Enterocyte Shedding and Epithelial Lining Repair Following Ischemia of the Human Small Intestine Attenuate Inflammation

Abstract

BackgroundRecently, we observed that small-intestinal ischemia and reperfusion was found to entail a rapid loss of apoptotic and necrotic cells. This study was conducted to investigate whether the observed shedding of ischemically damaged epithelial cells affects IR induced inflammation in the human small gut.Methods and FindingsUsing a newly developed IR model of the human small intestine, the inflammatory response was studied on cellular, protein and mRNA level. Thirty patients were consecutively included. Part of the jejunum was subjected to 30 minutes of ischemia and variable reperfusion periods (mean reperfusion time 120 (±11) minutes). Ethical approval and informed consent were obtained. Increased plasma intestinal fatty acid binding protein (I-FABP) levels indicated loss in epithelial cell integrity in response to ischemia and reperfusion (p<0.001 vs healthy). HIF-1α gene expression doubled (p = 0.02) and C3 gene expression increased 4-fold (p = 0.01) over the course of IR. Gut barrier failure, assessed as LPS concentration in small bowel venous effluent blood, was not observed (p = 0.18). Additionally, mRNA expression of HO-1, IL-6, IL-8 did not alter. No increased expression of endothelial adhesion molecules, TNFα release, increased numbers of inflammatory cells (p = 0.71) or complement activation, assessed as activated C3 (p = 0.14), were detected in the reperfused tissue.ConclusionsIn the human small intestine, thirty minutes of ischemia followed by up to 4 hours of reperfusion, does not seem to lead to an explicit inflammatory response. This may be explained by a unique mechanism of shedding of damaged enterocytes, reported for the first time by our group.

Hypoxia: an alarm signal during intestinal inflammation

“…Originally shown by microarray analysis of hypoxic intestinal epithelial cells 21 , these studies have been validated in animal models of intestinal inflammation 13,23–27 and in human intestinal inflammation tissues 28–30 . The functional proteins encoded by hypoxia-induced, HIF-dependent mRNAs localize primarily to the most luminal aspect of polarized epithelia.…”

Deleterious effects of intestinal ischemia/reperfusion injury in the mouse enteric nervous system are associated with protein nitrosylation

“…The intestinal damage that ensues includes injury to the mucosal barrier and to enteric neurons. Damage to the mucosa can include epithelial shedding, bacterial translocation from the lumen into the gut wall, alteration of absorptive function, disordered mucosal permeability and prolonged reduction in intestinal blood flow (Granger and Korthuis 1995;An et al 2005;Matthijsen et al 2009). Enteric neurons are damaged and some neurons die after ischemia/reperfusion injury (Piao et al 1999;Lindeström and Ekblad 2004;Calcina et al 2005;Silva et al 2007;Mei et al 2009;Rivera et al 2009).…”

Damaging effects of ischemia/reperfusion on intestinal muscle

“…The epithelial surface of the mucosa can be lost, at least in the short term, which allows bacteria and toxins to enter the gut wall, compromises the ordered absorption of nutrients, and disturbs regulated water and electrolyte transport (Granger and Korthuis 1995;An et al 2005;Matthijsen et al 2009). The epithelium repairs within a few days of the restoration of blood flow , but abnormalities of absorptive function are seen beyond this time (Kuenzler et al 2002;Sileri et al 2002).…”