title: Thalidomide impairment of trinitrobenzene sulphonic acid-induced colitis in the rat - role of endothelial cell-leukocyte interaction.
abstract: 1. Immune response-modulating drugs such as thalidomide may be of therapeutic value in the treatment of chronic inflammatory bowel diseases including Crohn's disease (CD). In the present study, we have investigated whether thalidomide exerts this effect by impairing endothelial cell-leukocyte interaction through down-regulation of the expression of pro-inflammatory gene products in these cells. 2. Transient CD-like colitis was induced in male Wistar rats by single enema with trinitrobenzene sulphonic acid (TNBS) in ethanol followed by macroscopic scoring, histology, intravital microscopy, RT - PCR and immunohistochemistry (IHC) analyses. Thalidomide or its analogue supidimide were administered in olive oil by intragastric instillation 6 h prior to the induction of colitis and then daily for one week. 3. Both thalidomide and supidimide (200 mg kg(-1) d(-1)) significantly attenuated TNBS-induced colitis as compared to vehicle-treated control animals (44 and 37% inhibition, respectively), and this effect persisted for 7 days post cessation of thalidomide treatment (46% inhibition). 4. Moreover, thalidomide significantly reduced leukocyte sticking to postcapillary venular endothelial cells in the submucosa (by 45%), improved functional capillary density and perfusion, and attenuated endothelial interleukin-8 expression, as judged by IHC analysis. According to RT - PCR analysis, both thalidomide and supidimide also significantly reduced vascular cell adhesion molecule-1 mRNA expression in the affected part of the descending colon. 5. These findings suggest that thalidomide and one of its derivatives impairs CD-like TNBS-induced colitis in the rat by down-regulating endothelial adhesion molecule and chemokine expression and, as a consequence, the interaction of these cells with circulating leukocytes.
authors.affiliation: Department of Cardiovascular Physiology, University of Goettingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Lienenlüke
authors.forename: T
authors.initials: T
authors.lastname: Stojanovic
authors.forename: T
authors.initials: T
authors.lastname: Fiebig
authors.forename: A
authors.initials: A
authors.lastname: Fayyazi
authors.forename: T
authors.initials: T
authors.lastname: Germann
authors.forename: M
authors.initials: M
authors.lastname: Hecker
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy*; D003106:Colon / Q000166:cytology / Q000187:drug effects; D004727:Endothelium / Q000166:cytology* / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D013792:Thalidomide / Q000494:pharmacology*; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D016209:Interleukin-8; D019010:Vascular Cell Adhesion Molecule-1; D023201:CD40 Ligand; D013792:Thalidomide; D014302:Trinitrobenzenesulfonic Acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat