Pulmonary Injury Following Intestinal Ischemia and Reperfusion in Rats

Sammanfattning: Intestinal ischemia and reperfusion (I/R) is a potentially life-threatening condition, sometimes leading to a systemic inflammatory response and the potential development of the multiple organ dysfunction syndrome. The overall aim of the thesis was to study the effects of intestinal I/R on pulmonary function with special emphasis on removal of excess alveolar fluid, pulmonary endothelial barrier permeability, leukocyte accumulation and function, and possible therapeutic strategies to prevent the development of pulmonary injury following intestinal I/R. Intestinal I/R was induced by clamping of the superior mesenteric artery for 40-45 min in male Sprague-Dawley rats, after which reperfusion was allowed for up to 12 hours. Results show that intestinal I/R leads to an inflammatory response locally as well as in the lungs, with increased tissue and plasma levels of TNF-alpha and MCP-1, neutrophil accumulation in intestinal and pulmonary tissue, and an increase in pulmonary phagocytic capacity. The results also demonstrate increased intestinal and pulmonary endothelial permeabilities, a decrease in pulmonary tissue blood content, disruption of normal alveolar type II epithelial cell morphology, and stimulation of alveolar fluid clearance (AFC) through a non-catecholamine dependent mechanism. Protective effects of NAC, a broad-acting antioxidant, administration before the onset of reperfusion indicates involvement of oxygen free radicals in intestinal I/R-induced macrophage activation and decreased blood content. TNF-alpha monoclonal antibodies administered before the onset of intestinal I/R decreased AFC stimulation, indicating the involvement of TNF-alpha in the AFC stimulation. Inhibition of the tissue factor (TF) VIIa complex formation by FVIIa-inhibition can attenuate the inflammatory response that occurs in assocation with intestinal I/R. The selective Factor Xa-inhibitor fondaparinux did, however, not demonstrate a convincing anti-inflammatory effect. Such properties are though not to be excluded since very limited dose response data exists with regard to potential anti-inflammatory properties also for FXa-inhibition.