Final Progress Report

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

Summary of project aims:
 
Unsaturated fatty acids such as oleic or linoleic acid can undergo nitration reactions with nitric oxide (NO) or nitrite (NO2-) or their reaction products to form nitro-alkenes (nitro fatty acids). These novel compounds have surprising anti-inflammatory activity in vitro. We wanted to test if in vivo administration of nitro fatty acids would have a therapeutic effect in an experimental model of ulcerative colitis.
 
Accomplishments: 

The initial aim has been fully accomplished and we have been able to demonstrate robust anti-inflammatory activity of nitro fatty acids in experimental colitis.
 
Results:
 
The DSS model of colitis was established in our lab and a suitable dose of DSS was titrated so as to create a mild to moderate disease activity in the mice. Next we evaluated mode of administration of drug, dose and timing and established that measurable amounts of nitro fatty acids could be detected in colon tissue. The subcutaneous route was chosen with implanted osmotic minipumps. We also decided to test two different doses of the drug. We then ran the study and found that the colon inflammation was markedly attenuated by the treatment. This was obvious from measurements of colon length, Disease Activity Index (DAI) and immunohistochemical studies of NF-kappa B expression. Mechanistically, nitrated fatty acids upregulated colonic expression of PPAR-gamma, a potent down regulator of the inflammatory cascade. This finding was confirmed in extensive cell culture studies where the addition of nitro fatty acids to colon cells potently activated PPAR-gamma. 

Lay summary

The relationship between the host cells in the gut and the myriads of bacteria that live there is normally a peaceful one. For some reason however, in patients with inflammatory bowel disease (IBD) this relationship has turned into open war. The key cells that regulate bacterial-mucosal interactions are the epithelial cells on the inner surface of the intestines. These cells are in direct contact with the gut bacteria and they communicate with the underlying host cells to regulate the host immune responses. In the present study we will look at an entirely new class of substances that could be useful in treatment of IBD.
 
Preliminary studies indicate that so called nitroalkenes (or nitrated fatty acids) can be formed in the body and interestingly, these compounds seem to have strong anti-inflammatory activity, mainly via stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of PPAR- γ leads to a strong down-regulation of the host inflammatory response. Interestingly, the expression of PPAR-γ is particularily high in colon epithelial cells and these cells are therefore good candidate targets for compounds that act via this pathway. In a first series of experiments we have tested the anti-inflammatory effects of nitrated fatty acids in an animal model of IBD. These studies were successful and we could demonstrated strong anti-inflammatory effects of nitrated fatty acids in this model. Also, we found that PPAR-gamma was strongly upregulated, confirming our mechanistic hypothesis. By targeting one critical part of the inflammatory pathway instead of the entire cascade, we hope to be able to develop new drugs with less unwanted side effects than many of the drugs used today.

 

Last updated 07/08/2010