Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
Department of General Surgery, Sir Run‑Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
Int J Mol Med. 2023 Jan;51(1). doi: 10.3892/ijmm.2022.5212. Epub 2022 Dec 9.
Disruption of iron homeostasis is associated with multiple diseases. It has been found that patients with genetic iron overload develop massive iron deposition in the pancreas. However, few studies have focused on the effect of secondary iron overload on the pancreas. The objective of the present study was to investigate the pathogenic consequences of secondary iron overload in mice. An iron overload mouse model was constructed by intraperitoneal injection of 120 mg/kg body weight of iron dextran every other week for 12 weeks. Iron deposition, immunocyte infiltration, fibrosis, oxidative stress and ferroptosis were assessed using Prussian blue staining, immunohistochemical analysis, Masson staining, Sirius red staining, RT‑qPCR analysis and western blot analysis. It was found that iron‑overloaded mice showed pancreatic iron overload, together with elevated gene expression of the iron storage factor ferritin H, and decreased expression of the iron transportation mediator divalent metal transporter 1, ferroportin 1 and transferrin receptor. Iron‑overloaded mice developed mild pancreatitis with increased serum amylase and lipase activities, as well as elevated gene expression levels of pro‑inflammatory cytokines, including interleukin (IL)‑1β, IL‑6 and inducible nitric oxide synthase. Acinar atrophy, massive immunocyte infiltration and pancreatic fibrosis were noted in the iron‑overloaded mice. As an underlying mechanism, iron‑overloaded mice showed increased pancreatic oxidative stress, with an elevated malondialdehyde level, and decreased SOD and glutathione peroxidase activity. Furthermore, iron overload led to ferroptosis with promoted expression of cytochrome c oxidase subunit II, and decreased transcripts of glutathione peroxidase 4 and solute carrier family 7 member 11. These results provided evidence that multiple intraperitoneal injections of iron dextran in mice lead to iron overload‑induced chronic pancreatitis, which suggested that secondary iron overload is a risk factor for pancreatitis and highlights the importance of iron in maintaining the normal functions of the pancreas.
铁稳态失调与多种疾病有关。已经发现，遗传性铁过载的患者在胰腺中会发生大量铁沉积。然而，很少有研究关注铁过载对胰腺的影响。本研究旨在探讨铁过载对小鼠胰腺的致病后果。通过每两周腹腔注射 120mg/kg 体重的右旋糖酐铁 12 周，构建铁过载小鼠模型。使用普鲁士蓝染色、免疫组织化学分析、Masson 染色、天狼星红染色、RT-qPCR 分析和 Western blot 分析评估铁沉积、免疫细胞浸润、纤维化、氧化应激和铁死亡。结果发现，铁过载小鼠表现出胰腺铁过载，同时铁储存因子铁蛋白 H 的基因表达升高，铁转运介质二价金属转运蛋白 1、铁蛋白 1 和转铁蛋白受体的表达降低。铁过载小鼠发生轻度胰腺炎，血清淀粉酶和脂肪酶活性升高，促炎细胞因子白细胞介素（IL）-1β、IL-6 和诱导型一氧化氮合酶的基因表达水平升高。铁过载小鼠的胰腺出现腺泡萎缩、大量免疫细胞浸润和纤维化。作为潜在机制，铁过载小鼠的胰腺氧化应激增加，丙二醛水平升高，超氧化物歧化酶和谷胱甘肽过氧化物酶活性降低。此外，铁过载导致铁死亡，细胞色素 c 氧化酶亚基 II 表达增加，谷胱甘肽过氧化物酶 4 和溶质载体家族 7 成员 11 的转录物减少。这些结果提供了证据表明，多次腹腔注射右旋糖酐铁会导致铁过载诱导的慢性胰腺炎，这表明铁过载是胰腺炎的一个危险因素，并强调了铁在维持胰腺正常功能方面的重要性。
