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Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease

Franco Scaldaferri1, Miquel Sans, Stefania Vetrano

  • 1Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Clinico Humanitas, Rozzano, Italy.

The Journal of Clinical Investigation
|June 9, 2007
PubMed

Insights

Loss of endothelial protein C receptor (EPCR) and thrombomodulin (TM) in inflammatory bowel disease impairs protein C activation. Activated protein C (APC) administration reduced inflammation and leukocyte adhesion in experimental colitis, suggesting a new therapeutic target.

Area of Science:

  • Molecular biology
  • Immunology
  • Gastroenterology

Background:

  • Endothelial protein C receptor (EPCR) and thrombomodulin (TM) are crucial for protein C (PC) activation, yielding anticoagulant and anti-inflammatory effects.
  • Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), involves complex inflammatory processes in the gut.
  • The role of the PC pathway in intestinal homeostasis and IBD pathogenesis is not fully understood.

Purpose of the Study:

  • To investigate the expression of EPCR and TM in the inflamed intestinal microvasculature of IBD patients.
  • To evaluate the therapeutic potential of activated protein C (APC) in experimental colitis models.
  • To elucidate the role of the PC pathway in maintaining intestinal mucosal homeostasis.

Main Methods:

  • Assessed EPCR and TM expression in intestinal endothelial cells from IBD patients.
  • Administered recombinant APC to isolated human intestinal endothelial cells and in vivo experimental colitis models.
  • Measured cytokine-dependent cell adhesion molecule expression, chemokine production, leukocyte adhesion, weight loss, disease activity index, and histological scores.

Main Results:

  • Reduced expression of EPCR and TM was observed in the inflamed intestinal microvasculature of CD and UC patients, leading to impaired PC activation.
  • APC administration demonstrated potent anti-inflammatory effects in vitro by downregulating adhesion molecules and chemokine production.
  • In vivo, APC treatment effectively ameliorated experimental colitis, reducing disease severity and inhibiting leukocyte adhesion to inflamed intestinal vessels.

Conclusions:

  • The protein C (PC) pathway is critically involved in maintaining intestinal homeostasis via the mucosal microvasculature.
  • Impaired EPCR and TM expression in IBD compromises the protective functions of the PC pathway.
  • Restoring the PC pathway through APC administration represents a promising therapeutic strategy for suppressing intestinal inflammation in IBD.

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