Sun Shukun, Han Yu, Zhang Chuanxin, Liu Han, Wang Bailu, Cao Shengchuan, Yuan Qiuhuan, Wei Shujian, Chen Yuguo
Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China.
Front Cell Dev Biol. 2022 Feb 23;10:827714. doi: 10.3389/fcell.2022.827714. eCollection 2022.
Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the effects of ADK inhibition on cerulein-induced inflammation and necroptotic cell death. ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein-treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both and . Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A receptor antagonist. ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP the adenosine A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.
炎症紊乱和腺泡细胞死亡促成了重症急性胰腺炎（SAP）的起始和进展。腺苷激酶（ADK）对炎症和细胞死亡均具有潜在影响。然而，ADK在SAP中的作用仍有待探索。为建立实验性SAP模型，给雄性C57BL/6小鼠腹腔注射雨蛙素（50μg/kg，每小时注射一次，共七剂）和脂多糖（10mg/kg，在最后一次注射雨蛙素时注射）。为抑制ADK，在雨蛙素处理前1小时腹腔注射ABT702（1.5mg/kg）。收集胰腺和血清并进行分析，以确定胰腺损伤的严重程度并探索潜在的病理生理机制。使用胰腺腺泡细胞（AR42J）来探究ADK抑制对雨蛙素诱导的炎症和坏死性细胞死亡的影响。ADK抑制显著减轻了SAP的严重程度，血清淀粉酶（7,416.76±1,457.76对4,581.89±1,175.04U/L）和脂肪酶（46.51±11.50对32.94±11.46U/L）水平降低以及胰腺组织病理学改变减少（组织学评分：6.433±0.60对3.77±0.70）表明了这一点。MOMA-2和CD11b染色证实ADK抑制可防止中性粒细胞和巨噬细胞浸润。ADK抑制还降低了核因子-κB（NF-κB）的磷酸化水平。ADK抑制显著限制了胰腺的坏死面积并阻止了坏死性信号通路的激活。使用SAP模型和雨蛙素处理的AR42J细胞激活了胰腺中的内质网（ER）应激，而ADK抑制在体内和体外均逆转了ER应激的激活。此外，腺苷A受体拮抗剂消除了ADK抑制对ER应激、炎症和细胞坏死性凋亡的缓解作用。ADK抑制通过腺苷A受体/ER应激途径减少了SAP中的炎症和坏死性腺泡细胞死亡，这表明ADK可能是SAP的一个潜在治疗靶点。
