Scientific Abstract

Proposal No. IBD-0206
Principal Investigator:  Jon Lundberg, M.D., Ph.D.
Applicant Organization:  Karolinska Institutet (Stockholm, Sweden)
Project Title:  Nitrated fatty acids and inflammatory bowel disease
Period of Award:  March 1, 2008 – February 28, 2009

Nitroalkenes (or nitrated fatty acids, NO2-FAs) are formed endogenously when unsaturated fatty acids such as linoleic- or oleic acid react with nitric oxide (NO) or related compounds. These newly described compounds have potent anti-inflammatory activity in vitro. One mechanism for this effect is the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) with concomitant down regulation of NF-kappa B. In fact, NO2-FAs are some of the most potent classes of PPAR-γ agonists described to date.  Inflammatory bowel disease (IBD) is a particularly interesting target disease for PPAR-γ agonists since this nuclear hormone receptor is highly expressed in colon epithelial cells.

We will explore anti-inflammatory effects of NO2-FAs in a mouse model of IBD (IL-10 knockout). The drug is administered either perorally or as a rectal enema. In an extension we also intend to explore if the endogenous generation of NO2-FAs can be enhanced by dietary interventions and if this strategy can prevent exacerbation of colitis. If animal experiments are successful we foresee that we can initiate clinical studies in patients in the near future, since the toxicity of these endogenous compounds is most likely very low.