Liu Zhu, Zhang Tan, Ergashev Akmal, Bo Zhiyuan, Wang Jinhui, Shi Fengyu, Pan Zhenyan, Xie Haonan, Chen Gang, Ma Feng, Kong Lingming
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Zhejiang Key Laboratory of intelligent Cancer Biomarker Discovery & Translation, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, 325035, China; Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, Wenzhou, Zhejiang, 325035, China; Department of Hepatobiliary Surgery, Pingyang People's Hospital Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Zhejiang Key Laboratory of intelligent Cancer Biomarker Discovery & Translation, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, 325035, China; Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, Wenzhou, Zhejiang, 325035, China.
Phytomedicine. 2025 Jan;136:156263. doi: 10.1016/j.phymed.2024.156263. Epub 2024 Nov 19.
Acute pancreatitis (AP) is a prevalent and serious condition within the digestive system, with approximately 20 % to 30 % of cases advancing to severe acute pancreatitis (SAP). During the initial phases of SAP, macrophages are activated in response to the substantial amounts of acinar cell contents and damage-associated molecular patterns (DAMPs) resulting from acinar cell destruction. Subsequently, activated macrophages release a significant array of pro-inflammatory factors that exacerbate the progression of SAP. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic protein that is intimately linked to immune regulation. While the role of CIP2A in T-cell-mediated specific immune responses has been reported, its function and mechanism in macrophages, a component of non-specific immunity, have not been widely studied. This research fills this knowledge gap by elucidating the critical role of CIP2A in regulating macrophage autophagy and inflammation. This finding not only expands our understanding of CIP2A in immune modulation but also provides a new scientific basis and potential application prospects for targeting CIP2A in the treatment of AP.
We established AP using a combination of palmitoleic acid with anhydrous ethanol or using caerulein alone. The effects of TD52 and Ethoxysanguinarine (Etho) on SAP were evaluated through serological, histopathological, and tissue inflammation observations. The effect of TD52 on macrophage activation in vitro was examined using primary macrophages (PMs) and RAW264.7 cells.
We found that TD52 and Etho inhibit CIP2A expression while reducing the levels of serum amylase, lipase, and inflammatory cytokines, thereby alleviating the pathological symptoms of SAP. Additionally, TD52 could reduce the infiltration of macrophages into pancreatic tissue. Therefore, we established a model of macrophage inflammatory response mimicking the pathophysiological process of AP and detected changes in inflammation, apoptosis, and autophagy through pre-treatment of macrophages with TD52. The results show that inhibiting CIP2A expression decreases the release of inflammatory cytokines and reduces apoptosis in macrophages. Further exploration revealed that TD52 promoted macrophage autophagy regulation and inhibited the AKT-mTOR pathway to modulate macrophage activation.
In summary, our findings indicate that TD52 and Etho can alleviate the severity of SAP. TD52 can block the AKT-mTOR pathway to promote macrophage autophagy, thereby improving SAP. Thus, CIP2A may serve as one of the molecular targets in SAP, highlighting its potential as a therapeutic option.
急性胰腺炎（AP）是消化系统中一种常见且严重的病症，约20%至30%的病例会进展为重症急性胰腺炎（SAP）。在SAP的初始阶段，巨噬细胞会因腺泡细胞大量内容物以及腺泡细胞破坏产生的损伤相关分子模式（DAMPs）而被激活。随后，活化的巨噬细胞会释放大量促炎因子，加剧SAP的进展。蛋白磷酸酶2A癌性抑制剂（CIP2A）是一种致癌蛋白，与免疫调节密切相关。虽然已有报道CIP2A在T细胞介导的特异性免疫反应中的作用，但其在作为非特异性免疫组成部分的巨噬细胞中的功能和机制尚未得到广泛研究。本研究通过阐明CIP2A在调节巨噬细胞自噬和炎症中的关键作用填补了这一知识空白。这一发现不仅扩展了我们对CIP2A在免疫调节中的理解，还为靶向CIP2A治疗AP提供了新的科学依据和潜在应用前景。
我们通过棕榈油酸与无水乙醇联合使用或单独使用雨蛙素建立AP模型。通过血清学、组织病理学和组织炎症观察评估TD52和乙氧基血根碱（Etho）对SAP的影响。使用原代巨噬细胞（PMs）和RAW264.7细胞检测TD52对体外巨噬细胞活化的影响。
我们发现TD52和Etho抑制CIP2A表达，同时降低血清淀粉酶、脂肪酶和炎性细胞因子水平，从而减轻SAP的病理症状。此外，TD52可减少巨噬细胞向胰腺组织的浸润。因此，我们建立了一个模拟AP病理生理过程的巨噬细胞炎症反应模型，并通过用TD52预处理巨噬细胞来检测炎症、凋亡和自噬的变化。结果表明，抑制CIP2A表达可减少炎性细胞因子的释放并降低巨噬细胞凋亡。进一步探索发现，TD52促进巨噬细胞自噬调节并抑制AKT - mTOR途径以调节巨噬细胞活化。
总之，我们的研究结果表明TD52和Etho可减轻SAP的严重程度。TD52可阻断AKT - mTOR途径以促进巨噬细胞自噬，从而改善SAP。因此，CIP2A可能作为SAP的分子靶点之一，突出了其作为治疗选择的潜力。
