Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress.
Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress.
复制标题
地塞米松预处理减轻异烟肼/脂多糖肝毒性：抑制炎症和氧化应激
DOI：
10.3389/fphar.2017.00133
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发表时间：
2017
影响因子：
5.6
通讯作者：
Jiang Z
中科院分区：
文献类型：
--
作者：
Hassan HM;Guo H;Yousef BA;Ping-Ping D;Zhang L;Jiang Z
异烟肼(INH)仍然是当前结核病治疗策略的基石关键组成部分，但其肝毒性潜力仍然是一个重要的临床问题。我们以前的发现成功地利用炎症应激理论建立了异烟肼肝毒性大鼠模型，在该模型中，非损伤性剂量的炎症介质细菌脂多糖(LPS)增强了异烟肼的毒性，有助于揭示异烟肼肝毒性背后的机制。在内毒素暴露后，几个炎性细胞被激活，很可能是这种激活的后果，而不是内毒素的直接肝细胞效应，奠定了内毒素增强毒性反应的能力。在本研究中，我们研究了抗炎药地塞米松(DEX)对INH/LPS肝毒性大鼠模型的潜在保护作用。通过血液生化和肝脏组织病理学分析，地塞米松预处理成功地消除了炎症应激的成分。地塞米松增强了肝脏的抗氧化机制，同时降低了血清和肝脏的血脂水平。但地塞米松不能阻断细胞色素P450 2E1在异烟肼/脂多糖诱导的肝损伤中的主要作用。综上所述，本研究通过地塞米松诱导的有效抗炎作用阐明了地塞米松对异烟肼/内毒素肝毒性模型的预防作用，而该模型的部分毒性作用可能归因于肝脏细胞色素P4502的表达。这些发现加强了地塞米松联合异烟肼治疗的临床应用，以减少潜在的肝毒性发生率。
Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity.