Zhang Wen-Hai, Li Jian-Yi, Zhou Yong
Department of 5th General Surgery, Second Affiliated Hospital (Shengjing Hospital), China Medical University, Shenyang 110004, China.
Hepatobiliary Pancreat Dis Int. 2006 Nov;5(4):574-9.
Melatonin exerts complex physiological and pharmacological effects on multiple systems and organs. We hypothesized that melatonin might abate ischemia/reperfusion (I/R) injury in the liver by inhibiting excessive oxidative stress and keeping nitric oxide (NO) from being scavenged by free radicals. The aim of the present study was to investigate whether melatonin protects the liver from I/R injury and, if so, by what underlying mechanism.
Under anesthesia, Wistar rats were intraperitoneally injected with 20 mg/kg melatonin (dissolved in physiological saline containing 4% ethanol, Mel group), 4% alcohol (Alc group), or physiological saline (NS group). The artery, portal vein and bile duct of the left lobe of the liver were clamped for 60 minutes and then released. At different time points after I/R, the rats were sacrificed and blood samples were collected to measure the levels of serum alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and NO. Hepatic tissue samples were collected for measuring endothelin expression by immunohistochemical staining and for routine morphological and histological examination.
The levels of both ALT and LDH in the Mel group were significantly reduced for up to 24 hours after I/R compared with the Alc and NS groups (P<0.05). The levels of NO in the Mel group were significantly elevated for up to 12 hours after I/R relative to the NS group (P<0.05). The NO levels were also elevated at 0.5 and 6 hours after I/R in the Alc group (P<0.05). The immunohistochemical staining of hepatic tissue showed that endothelin-positive cells were significantly fewer in the Mel group than in the Alc and NS groups at 6 hours after I/R (P<0.01). The necrosis of hepatocytes and the destruction of hepatic cords in the Alc and NS groups were greatly improved in Mel-treated rats, which is in concert with our functional data.
Pretreatment with melatonin increased NO bioavailability and decreased endothelin expression, and consequently played a protective role in preserving both liver function and structure during ischemia and reperfusion injury.
褪黑素对多个系统和器官发挥着复杂的生理和药理作用。我们推测，褪黑素可能通过抑制过度的氧化应激以及防止一氧化氮（NO）被自由基清除，从而减轻肝脏的缺血/再灌注（I/R）损伤。本研究的目的是探究褪黑素是否能保护肝脏免受I/R损伤，若能，则其潜在机制是什么。
在麻醉状态下，给Wistar大鼠腹腔注射20mg/kg褪黑素（溶解于含4%乙醇的生理盐水中，Mel组）、4%乙醇（Alc组）或生理盐水（NS组）。夹闭肝脏左叶的动脉、门静脉和胆管60分钟，然后松开。在I/R后的不同时间点，处死大鼠并采集血样，检测血清丙氨酸氨基转移酶（ALT）、乳酸脱氢酶（LDH）和NO的水平。采集肝组织样本，通过免疫组织化学染色检测内皮素表达，并进行常规形态学和组织学检查。
与Alc组和NS组相比，Mel组在I/R后长达24小时内ALT和LDH水平均显著降低（P<0.05）。与NS组相比，Mel组在I/R后长达12小时内NO水平显著升高（P<0.05）。Alc组在I/R后0.5小时和6小时时NO水平也升高（P<0.05）。肝组织免疫组织化学染色显示，在I/R后6小时，Mel组内皮素阳性细胞明显少于Alc组和NS组（P<0.01）。Alc组和NS组中肝细胞坏死和肝索破坏在褪黑素处理的大鼠中得到显著改善，这与我们的功能数据一致。
褪黑素预处理可提高NO生物利用度并降低内皮素表达，从而在缺血和再灌注损伤期间对肝脏功能和结构的保护中发挥作用。
