New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage
New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage
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DOI：
10.1016/j.taap.2012.04.012
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发表时间：
2012-06-15
影响因子：
3.8
通讯作者：
El-Demerdash, Ebtehal
中科院分区：
文献类型：
--
作者：
Hamdy, Nadia;El-Demerdash, Ebtehal
门脉高压症是慢性肝病合并肝纤维化和肝硬变的常见并发症。目前，卡维地洛等β-受体阻滞剂仍然是预防静脉曲张出血和其他并发症的首选药物。由于卡维地洛具有强大的抗氧化性能，我们利用四氯化碳(CCl4)诱导的慢性肝毒性模型，评估了卡维地洛潜在的抗纤维化作用以及可能为其临床应用增加进一步益处的潜在机制。CCl4致大鼠慢性肝毒性2周后，给予卡维地洛(10 mg/kg)灌胃，每日1次，连续6周。研究发现，卡维地洛对动物的治疗可明显对抗CCl4所致的肝功能改变和组织病理学损害。卡维地洛还能显著对抗CCl4诱导的脂质过氧化、谷胱甘肽耗竭和抗氧化酶、谷胱甘肽-S-转移酶和过氧化氢酶活性的降低。此外，卡维地洛还可通过降低血清急性时相蛋白标记物α2-巨球蛋白水平和肝脏核因子-kappaB(NF-kappa B)的表达来减轻CCl4诱导的炎症。最后，卡维地洛显著降低肝纤维化指标，包括羟脯氨酸、胶原堆积和肝星状细胞(HSC)激活标志物--α-平滑肌肌动蛋白的表达。综上所述，本研究为卡维地洛具有良好的抗肝纤维化作用提供了证据，卡维地洛主要通过补充GSH、恢复抗氧化酶活性和减少脂质过氧化，以及通过减少胶原堆积、急性时相蛋白水平、核因子-kappaB的表达和HSC的激活来减轻炎症和纤维化，从而减轻氧化应激。(C)2012 Elsevier Inc.保留所有权利。
Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10 mg/kg, orally) daily for 6 weeks. It was found that treatment of animals with carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2-macroglobulin and the liver expression of nuclear factor-kappa B (NF-kappa B). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-kappa B expression and finally HSC activation. (C) 2012 Elsevier Inc. All rights reserved.