Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Chem Biol Interact. 2014 Sep 5;220:116-27. doi: 10.1016/j.cbi.2014.06.017. Epub 2014 Jun 25.
Therapeutic targeting of the JAK/STAT pathway, the principal signaling mechanism for numerous cytokines, might be an effective approach for limiting inflammation in different organs, including the liver. Therefore, we investigated whether targeting this pathway by the novel JAK inhibitor ruxolitinib could mitigate hepatic damage provoked by carbon tetrachloride (CCl4). Male mice received ruxolitinib treatments (75 and 150 mg/kg, oral) 2 h prior to intoxication with CCl4 (10 ml/kg of 0.3% v/v CCl4 solution in olive oil, intraperitoneal) for 24 h. Our results showed that ruxolitinib treatments dose-dependently alleviated CCl4-induced hepatic injury and necroinflammation, as indicated by biochemical markers of injury and histopathology. We unraveled also the mechanisms involved in these hepatoprotective effects. These comprise (i) reducing infiltration of neutrophils and macrophages, as demonstrated by reducing myeloperoxidase activity and F4/80 positive macrophages; (ii) abating apoptosis of hepatocytes, as denoted by decreasing hepatocytes positive for Bax protein; (iii) inhibiting elevation of TNF-α, IL-1β and IL-10; (iv) inhibiting NF-κB activation and translocation to the nucleus, as visualized immunohistochemically; (v) attenuating activation of the IL-23/IL-17 pathway via targeting IL-17, but not IL-23; (vi) antagonizing hepatic oxidative stress by increasing the antioxidant levels (reduced glutathione, glutathione-S-transferase and superoxide dismutase) and decreasing products of lipid peroxidation (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite; and (vii) more interestingly, modulating hepatocyte regeneration according to the extent of damage, as quantified by PCNA-immunohistochemistry. In conclusion, our study sheds light on the therapeutic usefulness and the potential underlying mechanisms of the novel JAK inhibitor ruxolitinib in hepatic inflammatory disorders.
靶向 JAK/STAT 通路（该通路是众多细胞因子的主要信号转导机制）可能是限制包括肝脏在内的不同器官炎症的有效方法。因此，我们研究了新型 JAK 抑制剂芦可替尼是否可以通过靶向该通路来减轻四氯化碳（CCl4）引起的肝损伤。雄性小鼠在腹腔注射 0.3%（v/v）CCl4 橄榄油溶液 10ml/kg （CCl4 中毒）前 2 小时分别给予芦可替尼（75 和 150mg/kg，口服）治疗 24 小时。结果显示，芦可替尼治疗剂量依赖性地减轻了 CCl4 诱导的肝损伤和坏死性炎症，这一点通过生化损伤标记物和组织病理学得到证实。我们还揭示了这些肝保护作用的相关机制，包括：（i）减少中性粒细胞和巨噬细胞浸润，表现为髓过氧化物酶活性和 F4/80 阳性巨噬细胞减少；（ii）减少肝细胞凋亡，表现为 Bax 蛋白阳性肝细胞减少；（iii）抑制 TNF-α、IL-1β 和 IL-10 的升高；（iv）抑制 NF-κB 的激活和核转位，通过免疫组化观察到；（v）通过靶向 IL-17 而不是 IL-23 来抑制 IL-23/IL-17 通路的激活；（vi）通过增加抗氧化剂水平（还原型谷胱甘肽、谷胱甘肽-S-转移酶和超氧化物歧化酶）和减少脂质过氧化产物（丙二醛和 4-羟基壬烯醛）和总硝酸盐/亚硝酸盐来拮抗肝氧化应激；（vii）更有趣的是，根据 PCNA 免疫组化的结果，定量评估了芦可替尼对肝细胞再生的调节作用。综上所述，本研究揭示了新型 JAK 抑制剂芦可替尼在肝脏炎症性疾病中的治疗作用及其潜在的作用机制。
