The protective efficacy of baricitinib against lipopolysaccharide / D-Galactosamine–Induced acute liver Injury

Résumé

Intorduction: Baricitinib (BARI), the selective JAK1/JAK2 inhibitor demonstrates enhanced immunological activity against several inflammatory conditions. Given the complex, multiple pathogeneses of acute liver inflammatory injury (ALIs), this study investigates BARI in a non-sterile murine model of fulminant hepatic failure to address existing management gaps. Methods: Mice were exposed to a toxic challenge with a single dose of lipopolysaccharide (LPS, 80 μg/kg, ip) and D-galactosamine (D-GaIN, 800 mg/kg, ip) on day 3. BARI (10 and 20 mg/kg, po) were administered prophylactically from day 1 to day 3 with the last dose of BARI given 2 h before LPS/D-GaIN. Results: Investigations revealed substantial lowering in liver function indices in BARI-treated groups after the pathogenic elevation in the LPS/D-GaIN group. These results coincided with remarkable reduction of necrosis and an improvement of hepatic architecture identified by the H&E staining in the BARI-treated groups compared to the disrupted histological features with substantial infiltration of inflammatory cells. The inflammatory cells observed in the LPS/ D-GaIN group represent a major source of ROS that contributes to nitrosative stress via the respiratory burst (NO), peroxidation of the PUFA of the cell membrane (MDA), and consumption of the cellular antioxidant molecules (TAC). This oxidative condition was reversed in BARI groups together with reestablishment of the antioxidant axis of Nrf2/HO-1 showing a remarkable capacity to restore redox equilibrium. The observed ameliorative potential of BARI is probably attributed to inhibition of IL-6 transcription, as confirmed by the inhibited activation of the transcription factor NF-κB, with subsequent inhibition of JAK2/STAT3. While curbing apoptosis as evidenced by reduced levels of cleaved caspase-3, BARI presented its ability to preserve the level of PI3K/AKT/ mTOR signaling. Conclusion: These findings highlight the protective capacity of BARI and its value for repurpose in medical management of acute liver failure.

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