Role of haem oxygenase in ischaemic preconditioning on the intestinal microcirculation following ischaemia reperfusion injury
Intestinal ischaemia reperfusion (IR) injury is associated with various clinical conditions such as hypovolemic shock, strangulation-obstruction, cardiovascular surgery, abdominal aortic surgery and small bowel transplantation. IR injury of the intestine is a systemic phenomenon resulting in bacterial translocation, endotoxaemia, acute respiratory distress syndrome and acute hepatic injury culminating in multiple organ failure. It has been hypothesised that ischaemic preconditioning may protect against IR injury of the intestine through haem oxygenase formation. This thesis (study) investigated the relationship of haem oxygenase metabolism with intestinal microvascular perfusion, tissue oxygenation and function with ischaemic preconditioning of the intestine in an experimental model of ischaemia reperfusion injury of the small intestine. Male Sprague Dawley rats (250-300 grams) were subjected to 30 mins of ischaemia by clamping of superior mesenteric artery followed by 2 hrs (early phase) or 24 hrs (late phase) of reperfusion. Ischaemic preconditioning was performed with 10 min ischaemia and 10 min reperfusion before the sustained ischaemia. Pyrrolidine dithiocarbamate (PDTC) or Zinc Protoporrphyrrin (ZnPP) were administered to stimulate or block heme oxygenase synthesis. The study demonstrated that ischaemic preconditioning resulted in significantly improvement in intestinal microvascular perfusion, tissue oxygenation as well as decreased leukocyte-endothelial interactions and intestinal and pulmonary injury following both early and late phases of IR injury. The preconditioning effect was associated with significantly increased haem oxygenase production suggested by intestinal tissue haeme oxygenase levels as demonstrated by haem oxygenase assays and western blotting. PDTC treatment reproduced the protective effect of ischaemic preconditioning. Haem oxygenase inhibition with ZnPP antagonized the protective effect of ischaemic preconditioning. This thesis has shown that the protective effect of intestinal ischaemic preconditioning against both early and late phases of IR injury is associated with increased haem oxygenase production. These data may have important implications in intestinal surgery and transplantation and may lead to the development of pharmacological strategies for protecting the intestine from ischaemic injury.