Abstract
BackgroundIntestinal ischemia-reperfusion (IR) is a phenomenon related to physiological conditions (e.g. exercise, stress) and to pathophysiological events (e.g. acute mesenteric ischemia, aortic surgery). Although intestinal IR has been studied extensively in animals, results remain inconclusive and data on human intestinal IR are scarce. Therefore, an experimental harmless model for human intestinal IR was developed, enabling us to clarify the sequelae of human intestinal IR for the first time.Methods and FindingsIn 30 patients undergoing pancreatico-duodenectomy we took advantage of the fact that in this procedure a variable length of jejunum is removed. Isolated jejunum (5 cm) was subjected to 30 minutes ischemia followed by reperfusion. Intestinal Fatty Acid Binding Protein (I-FABP) arteriovenous concentration differences across the bowel segment were measured before and after ischemia to assess epithelial cell damage. Tissue sections were collected after ischemia and at 25, 60 and 120 minutes reperfusion and stained with H&E, and for I-FABP and the apoptosis marker M30. Bonferroni's test was used to compare I-FABP differences. Mean (SEM) arteriovenous concentration gradients of I-FABP across the jejunum revealed rapidly developing epithelial cell damage. I-FABP release significantly increased from 290 (46) pg/ml before ischemia towards 3,997 (554) pg/ml immediately after ischemia (p<0.001) and declined gradually to 1,143 (237) pg/ml within 1 hour reperfusion (p<0.001). Directly after ischemia the intestinal epithelial lining was microscopically normal, while subepithelial spaces appeared at the villus tip. However, after 25 minutes reperfusion, enterocyte M30 immunostaining was observed at the villus tip accompanied by shedding of mature enterocytes into the lumen and loss of I-FABP staining. Interestingly, within 60 minutes reperfusion the epithelial barrier resealed, while debris of apoptotic, shedded epithelial cells was observed in the lumen. At the same time, M30 immunoreactivity was absent in intact epithelial lining.ConclusionsThis is the first human study to clarify intestinal IR induced cell damage and repair and its direct consequences. It reveals a unique, endogenous clearing mechanism for injured enterocytes: rapid detachment of damaged apoptotic enterocytes into the lumen. This process is followed by repair of the epithelial continuity within an hour, resulting in a normal epithelial lining.
Highlights
Intestinal ischemia-reperfusion (IR) injury is an importantphysiological mechanism, potentially leading to a compromised mucosal barrier in numerous situations [1,2]
Endogenous clearing mechanism for injured enterocytes: rapid detachment of damaged apoptotic enterocytes into the lumen. This process is followed by repair of the epithelial continuity within an hour, resulting in a normal epithelial lining
Intensive immunostaining for Intestinal Fatty Acid Binding Protein (I-FABP) was observed in the control jejunal epithelium, mainly in the cytoplasm of the mature enterocytes and goblet cells in the upper half of the villi, whereas cells in the crypts were not stained, as previously observed in experiments by our group (Figure 2A)
Summary
Intestinal ischemia-reperfusion (IR) injury is an important (patho)physiological mechanism, potentially leading to a compromised mucosal barrier in numerous situations [1,2]. Intestinal hypoperfusion occurs during exercise both in healthy relatively untrained volunteers and in highly trained athletes, which stresses the abdominal vasodilator reserve by diverting blood flow from the splanchnic circulation to the exercise muscles [3,4,5]. An example of inherent vascular disease is acute mesenteric ischemia (AMI), which carries a high morbidity and mortality rate, both increased by frequent delays in diagnosis. Such diagnostic delays are mainly caused by non-specific signs and symptoms and limited diagnostic accuracy of the laboratory and radiological tests currently in use. An experimental harmless model for human intestinal IR was developed, enabling us to clarify the sequelae of human intestinal IR for the first time
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