Qassam Heider, Janabi Ali M, Gaen Karrar Kareem, Hadi Najah Rayish
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Kufa, Najaf, Iraq.
Department of Molecular and Cell Biology, Henry Wellcome Building, University of Leicester, Lancester Road, Leicester, LE1 7RH, UK.
BMC Pharmacol Toxicol. 2025 Jul 17;26(1):134. doi: 10.1186/s40360-025-00968-2.
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.
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.
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.
This study suggests that DMF has hepatoprotective effects on septic mice via the modulation of inflammation, adhesion molecules, angiopoietin 2 and pyroptosis.
脓毒症是一种普遍存在的疾病，严重影响全球住院患者。其特征是炎症反应失控，导致器官损伤，进而引起高发病率和死亡率。肝脏作为重要器官，会受到脓毒症影响，导致肝功能障碍。已被批准用于治疗多发性硬化症的富马酸二甲酯（DMF），通过抑制多种炎症介质具有抗炎和神经保护特性。因此，本研究旨在评估DMF对脓毒症的肝脏保护潜力。
将四组小鼠（每组6只动物）分为假手术组，仅接受麻醉和腹部正中切口；盲肠结扎穿孔（CLP）组进行麻醉并接受腹部切口，然后在回盲瓣下方结扎盲肠并用针穿刺两次；溶剂对照组在CLP前1小时给予DMF溶剂，CLP组在CLP前1小时通过腹腔注射给予50mg/kg DMF。手术后（CLP后24小时），小鼠全天可自由进食和饮水。用血清检测血管生成素2、AST和ALT水平。采用酶联免疫吸附测定（ELISA）法检测肝组织中TNF-α、IL-6、MIF、ICAM-1、F2-异前列腺素、VEGF和半胱天冬酶11的水平。为评估肝损伤程度，进行肝脏活检。
结果显示，与假手术小鼠相比，接受CLP的小鼠AST和ALT水平较高。此外，与假手术小鼠相比，肝组织中TNF-α、IL-6、MIF、ICAM-1、F2-异前列腺素、VEGF和半胱天冬酶11的水平也显著升高。用DMF预处理的脓毒症小鼠这些参数水平显著降低。与假手术小鼠相比，CLP小鼠表现出严重的肝损伤。DMF预处理减轻了肝损伤。
本研究表明，DMF通过调节炎症、黏附分子、血管生成素2和细胞焦亡对脓毒症小鼠具有肝脏保护作用。
