Introduction: More than 90% of patients undergoing abdominal surgery develop adhesions and adhesion formation is nowadays the most common cause of small bowel obstruction. Surgery and inflammation is associated with adhesion formation. There is a growing body of evidence showing that a balance between fibrin deposition and breakdown is pivotal in an early phase of adhesion development, but the molecular mechanisms are not fully understood.Aims: 1) To characterise the expression of fibrinolytic components in peritoneal tissue in patients with and without peritonitis. 2) To investigate which cells express fibrinolytic components. 3) To culture human mesothelial cells and to characterise their fibrinolytic response to proinflammatory mediators. 4) To investigate if there is a relationship between peritoneal fibrinolytic capacity and the propensity to develop adhesions.Material and methods: Plasma samples, peritoneal biopsies and adhesion tissue were sampled during surgery. In addition, peritoneal fluid and lavage were collected. Plasma, tissue extracts and conditioned cell medium were analysed with ELISAs. Levels of the fibrinolytic components including tissue plasminogen activator (t-PA), urokinase plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and the inactive t-PA/PAI complex were measured. Immunohistochemistry was carried out using specific antibodies to localise fibrinolytic components.Results: Patients with peritonitis had a reduced peritoneal fibrinolytic capacity, with a decreased t-PA activity (p<0.05) and increased PAI-1 (p<0.05) compared with those without inflammation.During surgery there was a rapid decline in t-PA activity (p<0.0001) and increase in uPA (p<0.01), PAI-1 (p<0.01) and t-PA/PAI complex (p<0.01). The peripheral blood and peritoneal concentrations of fibrinolytic parameters did not correlate. Mesothelial cells expressed immunoreactivity for t-PA, uPA and PAI-1, irrespective of the presence of inflammation. In inflammation PAI-1 and PAI-2 expression was more wide spread. The submesothelial expression of uPA and PAI-1 was partly co-localised with macrophages. Cultured mesothelial cells expressed t-PA, uPA, PAI-1 and PAI-2 constitutively. Treatment with the proinflammatory mediators LPS and TNF-a resulted in an overall decreased fibrinolytic capacity. Patients with severe adhesions had increased PAI-1 (p<0.01) and t-PA/PAI complex (p<0.01) in peritoneum compared to those that were less prone to develop adhesions. Adhesion tissue had reduced fibrinolytic capacity by a decrease in t-PA activity (p<0.01) and an increase in PAI-1 (p=0.01) reflected in elevated t-PA/PAI complex (p<0.01) compared to adjacent unaffected peritoneum.Conclusions: These observations provide novel insight into tissue response to surgery and inflammation that may lead to new therapeutic strategies. These results also suggest that components of the fibrinolytic system, particularly PAI-1 could be used as tissue markers of the propensity to develop extensive postsurgical adhesions.
Göteborgs universitet/University of Gothenburg
Department of Surgery
Avdelningen för kirurgi
Date of defence