The combinations C1 esterase inhibitor with coagulation factor XIII and N-acetylcysteine with tirilazad mesylate reduce the leukocyte adherence in an experimental endotoxemia in rats

Article type: Research Article

Authors: Birnbaum, Jürgen^; | Klotz, Edda | Spies, Claudia D. | Hein, Ortrud Vargas | Mallin, Katja | Kawka, Renata | Ziemer, Sabine | Lehmann, Christian

Affiliations: Klinik für Anaesthesiologie und operative Intensivmedizin, Charité – Universitätsmedizin Berlin, Campus Charité Mitte und Campus Virchow-Klinikum, Berlin, Germany | Institut für Laboratoriumsmedizin und Pathobiochemie, Charité – Universitätsmedizin Berlin, Campus Charité Mitte und Campus Virchow-Klinikum, Berlin, Germany | Departments of Anesthesia, Pharmacology, Microbiology and Immunology, Dalhousie University, Victoria General Hospital, Halifax, NS, Canada

Note: [] Corresponding author: Jürgen Birnbaum, MD, Klinik für Anästhesiologie und operative Intensivmedizin, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117 Berlin, Germany. Tel.: +49 030 450 531 012; Fax: +49 030 450 531 911; E-mail: [email protected].

Abstract: The study's objective was to determine the effects of the administration of combinations of C1 esterase inhibitor (C1-INH) with coagulation factor XIII (F XIII) and N-acetylcysteine (NAC) with tirilazad mesylate (TM) on leukocyte adherence and on intestinal functional capillary density during experimental endotoxemia in rats. In a prospective, randomized, controlled animal study, 40 male Wistar rats were divided into 4 groups. Group 1 (CON group) served as control group. Group 2 (LPS group), group 3 (C1-INH+F XIII group) and group 4 (NAC+TM group) received endotoxin infusions (10 mg/kg/h for 2 h). In C1-INH+F XIII group, 100 U/kg b.w. C1-INH and 50 U/kg b.w. F XIII were administered after the first 30 min of endotoxemia. In the NAC+TM group, 150 mg/kg b.w. N-acetylcysteine and 10 mg/kg b.w. Tirilazad mesylate were administered after 30 min of endotoxemia. Leukocyte adherence at venules of the intestinal submucosal layer and functional capillary density in the villi intestinales and in the longitudinal and circular muscle layers were estimated by intravital fluorescence microscopy (IVM). C1-INH+F XIII reduced the count of firmly adherent leukocytes that was increased after LPS administration in the V3 venules (CON group 69 (17–160)/mm2; LPS group 635 (556–814)/mm2; C1-INH+F XIII group 503 (337–646)/mm2). NAC+TM reduced the firmly adherent leukocytes in the V3 venules (NAC+TM group 403 (309–572)/mm2) and in the V1 venules (CON group 55 (16–131)/mm2; LPS group 368 (306–475)/mm2; NAC+TM group 270 (216–308)/mm2) as well. FCD was not impaired after LPS challenge and there was no influence of both combinations on the FCD. We conclude that both drug combinations can reduce the leukocyte adherence in a sepsis model in rats.

Keywords: Endotoxin, rat, F XIII, C1-INH, NAC, tirilazad mesylate, intravital microscopy, intestine, leukocyte adherence, perfusion

DOI: 10.3233/CH-2008-1127

Journal: Clinical Hemorheology and Microcirculation, vol. 40, no. 3, pp. 167-176, 2008