Intestinal Ischemia and Reperfusion Injury - Pathophysiology as basis for novel treatment

Abstract: Intestinal ischemia and reperfusion (I/R) is not infrequent in the clinical situation and the intestinal barrier plays an important role in gut barrier function, preventing not at least septic complications and potentially the development of the multiple organ dysfunction syndrome. Mechanisms of intestinal I/R induced gut epithelial and endothelial barrier dysfunction and remote organ dysfunction, as well as potential preventive and therapeutic modes of management were evaluated in the rat. A short period of intestinal ischemia (20 min) was followed by an early epithelial barrier recovery as compared to longer (40 min) ischemia and same time period of reperfusion, though without obvious recovery of endothelial barrier permeability. Following the longer period of ischemia, no increased incidence of apoptosis and composition of epithelial DNA could be found. Intestinal I/R induced epithelial and endothelial barrier and remote organ dysfunction seemed to be the result not only from oxygene free radicals (OFRs), but also by other effects of over-activated phagocytic cells, cytokines like interleukin-1beta and 6, platelet-activating factor (PAF), imbalance of the protease- antiprotease system (including alfa1-macroglobulin, alfa2-antiplasmin, antithrombin III, prekallikrein, factor X) and effects depending on adhesion molecules such as ICAM-1 and PECAM-1. Pretreatment and treatment both at the early and late stage of I/R with OFR-scavengers, the antioxidant NAC, the PAF inhibitor lexipafant, and monoclonal antibodies against ICAM-1 or PECAM-1 were effective in reversing the otherwise occurring changes found like gut barrier dysfunction with increased barrier permeability, increased ileal MPO activity and bacterial translocation, consumption of protease inhibitors, and increased systemic levels of cytokines. Conclusion: Activated phagocytes, OFRs, cytokines, PAF, adhesion molecules, and imbalance in the protease-antiprotease system all seems involved in intestinal I/R induced gut endothelial and epithelial barrier as well as remote organ dysfunction. Treatment with NAC, lexipafant and/or monoclonal antibodies against PECAM-1 inserted before reperfusion or at both early or later stages of I/R were effective in reducing the changes that otherwise ocurrred after intestinal I/R.