title: Molecular determinants of the prothrombogenic phenotype assumed by inflamed colonic venules.
abstract: Although platelets have been implicated in the pathogenesis of human inflammatory bowel diseases, little is known about the magnitude of platelet accumulation in the inflamed bowel, what regulates this process, and its relevance to the overall inflammatory response. In this study, intravital video microscopy was used to monitor the trafficking of platelets and leukocytes and vascular permeability in colonic venules during the development of colonic inflammation induced by 3% dextran sodium sulfate (DSS). Blocking antibodies directed against different adhesion molecules as well as P-selectin-deficient mice were used to define the adhesive determinants of DSS-induced platelet recruitment. DSS induced an accumulation of adherent platelets that was temporally correlated with the appearance of adherent leukocytes and with disease severity. Platelet adhesion and, to a lesser extent, leukocyte adhesion were attenuated by immunoblockade of P-selectin and its ligand P-selectin glycoprotein ligand-1 (PSGL-1), with contributions from both platelet- and endothelial cell-associated P-selectin. DSS induced a rapid and sustained increase in vascular permeability that was greatly attenuated in P-selectin-deficient mice. P-selectin bone marrow chimeras revealed that both endothelial cell- and platelet-associated P-selectin contribute to the P-selectin expression detected in the inflamed colonic microvasculature, with endothelial P-selectin making a larger contribution. Our findings indicate that colonic inflammation is associated with the induction of a prothrombogenic phenotype in the colonic microcirculation, with P-selectin and its ligand PSGL-1 playing a major role in the recruitment of platelets.
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, Louisiana 71130-3932, USA.
authors.forename: Mikiji
authors.initials: M
authors.lastname: Mori
authors.forename: James W
authors.initials: JW
authors.lastname: Salter
authors.forename: Thorsten
authors.initials: T
authors.lastname: Vowinkel
authors.forename: Christian F
authors.initials: CF
authors.lastname: Krieglstein
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D003092:Colitis / Q000097:blood / Q000503:physiopathology*; D003106:Colon / Q000098:blood supply*; D016264:Dextran Sulfate / Q000494:pharmacology; D015870:Gene Expression; D007249:Inflammation / Q000503:physiopathology; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000502:physiology; D010641:Phenotype; D014699:Venules / Q000503:physiopathology
chemical_list: D000925:Anticoagulants; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D016264:Dextran Sulfate