Die selektive C0X-2-lnhibition reduziert das Leukozytensticking und verbessert die Mikrozirkulation bei der TNBS-Colitis

Abstract

Background: Increased leukocyte-endothelium interaction occurs during the acute phase of human colitis. It may promote the endoscopically confirmed reduction of mucosal blood flow and thus the disease activity. There are indications that this interaction is influenced by selective COX-2 inhibitors. This study examines in a rat TNBS colitis model (1) whether increased leukocyte stickers can be detected beside these capillary blood flow restrictions, as reported in earlier studies, (2) whether this phenomenon can be positively influenced by selective administration of COX-2 inhibitors, and (3) whether this has any effect on the microcirculation and (4) disease activity. Methods: Induction of colitis in rats by intrarectal instillation of 0.25 ml trinitrobenzosulfonic acid (TNBS). After 12 hours, randomization into 2 groups: group A (placebo): 1 mmol/kg b.w./day 0.9% NaCl solution. Group B (verum): 10 mg/kg b.w./day a selective COX-2 inhibitor (NS-398; Alexis Deutschland GmbH, Grünberg, Germany). Healthy animals (intrarectal saline injection) served as controls. After 48 hours, laparotomy was performed in 8 animals per group for intravital microscopic determination of (1) capillary blood flow, (2) capillary permeability, (3) leukocyte sticking, and (4) functional capillary density. Additional target parameters: hematocrit, weight, etc. Results: A significant reduction of capillary blood flow (0.6 ± 0.02 nl/cap/min) and significant increase in leukocyte sticking (n= 16.3 ± 1.54) was observed in group A compared to controls (2.3 ± 0.02 nl/cap/min and n = 0.1 ± 0.06). On the other hand, the administration of selective COX-2 inhibitors (NS-398) in group B led to a significant improvement of both capillary blood flow (1.1 ±0.02 nl/cap/min) and leukocyte sticking (n = 6.7 ±0.52). Hematocrit and weight course as an indicator of disease activity were congruent (hematocrit in %: 45.8 ± 0.5 (control), 48.6 ± 0.5 (group A), 43.5 ± 0.7 (group B), weight course in g: +4.2 ± 1.1 (control), - 35.8 ± 2.2 (group A). - 26.5 ± 2.3 (group B). Conclusion: (1) The acute phase of TNBS colitis is characterized by reduced capillary blood flow as well as significantly increased leukocyte-endothelium interaction in conjunction with increased capillary permeability and decreased functional capillary density. (2) The administration of selective COX-2 inhibitors leads to a significant decrease of leukocyte sticking. (3) Moreover, there is a significant improvement of capillary blood flow, functional capillary density and capillary permeability. (4) The hematocrit and weight course are indicative of decreased disease activity in the treated animals.