Chakass Dania, Philippe David, Erdual Edmone, Dharancy Sébastien, Malapel Mathilde, Dubuquoy Caroline, Thuru Xavier, Gay Jerome, Gaveriaux-Ruff Claire, Dubus Pierre, Mathurin Philippe, Kieffer Brigitte L, Desreumaux Pierre, Chamaillard Mathias
Institut National de la Santé et de la Recherche Médicale (INSERM) U795, University of Lille 2, Digestive Tract Diseases and Nutrition Department, 59037, Lille Cedex, France.
Gut. 2007 Jul;56(7):974-81. doi: 10.1136/gut.2006.105122. Epub 2007 Feb 13.
The detrimental impact of opioid agonist on the clinical management of inflammatory diseases remains elusive. Given the anti-inflammatory properties of the mu-opioid receptor (MOR) agonists at the intestinal barrier, we hypothesised that MOR activation might also dampen acute hepatic inflammation and cell death-major determinants in the pathogenesis of liver diseases.
The expression of MOR in liver biopsy specimens and peripheral blood mononuclear cells of untreated patients with chronic hepatitis C virus infection and controls, primary hepatocytes and cell lines was determined by quantitative PCR, immunoblotting and/or immunohistochemistry. The effects of peripheral MOR agonist (d-Ala2,NMe-Phe4,Gly5-ol (DAMGO)) and/or antagonist (naloxone methiodide) were explored in two models of acute hepatitis in mice. MOR-deficient mice were used to evaluate the essential regulatory role of MOR during carbon tetrachloride (CCl(4))-induced hepatitis. The role of DAMGO in cell death was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) analysis and quantification of lactate dehydrogenase release.
The key role of MOR in the prevention of acute hepatic inflammation and cell death in vivo and in vitro is reported. Whereas MOR gene expression increased transiently in the model of acute liver injury and TNFalpha-treated HepG2 cells, an impaired expression of MOR mRNA in human chronic hepatitis C samples was found. Furthermore, preventive administration of the selective MOR agonist DAMGO enhanced hepatoprotective-signalling pathways in vivo that were blocked by using naloxone methiodide. Consistently, genetic and pharmacological inhibition of MOR enhanced the severity associated with experimental hepatotoxin-induced hepatitis. Finally, treatment with DAMGO was shown to prevent cell death in vitro in HepG2 cells in a MOR-dependent manner and to prevent concanavalin A- and CCl(4)-induced cell death in vivo, providing a possible explanation for the anti-inflammatory role of MOR activation in the liver.
The results indicate that MOR agonists may prevent acute hepatitis and hold promising therapeutic use to maintain remission in both chronic inflammatory bowel and liver diseases.
阿片类激动剂对炎症性疾病临床治疗的有害影响尚不清楚。鉴于μ-阿片受体（MOR）激动剂在肠道屏障具有抗炎特性，我们推测MOR激活可能也会减轻急性肝脏炎症和细胞死亡，而这两者是肝脏疾病发病机制中的主要决定因素。
通过定量PCR、免疫印迹和/或免疫组化法，测定未经治疗的慢性丙型肝炎病毒感染患者及对照、原代肝细胞和细胞系的肝活检标本及外周血单个核细胞中MOR的表达。在两种小鼠急性肝炎模型中，探究外周MOR激动剂（D-Ala2，NMe-Phe4，Gly5-ol（DAMGO））和/或拮抗剂（甲碘化纳洛酮）的作用。利用MOR缺陷小鼠评估MOR在四氯化碳（CCl₄）诱导的肝炎中的重要调节作用。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）分析和乳酸脱氢酶释放量的测定，研究DAMGO在细胞死亡中的作用。
报道了MOR在体内和体外预防急性肝脏炎症和细胞死亡中的关键作用。在急性肝损伤模型和经肿瘤坏死因子α（TNFα）处理的HepG2细胞中，MOR基因表达短暂增加，而在人类慢性丙型肝炎样本中发现MOR mRNA表达受损。此外，预防性给予选择性MOR激动剂DAMGO可增强体内肝保护信号通路，而甲碘化纳洛酮可阻断该通路。同样，MOR的基因和药理学抑制作用增强了实验性肝毒素诱导肝炎的严重程度。最后，结果表明，DAMGO治疗可在体外以MOR依赖的方式预防HepG2细胞死亡，并在体内预防刀豆蛋白A和CCl₄诱导的细胞死亡，这为MOR激活在肝脏中的抗炎作用提供了一种可能的解释。
结果表明，MOR激动剂可能预防急性肝炎，并在维持慢性炎症性肠病和肝病缓解方面具有有前景的治疗用途。
