6,9 By contrast, the present study provides evidence for the first time that intestinal dysfunction, and more specifically jejunal MD, occurs within hours of the onset of mild to moderate acute pancreatitis. Our findings challenge Ganetespib OSA conventional thinking by demonstrating that this early MD in the jejunum also occurs in less severe acute pancreatitis and occurs before the development of MODS or hypovolaemic shock. Consistent with our findings is previous work suggesting that intestinal mucosal injury after the induction of endotoxic shock was independent of hypoperfusion, and might be as a result of impaired mitochondrial respiration or cytopathic hypoxia.15 Interestingly, no evidence for mitochondrial dysfunction was found in the duodenum during the present study.

It has previously been reported that the jejunum has areas more susceptible to ischaemia�Creperfusion mucosal injury than the duodenum or ileum because of differences in vascular anatomy.47 This might be part of the explanation for our findings of increased MD in the jejunum but not the duodenum. Other factors, such as differences in microbes and intra-luminal content48 between the duodenum and jejunum, might also contribute to differences in mitochondrial function and this requires further investigation. Impairment of intestinal barrier function has been shown to correlate strongly with subsequent MODS and septic complications as a result of translocation of bacteria and the priming of neutrophils.6,9 Intestinal permeability to bacteria was reported to correlate inversely with enterocyte ATP levels, thereby supporting the idea that the intestinal barrier function is ATP dependent.

49 Early intestinal MD, with its concomitant decrease in ATP production and increase in ROS,10,41 may therefore underpin intestinal barrier failure, which then leads to not only the worsening of MODS by exacerbation of SIRS but also to the delayed septic complications. Thus our data suggests that jejunal mitochondria might represent a previously unrecognised and very early event in acute pancreatitis, long before increased intestinal permeability and bacterial translocation are thought to occur. As such, jejunal MD might therefore be understood as a primary step in the subsequent failure of the intestinal barrier function in MODS and thus offer a newly identified target for early intervention therapy. There are very few reports of mitochondrial function in tissues outside of the pancreas in acute pancreatitis. These have been restricted to the investigation of isolated Entinostat liver mitochondrial function in acute pancreatitis where hepatic MD has been reported in rodents with TIP.