title: Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease.
abstract: Endothelial protein C receptor (EPCR) and thrombomodulin (TM) are expressed at high levels in the resting microvasculature and convert protein C (PC) into its activated form, which is a potent anticoagulant and antiinflammatory molecule. Here we provide evidence that in Crohn disease (CD) and ulcerative colitis (UC), the 2 major forms of inflammatory bowel disease (IBD), there was loss of expression of endothelial EPCR and TM, which in turns caused impairment of PC activation by the inflamed mucosal microvasculature. In isolated human intestinal endothelial cells, administration of recombinant activated PC had a potent antiinflammatory effect, as demonstrated by downregulated cytokine-dependent cell adhesion molecule expression and chemokine production as well as inhibited leukocyte adhesion. In vivo, administration of activated PC was therapeutically effective in ameliorating experimental colitis as evidenced by reduced weight loss, disease activity index, and histological colitis scores as well as inhibited leukocyte adhesion to the inflamed intestinal vessels. The results suggest that the PC pathway represents a new system crucially involved in governing intestinal homeostasis mediated by the mucosal microvasculature. Restoring the PC pathway may represent a new therapeutic approach to suppress intestinal inflammation in IBD.
authors.affiliation: Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Clinico Humanitas, Rozzano, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Scaldaferri
authors.forename: Miquel
authors.initials: M
authors.lastname: Sans
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.forename: Cristina
authors.initials: C
authors.lastname: Graziani
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: Bruce
authors.initials: B
authors.lastname: Gerlitz
authors.forename: Alessandro
authors.initials: A
authors.lastname: Repici
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.forename: Julian
authors.initials: J
authors.lastname: Panes
authors.forename: Brian W
authors.initials: BW
authors.lastname: Grinnell
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D015536:Down-Regulation; D000074283:Endothelial Protein C Receptor; D004727:Endothelium / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D051379:Mice; D008833:Microcirculation / Q000378:metabolism / Q000473:pathology*; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018180:Thrombomodulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D018925:Chemokines; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011486:Protein C; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1