Lay Summary

Proposal No.   IBD-0080R
Principal Investigator:  Robert W. Colman, M.D.
Applicant Organization:   Temple University (Philadelphia, Pennsylvania, U.S.A.)
Project Title:  Kallikrein-kinin system in inflammatory bowel disease
Period of Award:  January 1, 2004 – December 31, 2006

Crohn’s disease, a form of inflammatory bowel disease (IBD), is characterized by acute and chronic transmural granulomatous inflammation with a predilection for the distal ileum and colon.  The etiology of the inflammatory responses and factor(s) responsible for its perpetuation are unknown.
 
In patients with IBD, a series of reactions occurring in the blood plasma (contact system) is known to lead to an active enzyme, plasma kallikrein, which itself stimulates white cells known to participate in the pathological changes in Crohn’s disease.  In addition, kallikrein cleaves another protein, kininogen, to yield bradykinin, which can indicate pain, swelling, diarrhea and cramps.  We have characterized a molecular difference in the activities of kininogen in susceptible and resistant rats.  We will define this defect and seek to determine whether cleaved kininogen or bradykinin are, in part, responsible for experimental colitis and immune activation, both in isolated cultured cells and mice with colitis.  We will also explore whether cleaved kininogen or bradykinin release of inflammatory molecules will activate cytokines from immune cells which are responsible for inflammation.  By defining the mechanisms in the pathogenesis of experimental intestinal inflammation, we hope to identify more precisely the biochemical targets at which to aim new medical treatments of Crohn’s disease and ulcerative colitis.