Özocak Ayşegül Bahar, Şen Leyla Semiha, Arıtürk Leman Arslan, Özkeçeci Nur, Yüksel Meral, Eyüboğlu İrem Peker, Erzik Can, Yenal Naziye Özkan, Ercan Feriha, Atıcı Ali Emre, Yeğen Berrak Ç
Department of General Surgery, Marmara University School of Medicine, Istanbul, Türkiye.
Department of Physiology, Marmara University School of Medicine, Istanbul, Türkiye.
Pflugers Arch. 2025 Jul 18. doi: 10.1007/s00424-025-03105-4.
Hepatic injury is one of the most critical problems in major liver surgeries, trauma, sepsis or shock. The novel Elabela (ELA) peptide was shown to exert protective effects against cardiac and renal injury. We hypothesized that ELA could also have protective effects in hepatic ischemia-reperfusion (HI/R) injury and associated remote organ injury. Male (n = 37) and female (n = 37) Sprague-Dawley rats were used. Rats were divided into short-term and long-term HI/R injury groups. Each group was then divided into saline-treated, N-acetylcysteine-treated (NAC, 150 mg/kg) and ELA-treated (40 μg/kg) subgroups. Immediately before hepatic ischemia and during reperfusion, rats were subcutaneously injected with saline, NAC or ELA, while injections in long-term groups were continued twice a day for four days. Short-term and long-term sham-operation groups received saline injections. Hepatic blood flow was measured via laser Doppler flowmetry. Intracardiac blood was obtained for analyses of aminotransferase, alanine aminotransferase, bilirubin, urea, creatinine and interleukin (IL)-6. Caspase-3 and 8-hydroxy-2'-deoxyguanosine levels were determined and histopathological analyses (hematoxylin-eosin and alpha-smooth muscle actin (SMA) immunohistochemical staining) were performed in hepatic tissues. Levels of malondialdehyde, antioxidant glutathione, myeloperoxidase activity, luminol and lucigenin-enhanced chemiluminescence were measured in liver, lung, and kidney. Significant improvement in hepatic blood flow was observed in both short- and long-term ELA-treated groups. HI/R-induced elevations in reactive oxygen species in all the studied tissues were decreased by ELA, indicating its efficient radical scavenging function similar to NAC treatment. ELA treatment improved hepatic function tests and alleviated liver fibrosis, as detected by increased alpha-SMA-immunoreactivity. Serum IL-6 levels were increased by ELA treatment, suggesting its role in the activation of IL-6-dependent intracellular pathways which may contribute to hepatocyte proliferation and liver regeneration. Similar to the common use of NAC in hepatic surgery, Elabela appears to have a therapeutic potential in alleviating the consequences of hepatic postreperfusion injury.
肝损伤是重大肝脏手术、创伤、脓毒症或休克中最关键的问题之一。新型Elabela（ELA）肽已被证明对心脏和肾脏损伤具有保护作用。我们推测ELA对肝缺血再灌注（HI/R）损伤及相关的远隔器官损伤也可能具有保护作用。选用雄性（n = 37）和雌性（n = 37）Sprague-Dawley大鼠。将大鼠分为短期和长期HI/R损伤组。然后每组再分为生理盐水处理组、N-乙酰半胱氨酸处理组（NAC，150 mg/kg）和ELA处理组（40 μg/kg）。在肝脏缺血前及再灌注期间，大鼠皮下注射生理盐水、NAC或ELA，长期组每天注射两次，持续4天。短期和长期假手术组接受生理盐水注射。通过激光多普勒血流仪测量肝血流量。采集心内血用于分析转氨酶、丙氨酸转氨酶、胆红素、尿素、肌酐和白细胞介素（IL）-6。测定Caspase-3和8-羟基-2'-脱氧鸟苷水平，并对肝组织进行组织病理学分析（苏木精-伊红染色和α-平滑肌肌动蛋白（SMA）免疫组化染色）。检测肝脏、肺和肾脏中丙二醛、抗氧化剂谷胱甘肽、髓过氧化物酶活性、鲁米诺和光泽精增强化学发光水平。短期和长期ELA处理组均观察到肝血流量显著改善。ELA降低了HI/R诱导的所有研究组织中活性氧的升高，表明其具有与NAC处理相似的有效自由基清除功能。ELA处理改善了肝功能检测指标并减轻了肝纤维化，α-SMA免疫反应性增加证明了这一点。ELA处理使血清IL-6水平升高，表明其在激活IL-6依赖性细胞内途径中的作用，这可能有助于肝细胞增殖和肝脏再生。与肝脏手术中常用NAC类似，Elabela在减轻肝再灌注损伤后果方面似乎具有治疗潜力。
