Department of Physiology, Medical School, University Complutense of Madrid, Madrid, Spain.
J Surg Res. 2012 Dec;178(2):922-34. doi: 10.1016/j.jss.2012.04.060. Epub 2012 May 14.
Ischemia/reperfusion (I/R) causes functional and structural damage to liver cells, this being more pronounced with increasing age of the tissue. Melatonin is a pineal indole that has been shown to play an important role as a free radical scavenger and anti-inflammatory molecule.
The age-dependent responses to I/R were compared in 2-mo-old and 14-mo-old male Wistar rats. After 35 min of hepatic ischemia followed by 36 h of reperfusion, rats were sacrificed. Sham-operated control rats underwent the same protocol without real vascular occlusion. Animals were intraperitoneally injected with 10 mg/kg melatonin 24 h before the operation, at the time of surgery, and 12 and 24 h after it. The tissues were submitted to histopathologic evaluation. The levels of ALT and AST were analyzed in plasma. The expression of TNF-α, IL-1β, IL-10, MCP-1, IFN-γ, iNOS, eNOS, Bad, Bax, Bcl2, AIF, PCNA, and NFKB1 genes were detected by RT-PCR in hepatic tissue.
I/R was associated with significant increases in the expression of pro-inflammatory and pro-apoptotic genes in liver. Older rats submitted to I/R were found to respond with increased liver damage as compared with young rats, with serum ALT and AST levels significantly higher than in young animals. Mature rats also showed more evident increases in expression of pro-inflammatory cytokines (IL-1β, MCP-1, and IFN-γ) as well as a decrease in the mRNA expression of IL-10 as compared with young animals. Pro-apoptotic genes (Bax, Bad, and AIF) were significantly enhanced in liver after I/R, without differences between young and mature animals. However, the expression of Bcl2 gene did not show any change. Melatonin treatment was able to lower the expression of pro-inflammatory cytokines and pro-apoptotic genes and to improve liver function, as indicated by normalization of plasma AST and ALT levels and by reduction of necrosis and microsteatosis areas.
Melatonin treatment was able to reduce the I/R-stimulated pro-inflammatory and pro-apoptotic genes in the rat liver. Since older animals showed a more marked increase in inflammation and in liver injury, the treatment was more effective in those subjects.
缺血/再灌注（I/R）会导致肝细胞的功能和结构损伤，随着组织年龄的增长，这种损伤更为明显。褪黑素是一种松果腺吲哚，已被证明在作为自由基清除剂和抗炎分子方面发挥着重要作用。
比较了 2 月龄和 14 月龄雄性 Wistar 大鼠的年龄依赖性 I/R 反应。肝缺血 35 分钟后，再灌注 36 小时，处死大鼠。假手术对照大鼠接受相同的方案，但不进行真正的血管闭塞。动物在手术前 24 小时、手术时和手术后 12 小时和 24 小时腹腔内注射 10mg/kg 褪黑素。对组织进行组织病理学评估。分析血浆中 ALT 和 AST 的水平。通过 RT-PCR 检测肝组织中 TNF-α、IL-1β、IL-10、MCP-1、IFN-γ、iNOS、eNOS、Bad、Bax、Bcl2、AIF、PCNA 和 NFKB1 基因的表达。
I/R 与肝脏中促炎和促凋亡基因的表达显著增加有关。与年轻大鼠相比，接受 I/R 的老年大鼠的肝损伤反应更大，血清 ALT 和 AST 水平明显高于年轻动物。成熟大鼠的促炎细胞因子（IL-1β、MCP-1 和 IFN-γ）表达也明显增加，而 IL-10 的 mRNA 表达则低于年轻动物。I/R 后，肝脏中的促凋亡基因（Bax、Bad 和 AIF）明显增强，但年轻和成熟动物之间没有差异。然而，Bcl2 基因的表达没有任何变化。褪黑素治疗能够降低促炎细胞因子和促凋亡基因的表达，改善肝功能，表现为血浆 AST 和 ALT 水平的正常化以及坏死和微脂肪变性区域的减少。
褪黑素治疗能够降低大鼠肝脏 I/R 刺激的促炎和促凋亡基因。由于老年动物的炎症和肝损伤增加更为明显，因此治疗对这些患者更有效。
