Dimethyl fumarate attenuates liver injury in a mouse model of cecal ligation and puncture by modulating inflammatory, angiogenic and pyroptotic pathways.

BACKGROUND

Sepsis is a prevalent ailment that significantly affects hospitalized individuals around the globe. It is characterized by uncontrolled inflammatory responses resulting in organ injury and leading to high morbidity and mortality. The liver, a vital organ, is affected by sepsis, resulting in liver dysfunction. Dimethyl fumarate (DMF), which is approved for the treatment of multiple sclerosis, has anti-inflammatory and neuroprotective properties through the inhibition of multiple inflammatory mediators. Hence, the present study aimed to assess the hepatoprotective potential of DMF against sepsis.

METHODS

Four groups of mice (6 animals per group) were divided into a sham group, which was subjected to only anaesthesia and a midline abdominal incision; the cecal ligation and puncture (CLP) group was anaesthetized and underwent an abdominal incision followed by the ligation of the cecum under the ileocecal valve and perforation twice with a needle; the vehicle group was given a solvent of DMF 1 h before the CLP, and the CLP group received 50 mg/kg of DMF via intraperitoneal (ip) injection 1 h before CLP. Following the procedure (24 h post-CLP), the mice were given unrestricted access to food and drink throughout the day. Serum was used to measure the levels of angiopoietin 2, AST and ALT. Enzyme-linked immunosorbent assay (ELISA) was used to investigate the levels of TNF-α, IL-6, MIF, ICAM-1, F2-isoprostanes, VEGF, and caspase 11 in liver tissues. To evaluate the degree of liver damage, a biopsy of the liver was performed.

RESULTS

The results revealed that mice exposed to CLP had high levels of AST and ALT in comparison with sham mice. Furthermore, levels of TNF-α, IL-6, MIF, ICAM-1, F2-isoprostanes, VEGF, and caspase 11 in liver tissues were also notably elevated as compared with sham mice. The levels of these parameters were significantly decreased in septic mice pre-treated with DMF. Mice with CLP showed a severe degree of liver damage as compared with sham mice. DMF pre-treatment mitigated liver injury.

CONCLUSION

This study suggests that DMF has hepatoprotective effects on septic mice via the modulation of inflammation, adhesion molecules, angiopoietin 2 and pyroptosis.