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茵陳蒿湯降低神經性肝損傷的效應與機轉

In-Chern-Hau-Tang and Genipin Reduces Norepinephrine-Induced Hepatocellular Dysfunction via the Inhibition of alpha2-Adrenoceptors Signaling

摘要


正腎上腺素會經由α2-腎上腺素受器增加肝臟Kupffer細胞之TNF-α細胞素的產生。我們先前的研究指出憋尿造成交感神經過度活化會透過發炎和細胞凋亡機轉造成急性肝損傷(Am J Physiol Renal Physiol, 2005)。我們假設憋尿造成交感神經過度活化會透過α2-腎上腺素受器而活化肝臟Kupffer細胞造成急性肝損傷。我們評估茵陳蒿湯和其主要活性成份genipin是否能減緩憋尿造成交感神經過度活化而透過α2-腎上腺素受器而活化肝臟Kupffer細胞造成之急性肝損傷。離體研究指出正腎上腺素會經由α2-腎上腺素受器增加肝臟Kupffer細胞活性氧的產生。而茵陳蒿湯和其主要活性成份genipin則顯著的降低正腎上腺素引發肝臟Kupffer細胞之活性氧的產生。活體研究則指出憋尿造成交感神經過度活化會導致肝臟產生類似缺血/再灌流和膽汁滯留。憋尿也會增加肝臟之經胞間吸附因子1(ICAM-1)蛋白表現、活化白血球NADPH氣化酶活性而增加叩刮生氧產生而導致血漿aspartate aminotransferase (AST)的升高。去除肝交感神經或口服茵陳蒿湯和其主要活性成份genipin一週可以降低憋尿造成肝臟之類似缺血/再灌流、膽汁滯留、肝臟之細胞間吸附因子1(ICAM-1)蛋白表現、白血球NADPH氧化酶活性、活性氧產生與血漿AST的升高數值。總結口服茵陳蒿湯和其主要活性成份genipin一週可以改善神經性肝損傷是藉由抑制白血球和Kupffer細胞之發炎和氧化訊息機轉。

並列摘要


Norepinephrine upregulates TNF-α production in Kupffer cells through a α 2-adrenergic pathway. Our previous study showed that exaggerated sympathetic activation by acute urine retention (AUR) contributes to acute liver injury (ALI) via the proinflammatory and proapoptotic signaling pathways (Am J Physiol Renal Physiol, 2005). We explored whether AUR induced oxidative injury in the liver via Kupffer cells-mediated α2-adrenergic signaling pathway. We aimed to determine whether In-Chern-Hau-Tang, an herb medicine, and its major ingredient genipin, could attenuate norepinephrine-induced oxidative stress in the Kupffer cells and AUR-induced ALT in the rat. In vitro study showed that norepinephrine enhanced reactive oxygen species (ROS) production and TNF a production in the isolated Kupifer cells. In-Chern-Hau-Tang and genipin significantly depressed norepinephrine enhanced ROS and TNF-α production. AUR activated hepatic sympathetic nervous activity leading to hepatic hypoxia hypoperfusion, and reduction in bile flow. AUR increased intercellular adhesion molecular 1 (ICAM-1) protein expression, hepatic ROS production from the activated leukocyte NADPH oxidase activity subsequently leading to plasma aspartate aminotransferase (AST) elevation. Hepatic sympathetic denervation, or oral pretreatment of In-Chern-Hau-Tang (120 mg/kg, daily) or genipin (10 mg/kg, daily) for one week ameliorated the level in AUR-induced hepatic hypoxia/hypoperfusion, and bile stasis. Hepatic denervation or In-Chem-Hau-Yang inhibited AUR-enhanced ICAM-1 expression, hepatic ROS production, leukocyte NADPH oxidase activity and plasma AST activity. In conclusion, In-Chern-Hau-Tang can ameliorate AUR-induced ALT via the attenuation of proinflammatory signaling possibly by the inhibition of sympathetic induced hypoxia/hypoperfusion and leukocyte NADPH oxidase activity.

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