Scientific Abstract

Proposal No.    IBD-0081R
Principal Investigator:  Martin J. Mangino, Ph.D.
Applicant Organization:   University of Wisconsin-Madison (U.S.A.)
Project Title:  Lipoxin metabolism in inflammatory bowel disease
Award Period:  February 1, 2004 – April 30, 2006

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the small and large intestine.  Functional changes include altered fluid secretion and absorption, altered nutrient absorption, changes in motility, and inflammation.  This constellation of processes contributes to patient pain, hematochezia, weight loss, fever and discomfort with various degrees of malnutrition.  Surgical resection of severely inflamed intestine can lead to short gut syndrome, diarrhea, malnutrition, loss of evacuation control, morbidity, and mortality.

The etiology of IBD is not known but mucosal inflammation is hallmark. Chronic cellular inflammation is present and is characterized by infiltration of mononuclear cells, lymphocytes, and polymorphonuclear neutrophils.  These cells are sources of proinflammatory mediators, which when released, activate inflammation in a self-perpetuating cycle.  The stimuli for cellular inflammation are not known.  Normal cellular inflammation proceeds in separate phases of initiation, escalation, maintenance and resolution.  Normal local mediator synthesis and cell signaling are responsible for orchestrating these phases, which can promote cell healing after resolution of the inflammation.  While some of these mediators initiate and maintain the inflammatory response (leukotrienes, PAF, Th1 cytokines, etc.), others have recently been identified that reverse and resolve the inflammatory response (lipoxins).

Much attention has been given to understanding the release of proinflammatory mediators to initiate and maintain inflammation in IBD and, in fact, many proinflammatory mediators are overexpressed in the disease.  However, the possibility that inflammation occurs in IBD secondary to impairments in resolving the mediator pathways has not been addressed.
 
This proposal hypothesizes that IBD may be caused, in part, by the inability of the inflamed intestine to resolve cellular inflammation due to a defect in either lipoxin synthesis or a defect in the transduction of lipoxin signals (lipoxin receptors) at the appropriate time.  Elucidation of lipoxin metabolism in mucosal biopsies from IBD patients will be measured. The ability of this tissue to synthesize anti-inflammatory aspirin triggered lipoxins with aspirin is also evaluated and correlated with the degree of disease and inflammation in the human IBD patient pool.  Animal models of IBD using dextran sulfate feeding will be studied in mice with homozygous deletion of the gene encoding mammalian 12/15-lipoxygenase, which is a necessary enzyme for the synthesis of lipoxins.  The inability of these animals to synthesize lipoxins and the ability of the wild type controls to make these mediators, will be used to predict the physiological, immunological, histological, and biochemical severity of the induced IBD. We will confirm the genetic lipoxin deletion results by reversing the exacerbated IBD effects with delivery of exogenous stable lipoxin analogs and by stimulating endogenous lipoxin synthesis with aspirin in knockout mice.  This study will clarify the role of lipoxins in the etiology of IBD and will lay the foundation for the rational use of lipoxin-based therapy in humans with IBD.