Matković Zoran, Gajić Bojić Milica, Maličević Uglješa, Krivokuća Aleksandra, Mandić-Kovačević Nebojša, Uletilović Snežana, Amidžić Ljiljana, Jovičić Sanja, Barudžija Maja, Stojiljković Miloš P, Gajanin Radoslav, Bolevich Sergej, Škrbić Ranko
Department of Surgery, General Hospital "Sveti Apostol Luka", 74000 Doboj, Bosnia and Herzegovina.
Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina.
Int J Mol Sci. 2025 Sep 18;26(18):9131. doi: 10.3390/ijms26189131.
Acute mesenteric ischemia (AMI) is a life-threatening condition characterised by oxidative stress, inflammation, apoptosis, and necrosis of intestinal epithelial cells. Different drugs with vasoactive, antioxidant, and anti-inflammatory properties have been used to treat AMI. Levosimendan is a drug with proven anti-ischemic effects used in the management of acute congestive heart failure. This study evaluated the protective effects of levosimendan pretreatment on intestinal, as well as lung, heart, and kidney tissue in a rat model of mesenteric artery ischemia/reperfusion (I/R) injury. Male Wistar rats (N = 24) were divided into four groups: control, I/R, levosimendan (LS) 1 mg/kg i.p, and LS + I/R (1 mg/kg i.p. 30 min before injury). I/R by itself caused elevation of oxidative markers (thyobarbituric acid reactive species (TBARS), hydrogen peroxide (HO), super oxide anjon radical (O), and nitrogen dioxide (NO)), induced inflammation (macrophage infiltration and Interleukin-6 (IL-6) production), and apoptosis (nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), cleaved caspase-3 (CC3), and terminal deoxy-nucleotidyl transferase (TdT)-mediated dUTP nick end labelling (TUNEL)). Levosimendan pretreatment significantly reduced oxidative stress markers and enhanced antioxidant defences (catalase (CAT), reduced glutathione (GSH), and superoxide dismutase (SOD)). Histological analysis revealed reduced mucosal damage and preserved goblet cells in intestinal tissue. Similar protective effects of levosimendan were observed in other organs such as lung, heart, and kidney. Immunohistochemistry showed reduced epithelial apoptosis and upregulation of antioxidant and anti-inflammatory proteins. These findings highlight levosimendan's ability to protect mesenteric I/R tissue injury and multi-organ damage by suppressing oxidative stress, inflammation, and apoptosis, emphasising its therapeutic potential in clinical settings.
急性肠系膜缺血（AMI）是一种危及生命的疾病，其特征为肠道上皮细胞发生氧化应激、炎症、凋亡和坏死。具有血管活性、抗氧化和抗炎特性的不同药物已被用于治疗AMI。左西孟旦是一种已被证实具有抗缺血作用的药物，用于治疗急性充血性心力衰竭。本研究评估了左西孟旦预处理对肠系膜动脉缺血/再灌注（I/R）损伤大鼠模型的肠道以及肺、心脏和肾脏组织的保护作用。雄性Wistar大鼠（N = 24）分为四组：对照组、I/R组、左西孟旦（LS）1 mg/kg腹腔注射组和LS + I/R组（损伤前30分钟腹腔注射1 mg/kg）。I/R本身导致氧化标志物（硫代巴比妥酸反应性物质（TBARS）、过氧化氢（HO）、超氧阴离子自由基（O）和二氧化氮（NO））升高，诱导炎症（巨噬细胞浸润和白细胞介素-６（IL-6）产生）以及凋亡（活化B细胞核因子κB轻链增强子（NF-κB）、裂解的半胱天冬酶-3（CC3）和末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记（TUNEL））。左西孟旦预处理显著降低了氧化应激标志物并增强了抗氧化防御（过氧化氢酶（CAT）、还原型谷胱甘肽（GSH）和超氧化物歧化酶（SOD））。组织学分析显示肠道组织中黏膜损伤减轻且杯状细胞得以保留。在肺、心脏和肾脏等其他器官中也观察到了左西孟旦类似的保护作用。免疫组织化学显示上皮细胞凋亡减少且抗氧化和抗炎蛋白上调。这些发现突出了左西孟旦通过抑制氧化应激、炎症和凋亡来保护肠系膜I/R组织损伤和多器官损伤的能力，强调了其在临床环境中的治疗潜力。
