Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

Abstract

Introduction: Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis.

Methods: Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n= 8), saline control; Group 2 (n= 6), caerulein-induced mild acute pancreatitis; Group 3 (n= 7) sham surgical controls; and Group 4 (n= 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry.

Results: Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected.

Conclusions: The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis.

Figure 1

Representative trace generated by the OROBOROS® Oxygraph 2 K. Solid line represents mitochondrial respiration (left y-axis) and the dotted line represents the oxygen concentration (right y-axis). LEAK: state 2 respiration with glutamate and malate. OXP-I: oxidative phosphorylation with Complex I substrates (state 3 respiration) with the addition of adenosine diphosphate (ADP). OXP-I,II: state 3 respiration with succinate a Complex II substrate. ETS-I,II: uncoupled respiration with addition of carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone (FCCP). ETS-I,II: addition of rotenone. CCO: addition of tetramethyl-p-phenylenediamine (TMPD)/ascorbate. CCOc addition of cytochrome C. Cyto C: cytochrome C. Ant A: antimycin A. Concomitant oxygen concentration (nmol/ml) is shown on the right y-axis

Figure 2

A summary of the effects of caerulein pancreatitis, sham surgery and taurocholate pancreatitis on the various respiratory chain complexes. For definitions of LEAK-I through to CCOc see legend for Figure 1. ‘-’ represents inhibition of the complex. Letters ‘a’, ‘b’ and ‘c’ represent significant inhibition of the complex whereby a: caerulein pancreatitis vs. saline control; b: sham surgery vs. saline control; c: taurocholate pancreatitis vs. sham surgery.