The novel Janus kinase inhibitor ruxolitinib confers protection against carbon tetrachloride-induced hepatotoxicity via multiple mechanisms

摘要: Therapeutic targeting of the JAK/STAT pathway, principal signaling mechanism for numerous cytokines, might be an effective approach limiting inflammation in different organs, including liver. Therefore, we investigated whether this pathway by novel JAK inhibitor ruxolitinib could mitigate hepatic damage provoked carbon tetrachloride (CCl4). Male mice received treatments (75 and 150 mg/kg, oral) 2 h prior to intoxication with CCl4 (10 ml/kg 0.3% v/v solution olive oil, intraperitoneal) 24 h. Our results showed that dose-dependently alleviated CCl4-induced injury necroinflammation, as indicated biochemical markers histopathology. We unraveled also mechanisms involved these hepatoprotective effects. These comprise (i) reducing infiltration neutrophils macrophages, demonstrated myeloperoxidase activity F4/80 positive macrophages; (ii) abating apoptosis hepatocytes, denoted decreasing hepatocytes Bax protein; (iii) inhibiting elevation TNF-α, IL-1β IL-10; (iv) NF-κB activation translocation nucleus, visualized immunohistochemically; (v) attenuating IL-23/IL-17 via IL-17, but not IL-23; (vi) antagonizing oxidative stress increasing antioxidant levels (reduced glutathione, glutathione-S-transferase superoxide dismutase) products lipid peroxidation (malondialdehyde 4-hydroxynonenal) total nitrate/nitrite; (vii) more interestingly, modulating hepatocyte regeneration according extent damage, quantified PCNA-immunohistochemistry. In conclusion, our study sheds light on therapeutic usefulness potential underlying inflammatory disorders.