New insights into the pathways initiating and driving pancreatitis.
New insights into the pathways initiating and driving pancreatitis.
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DOI：
10.1097/mog.0000000000000301
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发表时间：
2016-09
影响因子：
2.5
通讯作者：
Gukovsky I
中科院分区：
文献类型：
--
作者：
Gukovskaya AS;Pandol SJ;Gukovsky I
在这篇文章中，我们讨论了最近的研究，这些研究促进了我们对引发和推动胰腺炎的分子和细胞因素的理解，重点是腺泡细胞细胞器紊乱的作用。胰腺腺泡细胞的中枢生理功能--合成、储存和分泌消化酶--在很大程度上依赖于内质网(ER)、内溶酶系统、线粒体和自噬的协调作用。最近的研究开始揭示这些细胞器的紊乱在胰腺炎发病机制中的作用。缺乏关键自噬介质ATG5或ATG7或溶酶体相关膜蛋白-2的小鼠，表现出胰腺腺泡细胞多条信号和代谢途径的失调，并发展为自发性胰腺炎。在几个临床相关的实验模型中，由通透性转换孔持续开放引起的线粒体功能障碍被证明是介导胰腺炎的媒介，而药物或遗传手段对其的抑制大大降低了局部和全身的病理反应。ORAI1的抑制剂也可以缓解实验性胰腺炎，ORAI1是质膜通道的关键成分，介导腺泡细胞胞浆钙离子的病理性升高。促进胰腺炎的突变越来越多地与内质网应激有关。这些发现为治疗胰腺炎提供了新的途径和药物靶点。此外，最近的研究发现了胰腺炎炎症和其他反应的新介质(例如，中性粒细胞细胞外陷阱)。最近的研究结果阐明了细胞器在维持胰腺腺泡细胞内稳态和分泌功能中的关键作用，细胞器调节自噬、内溶体、线粒体和内质网途径；提供了有力的证据表明细胞器紊乱是引发和驱动胰腺炎的关键致病机制；并确定了可以靶向恢复细胞器功能从而减轻或治疗胰腺炎的分子和细胞因子。
In this article, we discuss recent studies that advance our understanding of molecular and cellular factors initiating and driving pancreatitis, with the emphasis on the role of acinar cell organelle disorders. The central physiologic function of the pancreatic acinar cell – to synthesize, store, and secrete digestive enzymes – critically relies on coordinated actions of the endoplasmic reticulum (ER), the endolysosomal system, mitochondria, and autophagy. Recent studies begin to unravel the roles of these organelles’ disordering in the mechanism of pancreatitis. Mice deficient in key autophagy mediators Atg5 or Atg7, or lysosome-associated membrane protein-2, exhibit dysregulation of multiple signaling and metabolic pathways in pancreatic acinar cells and develop spontaneous pancreatitis. Mitochondrial dysfunction caused by sustained opening of the permeability transition pore is shown to mediate pancreatitis in several clinically relevant experimental models, and its inhibition by pharmacologic or genetic means greatly reduces local and systemic pathologic responses. Experimental pancreatitis is also alleviated with inhibitors of ORAI1, a key component of the plasma membrane channel mediating pathologic rise in acinar cell cytosolic Ca2+. Pancreatitis-promoting mutations are increasingly associated with the ER stress. These findings suggest novel pathways and drug targets for pancreatitis treatment. In addition, the recent studies identify new mediators (e.g., neutrophil extracellular traps) of the inflammatory and other responses of pancreatitis. The recent findings illuminate a critical role of organelles regulating the autophagic, endolysosomal, mitochondrial, and ER pathways in maintaining pancreatic acinar cell homeostasis and secretory function; provide compelling evidence that organelle disordering is a key pathogenic mechanism initiating and driving pancreatitis; and identify molecular and cellular factors that could be targeted to restore organellar functions and thus alleviate or treat pancreatitis.