Lay Summary

Proposal No. IBD-0050
Principal Investigator:  Robert Steven Esworthy, Ph.D.
Applicant Organization:  City of Hope National Medical Center (Duarte, California, U.S.A.)
Project Title:  Barrier breakdown in mice deficient in antioxidant defenses leads to ileal colitis
Period of Award:  February 1, 2003 - May 31, 2004

Antioxidants may play a role in inflammatory bowel disease (IBD) by removing noxious chemicals called hydroperoxides.  Depletion of antioxidants is found in active IBD and therapy with antioxidants has shown promise in treatment of experimental IBD.  We have a mouse model of IBD in which hydroperoxides are not effectively removed because a major antioxidant, glutathione peroxidase (GPX) is missing from the intestine.  After two weeks of age, the mice develop acute IBD.
 
We plan to use these mice to probe the ways that hydroperoxides could contribute to the development of IBD.  Our major finding is that the cells that line the inside of the intestine deteriorate when they come in contact with bacteria or experience other types of stress.  The deterioration of these cells does not result in IBD unless bacteria are present.  We suspect that bacteria induce the cells of the intestine to produce hydroperoxides.  The hydroperoxides would  cause the cells of the intestine to deteriorate.  In turn, bacteria or their products would leak across the barrier and react with the immune system resulting in IBD.  The finding that the cells lining the inside of the intestine deteriorate when stressed by hydroperoxides is a new discovery and could aid in the formulation of new and effective therapies for IBD.