Boggio Veronica, Gonzalez Claudio Daniel, Zotta Elsa, Ropolo Alejandro, Vaccaro Maria Ines
Instituto de Bioquímica y Biología Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
Centro de Educación Medica e Investigaciones Clínicas (CEMIC), Hospital Universitario Saavedra, Buenos Aires 1431, Argentina.
Int J Mol Sci. 2025 Mar 29;26(7):3196. doi: 10.3390/ijms26073196.
Acute pancreatitis (AP) an inflammatory condition caused by the premature activation of pancreatic proteases, leads to organ damage, systemic inflammation, and multi-organ failure. Severe acute pancreatitis (SAP) has high morbidity and mortality, affecting the liver, kidneys, and lungs. Autophagy maintains pancreatic homeostasis, with VMP1-mediated selective autophagy (zymophagy) preventing intracellular zymogen activation and acinar cell death. This study examines the protective role of VMP1 (Vacuole Membrane Protein 1)-induced autophagy using ElaI-VMP1 transgenic mice in a necrohemorrhagic SAP model (Hartwig's model). ElaI-VMP1 mice show significantly reduced pancreatic injury, including lower necrosis, edema, and inflammation, compared to wild-type (WT) mice. Biochemical markers (lactate dehydrogenase-LDH-, amylase, and lipase) and histopathology confirm that VMP1 expression mitigates pancreatic damage. Increased zymophagy negatively correlates with acinar necrosis, reinforcing its protective role. Beyond the pancreas, ElaI-VMP1 mice exhibit preserved liver, kidney, and lung histology, indicating reduced systemic organ damage. The liver maintains normal architecture, kidneys show minimal tubular necrosis, and lung inflammation features are reduced compared to WT mice. Our results confirm that zymophagy functions as a protective pathophysiological mechanism against pancreatic and extrapancreatic tissue injury in SAP. Further studies on the mechanism of VMP1-mediated selective autophagy in AP are necessary to determine its relevance and possible modulation to prevent the severity of AP.
急性胰腺炎（AP）是一种由胰腺蛋白酶过早激活引起的炎症性疾病，可导致器官损伤、全身炎症和多器官功能衰竭。重症急性胰腺炎（SAP）具有高发病率和死亡率，会影响肝脏、肾脏和肺。自噬维持胰腺内环境稳定，VMP1介导的选择性自噬（酶原自噬）可防止细胞内酶原激活和腺泡细胞死亡。本研究使用ElaI-VMP1转基因小鼠在坏死性出血性SAP模型（哈特维希模型）中研究VMP1（液泡膜蛋白1）诱导的自噬的保护作用。与野生型（WT）小鼠相比，ElaI-VMP1小鼠的胰腺损伤明显减轻，包括坏死、水肿和炎症程度降低。生化标志物（乳酸脱氢酶-LDH-、淀粉酶和脂肪酶）和组织病理学证实VMP1表达减轻了胰腺损伤。酶原自噬增加与腺泡坏死呈负相关，增强了其保护作用。除胰腺外，ElaI-VMP1小鼠的肝脏、肾脏和肺组织学表现正常，表明全身器官损伤减轻。与WT小鼠相比，肝脏维持正常结构，肾脏显示最小程度的肾小管坏死，肺部炎症特征减轻。我们的结果证实，酶原自噬作为一种保护性病理生理机制，可抵御SAP中胰腺和胰腺外组织损伤。有必要进一步研究VMP1介导的AP选择性自噬机制，以确定其相关性以及可能的调节方式，从而预防AP的严重程度。
