Effects of the mitochondria-targeted antioxidant mitoquinone in murine acute pancreatitis.

Wei Huang,Rajarshi Mukherjee,Robert Sutton,Alexei V Tepikin,Jane Armstrong,Michael P Murphy,Nicole Cash,Peter Szatmary,David N Criddle,Michael Chvanov,Li Wen

doi:10.1155/2015/901780

Abstract

Although oxidative stress has been strongly implicated in the development of acute pancreatitis (AP), antioxidant therapy in patients has so far been discouraging. The aim of this study was to assess potential protective effects of a mitochondria-targeted antioxidant, MitoQ, in experimental AP using in vitro and in vivo approaches. MitoQ blocked H2O2-induced intracellular ROS responses in murine pancreatic acinar cells, an action not shared by the control analogue dTPP. MitoQ did not reduce mitochondrial depolarisation induced by either cholecystokinin (CCK) or bile acid TLCS, and at 10 µM caused depolarisation per se. Both MitoQ and dTPP increased basal and CCK-induced cell death in a plate-reader assay. In a TLCS-induced AP model MitoQ treatment was not protective. In AP induced by caerulein hyperstimulation (CER-AP), MitoQ exerted mixed effects. Thus, partial amelioration of histopathology scores was observed, actions shared by dTPP, but without reduction of the biochemical markers pancreatic trypsin or serum amylase. Interestingly, lung myeloperoxidase and interleukin-6 were concurrently increased by MitoQ in CER-AP. MitoQ caused biphasic effects on ROS production in isolated polymorphonuclear leukocytes, inhibiting an acute increase but elevating later levels. Our results suggest that MitoQ would be inappropriate for AP therapy, consistent with prior antioxidant evaluations in this disease.

Highlights

Acute pancreatitis (AP) is a severe inflammatory condition of the exocrine pancreas caused primarily by gallstones and excess alcohol [1, 2] with an incidence of approximately 30 per 100,000 per year in the United Kingdom [3]
Evidence suggests a pivotal role for calcium, with diverse AP precipitants, such as bile acids, cholecystokinin hyperstimulation, and nonoxidative ethanol metabolites, inducing calcium overload, mitochondrial dysfunction, and loss of ATP that result in acinar cell necrosis [8], the extent of which determines outcome in a clinical setting
In this study we have investigated the effects of MitoQ on isolated pancreatic acinar cells, polymorphonuclear leukocytes (PMNs), and in two murine in vivo experimental AP models

Summary

Introduction

Acute pancreatitis (AP) is a severe inflammatory condition of the exocrine pancreas caused primarily by gallstones and excess alcohol [1, 2] with an incidence of approximately 30 per 100,000 per year in the United Kingdom [3]. Most patients have a mild and self-limiting clinical course [4] roughly 15–20% of cases involve potentially lethal complications such as persistent organ failure and infected pancreatic necrosis [5], resulting in a heavy socioeconomical burden [6]. The initial site of damage in AP is considered to be the pancreatic acinar cell, which exhibits pathological features including premature activation of digestive enzyme precursors, inhibition of apical secretion, disordered autophagy and lysosomal degradation, mitochondrial dysfunction, and release of inflammatory cytokines [7]. Evidence suggests a pivotal role for calcium, with diverse AP precipitants, such as bile acids, cholecystokinin hyperstimulation, and nonoxidative ethanol metabolites, inducing calcium overload, mitochondrial dysfunction, and loss of ATP that result in acinar cell necrosis [8], the extent of which determines outcome in a clinical setting. Localised and systemic inflammatory responses are features of AP progression, involving activation

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