Lugea Aurelia, Waldron Richard T, Mareninova Olga A, Shalbueva Natalia, Deng Nan, Su Hsin-Yuan, Thomas Diane D, Jones Elaina K, Messenger Scott W, Yang Jiayue, Hu Cheng, Gukovsky Ilya, Liu Zhenqiu, Groblewski Guy E, Gukovskaya Anna S, Gorelick Fred S, Pandol Stephen J
Department of Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California.
Department of Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California.
Am J Pathol. 2017 Dec;187(12):2726-2743. doi: 10.1016/j.ajpath.2017.08.017. Epub 2017 Sep 19.
Knowledge of the molecular mechanisms of acute pancreatitis is largely based on studies using rodents. To assess similar mechanisms in humans, we performed ex vivo pancreatitis studies in human acini isolated from cadaveric pancreata from organ donors. Because data on these human acinar preparations are sparse, we assessed their functional integrity and cellular and organellar morphology using light, fluorescence, and electron microscopy; and their proteome by liquid chromatography-tandem mass spectrometry. Acinar cell responses to the muscarinic agonist carbachol (CCh) and the bile acid taurolithocholic acid 3-sulfate were also analyzed. Proteomic analysis of acini from donors of diverse ethnicity showed similar profiles of digestive enzymes and proteins involved in translation, secretion, and endolysosomal function. Human acini preferentially expressed the muscarinic acetylcholine receptor M3 and maintained physiological responses to CCh for at least 20 hours. As in rodent acini, human acini exposed to toxic concentrations of CCh and taurolithocholic acid 3-sulfate responded with trypsinogen activation, decreased cell viability, organelle damage manifest by mitochondrial depolarization, disordered autophagy, and pathological endoplasmic reticulum stress. Human acini also secreted inflammatory mediators elevated in acute pancreatitis patients, including IL-6, tumor necrosis factor-α, IL-1β, chemokine (C-C motif) ligands 2 and 3, macrophage inhibitory factor, and chemokines mediating neutrophil and monocyte infiltration. In conclusion, human cadaveric pancreatic acini maintain physiological functions and have similar pathological responses and organellar disorders with pancreatitis-causing treatments as observed in rodent acini.
急性胰腺炎分子机制的知识很大程度上基于对啮齿动物的研究。为了评估人类中的类似机制，我们对从器官捐献者尸体胰腺中分离出的人类腺泡进行了体外胰腺炎研究。由于关于这些人类腺泡制剂的数据稀少，我们使用光学显微镜、荧光显微镜和电子显微镜评估了它们的功能完整性以及细胞和细胞器形态；并通过液相色谱-串联质谱分析了它们的蛋白质组。还分析了腺泡细胞对毒蕈碱激动剂卡巴胆碱（CCh）和胆汁酸牛磺石胆酸3-硫酸盐的反应。对来自不同种族捐献者的腺泡进行蛋白质组分析，结果显示参与翻译、分泌和内溶酶体功能的消化酶和蛋白质具有相似的谱型。人类腺泡优先表达毒蕈碱型乙酰胆碱受体M3，并对CCh保持至少20小时的生理反应。与啮齿动物腺泡一样，暴露于有毒浓度的CCh和牛磺石胆酸3-硫酸盐的人类腺泡会出现胰蛋白酶原激活、细胞活力下降、线粒体去极化表现的细胞器损伤以及自噬紊乱和病理性内质网应激。人类腺泡还分泌急性胰腺炎患者体内升高的炎症介质，包括白细胞介素-6、肿瘤坏死因子-α、白细胞介素-1β、趋化因子（C-C基序）配体-2和-3、巨噬细胞抑制因子以及介导中性粒细胞和单核细胞浸润的趋化因子。总之，人类尸体胰腺腺泡保持生理功能，并且在胰腺炎诱导治疗下具有与啮齿动物腺泡中观察到的相似的病理反应和细胞器紊乱。
