Kallikrein-kinin system activation in Crohn's disease : differences in intestinal and systemic markers

OBJECTIVES: Observations in experimental models and in human ulcerative colitis suggest that activation of the kallikrein-kinin system plays a role in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess activation of the plasma and tissue kallikrein-kinin system in Crohn's disease. METHODS: We studied plasma inflammatory and contact system parameters in 36 patients with Crohn's disease and in 36 control subjects with noninflammatory GI diseases. We also obtained tissue samples from the involved intestine of 12 patients with Crohn's disease, and from normal peritumoral tissue (12 patients) and diverticulitis tissue (seven patients) as controls. Full-thickness sections were tested for intestinal tissue kallikrein reactivity with a specific antibody. RESULTS: In Crohn's disease patients and controls, plasma levels of prekallikrein, factor XI, high molecular weight kininogen and its cleaved form were normal. Crohn's disease patients had significantly higher levels of antigen and functional Cl-inhibitor (+22%, +12%) than did controls (p = 0.005, p = 0.004). After surgical resection, antigen and functional Cl-inhibitor significantly decreased in Crohn's disease patients (-22%, -15%; p = 0.035, p = 0.006). Intestinal tissue kallikrein immunoreactivity was absent (75%) or weak (25%) in the goblet cells from Crohn's disease tissue sections but was normal in controls, with a highly significant difference in the staining score (p = 0.0001). Intestinal tissue kallikrein immunoreactivity in the interstitium was higher in Crohn's disease than in normal and diverticulitis samples (p = 0.0001 and p = 0.001, respectively). CONCLUSIONS: Our observations suggest that intestinal tissue kallikrein is involved in the inflammatory process in Crohn's disease. The lack of contact system activation in peripheral blood might be related to the high plasma levels of Cl-inhibitor, the most important inhibitor of the contact system in the circulation