Gukovskaya Anna S, Pandol Stephen J, Gukovsky Ilya
aUniversity of California; VA Greater Los Angeles Healthcare System bCedars-Sinai Medical Center, Los Angeles, California, USA.
Curr Opin Gastroenterol. 2016 Sep;32(5):429-435. doi: 10.1097/MOG.0000000000000301.
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.
在本文中，我们讨论了一些最新研究，这些研究增进了我们对引发和推动胰腺炎的分子及细胞因子的理解，重点关注腺泡细胞细胞器功能紊乱的作用。
胰腺腺泡细胞的核心生理功能——合成、储存和分泌消化酶——严重依赖于内质网（ER）、内溶酶体系统、线粒体和自噬的协同作用。最近的研究开始揭示这些细胞器功能紊乱在胰腺炎发病机制中的作用。缺乏关键自噬调节因子Atg5或Atg7，或溶酶体相关膜蛋白2的小鼠，胰腺腺泡细胞中多种信号和代谢途径失调，并发展为自发性胰腺炎。在多个临床相关实验模型中，通透性转换孔持续开放导致的线粒体功能障碍被证明可介导胰腺炎，通过药物或基因手段抑制该功能可大大减轻局部和全身的病理反应。抑制ORAI1（质膜通道的关键成分，介导腺泡细胞胞质Ca2+病理性升高）也可减轻实验性胰腺炎。越来越多的促胰腺炎突变与内质网应激相关。这些发现提示了胰腺炎治疗的新途径和药物靶点。此外，最近的研究还确定了胰腺炎炎症及其他反应的新介质（如中性粒细胞胞外诱捕网）。
最近的研究结果阐明了细胞器在调节自噬、内溶酶体、线粒体和内质网途径以维持胰腺腺泡细胞内稳态和分泌功能方面的关键作用；提供了令人信服的证据，表明细胞器功能紊乱是引发和推动胰腺炎的关键致病机制；并确定了可作为靶点以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。
