甲肾上腺素能途径加重急性肝损伤。
