Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease
Franco Scaldaferri, … , Brian W. Grinnell, Silvio Danese
Franco Scaldaferri, … , Brian W. Grinnell, Silvio Danese
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1951-1960. https://doi.org/10.1172/JCI31027.
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Research Article Gastroenterology

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

Franco Scaldaferri, Miquel Sans, Stefania Vetrano, Cristina Graziani, Raimondo De Cristofaro, Bruce Gerlitz, Alessandro Repici, Vincenzo Arena, Alberto Malesci, Julian Panes, Brian W. Grinnell, Silvio Danese

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Figure 10

aPC inhibits CAM expression, IL-8 production, and leukocyte adhesion to the endothelium in the intestine.

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aPC inhibits CAM expression, IL-8 production, and leukocyte adhesion to ...
Animals undergoing DSS treatment were given daily i.v. injections of recombinant murine aPC or placebo. After 10 days mice were sacrificed, and biopsies were collected for Western blot analysis for VCAM-1 and ICAM-1 (A) or organ culture for IL-8 measurement by ELISA (B). (C) Leukocyte–endothelial cell interactions were assessed by intravital microscopy in 3 groups of animals: healthy mice (n = 5); DSS colitic mice treated for 10 days with placebo (n = 8); and DSS colitic mice treated for 10 days with daily i.v. injections of recombinant aPC (n = 6). For each animal, 3–6 unbranched venules were studied and the mean value was calculated. Leukocyte adhesion is expressed as the number of firmly adherent leukocytes to the endothelium per 100 μm of venule. *P < 0.05 versus placebo; **P < 0.001 versus healthy mice.