Intestinal I/R is considered to be an important initiating event in several pathophysiological conditions such as trauma, bleeding, sepsis and pancreatitis, frequently leading to concomitant both single and potentially multiple organ dysfunction. The purpose of this thesis was to study mechanims underlying the development of multiple organ dysfunction, with special focus on intercellular proinflammatory regulation in the concurrent development of tissue injury. A further aim was to evaluate novel forms of therapy and prevention against the development of multipel organ dysfunction. Experimental intestinal I/R was induced by clamping the superior mesenteric artery in male Sprague-Dawley rats for 40 min, followed by reperfusion up to 12 hrs. Treatment attempts with N-Acetylcystein (NAC), the platelet activating factor (PAF) inhibitor lexipafant, monoclonal antibodies (MAbs) against platelet endothelial cell adhesion molecule-1 (PECAM-1), active-site-inactivated FVIIa (FVIIai) or the FXa inhibitor fondaparinux were tested. It was found that intestinal I/R induced an increase in intercellular adhesion molecule-1 (ICAM-1) expression in different tissues with marked organ variability. In parallel, an inflammatory response with neutrophil recruitment in the lungs and intestines as well as an increased endothelial barrier permeability in several organs was observed. Inflammatory mediators such as TNF-a, IL-1b, MCP-1 and MIP-2 also increased, with an earlier response in organs directly affected by the I/R-injury than in organs more distantly located. Treatment 15 min after the start of reperfusion with NAC and lexipafant attenuated the inflammatory response, but did not affect the ICAM-1 expression, suggesting that the protective effects of NAC and PAF-inhibition is not mediated via decreased expression of ICAM-1. Therapy inserted at 3 hrs of reperfusion, also decreased the inflammatory response and tissue injury, although not as pronounced as demonstrated after early treatment. Administration of the anticoagulants FVIIai or fondaparinux resulted in decreased plasma levels of the neutrophil chemoattractant MIP-2, whereas only FVIIai restored endothelial barrier dysfunction and decreased intestinal neutrophil recruitment. This demonstrates that inhibition of the TF-FVIIai complex formation by FVIIai can attenuate inflammatory responses in connection with intestinal I/R. Based on our results, we suggest that a multimodal treatment regime with inhibitors against inflammatory mediators such as oxygen free radicals, platelet activating factor and coagulation factors such as FVIIa and FXa, could represent potential future strategies in the prevention and treatment of organ dysfunction in hyperinflammatory states, seen e.g. in association with critical illness.
|Award date||2003 Nov 27|
|Publication status||Published - 2003|
Bibliographical noteDefence details
Place: Lecture room 3, Main building, Lund University Hospital
Name: Tönnesen, Else
Affiliation: Aarhus, Denmark
Article: I. Olanders K, Sun ZW, Börjesson A, Dib M, Andersson E, Lasson Å, Ohlsson T, Andersson R. The effect of intestinal ischemia and reperfusion injury on ICAM-1 expression, endothelial barrier function, neutrophil tissue influx and protease inhibitor levels in rats. Shock 2002; 18:86-92.
Article: II. Olanders K, Börjesson A, Zhao X, Wang XD, Andersson R. The influence of intestinal ischemia and reperfusion on tissue TNF-a and MCP-1 levels in rats. Submitted for publication.
Article: III. Olanders K, Börjesson A, Sun ZW, Andersson R. Protective effects of N-Acetyl-L-Cystein and platelet activating factor inhibition are not linked to intercellular adhesion molecule-1 expression after intestinal ischemia and reperfusion in rats. Scand J Gastroenterol 2003; 38:618-25.
Article: IV. Sun ZW, Olanders K, Lasson Å, Dib M, Annborn M, Andersson K, Wang X, Andersson R. Effective treatment of gut barrier dysfunction using an antioxidant, a PAF-inhibitor, and monoclonal antibodies against the adhesion molecule PECAM-1. J Surg Res 2002; 105:220-233.
Article: V. Olanders K, Börjesson A, Zhao X, Andersson R. Effects of anticoagulant treatment on intestinal ischemia and reperfusion injury in rats. Submitted for publication.
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