Background & Aims

Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca²⁺, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats.

Methods

Pancreatitis was induced in C57BL/6J mice (control) and mice deficient in peptidylprolyl isomerase D (cyclophilin D, encoded by Ppid) by administration of L-arginine (also in rats), caerulein, bile acid, or an AP-inducing diet. Parameters of pancreatitis, mitochondrial function, autophagy, ER stress, and lipid metabolism were measured in pancreatic tissue, acinar cells, and isolated mitochondria. Some mice with AP were given trehalose to enhance autophagic efficiency. Human pancreatitis tissues were analyzed by immunofluorescence.

Results

Mitochondrial dysfunction in pancreas of mice with AP was induced by either mitochondrial Ca²⁺ overload or through a Ca²⁺ overload-independent pathway that involved reduced activity of ATP synthase (80% inhibition in pancreatic mitochondria isolated from rats or mice given L-arginine). Both pathways were mediated by cyclophilin D and led to mitochondrial depolarization and fragmentation. Mitochondrial dysfunction caused pancreatic ER stress, impaired autophagy, and deregulation of lipid metabolism. These pathologic responses were abrogated in cyclophilin D-knockout mice. Administration of trehalose largely prevented trypsinogen activation, necrosis, and other parameters of pancreatic injury in mice with L-arginine AP. Tissues from patients with pancreatitis had markers of mitochondrial damage and impaired autophagy, compared with normal pancreas.

Conclusions

In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine–induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP.

中文翻译：

---

线粒体功能障碍，通过受损的自噬，导致动物模型中的内质网应激、脂质代谢失调和胰腺炎

背景与目标

关于引发和促进急性胰腺炎 (AP) 的信号通路知之甚少。AP的发病机制与胞质Ca ²⁺异常升高、线粒体功能障碍、自噬受损和内质网（ER）应激有关。我们分析了这些功能障碍的机制及其关系，以及它们如何促进小鼠和大鼠 AP 的发展。

方法

在 C57BL/6J 小鼠（对照）和缺乏肽基脯氨酰异构酶 D（亲环蛋白 D，由Ppid编码）的小鼠中，通过施用 L-精氨酸（也在大鼠中）、雨蛙素、胆汁酸或诱导 AP 的饮食诱导胰腺炎。在胰腺组织、腺泡细胞和分离的线粒体中测量胰腺炎、线粒体功能、自噬、ER 应激和脂质代谢的参数。一些患有 AP 的小鼠被给予海藻糖以增强自噬效率。通过免疫荧光分析人胰腺炎组织。

结果

AP小鼠胰腺线粒体功能障碍是由线粒体Ca ²⁺超载或通过Ca ^{2+引起的。}与 ATP 合酶活性降低有关的过载非依赖性途径（从给予 L-精氨酸的大鼠或小鼠分离的胰腺线粒体中抑制 80%）。两种途径均由亲环蛋白 D 介导并导致线粒体去极化和碎裂。线粒体功能障碍导致胰腺内质网应激、自噬受损和脂质代谢失调。这些病理反应在亲环蛋白 D 敲除小鼠中被消除。海藻糖的给药在很大程度上阻止了 L-精氨酸 AP 小鼠胰蛋白酶原活化、坏死和其他胰腺损伤参数。与正常胰腺相比，胰腺炎患者的组织具有线粒体损伤和自噬受损的标志物。

结论

在不同的动物模型中，我们发现线粒体功能障碍和受损自噬作为其主要下游效应器在 AP 发展中的核心作用。特别是，涉及增强亲环蛋白 D 与 ATP 合酶相互作用的途径介导 L-精氨酸诱导的胰腺炎，这是一种严重 AP 模型，其发病机制仍然未知。可以制定恢复线粒体和/或自噬功能的策略来治疗 AP。