Inflammatory bowel diseases (IBD) that are associate with a dramatic increase in colorectal cancer occur throughout the world with an annual incidence of approximately 12/100,000 people. Aberrant activation of neutrophils and a profound increase in lipid and peptide mediators are cardinal signs of these inflammatory diseases as well as for ischemia reperfusion injury, a known complication of surgical procedures. How acute inflammatory responses switch from vital host defense to aberrant inflammation and neutrophil mediated tissue injury remains to be completely elucidated. Therefore, endogenous mechanisms that disrupt pro-inflammatory circuits are of interest. Aspirin and omega-3 polyunsaturated fatty acids (PUFA) are therapeutic agents that demonstrate benefits in inflammatory diseases as well as prevention of colon cancer. However, their mechanisms of action still needs to be clearly defined but targets the formation of lipid mediators namely eicosanoids. Both therapeutic agents trigger the formation of novel classes of anti-inflammatory lipids, namely 15R-lipoxins and omega-3 PUFA derived 15R-and 18R-series eicosanoids. This study shall test the hypothesis that acute inflammation induces a regulated and temporal generation of anti-inflammatory lipid signals and that omega-3 fatty acid and aspirin augment these protective lipid mediator circuits.
The specific aims of this application will employ a combined approach of structural elucidation, molecular biology and transgenics to delineate three main aspect of the role of lipid signals in neutrophil mediated intestinal injury: i) Establish the temporal relationship of pro- and anti-inflammatory eicosanoids. ii) Determine the impact of aspirin and omega-3 PUFA on eicosanoid profiles and elucidate novel protective lipid mediators. iii) Determine if novel aspirin and omega-3 PUFA triggered lipid mediators are protective against aberrant PMN activation and if changes in expression of receptors for lipid mediators are markers for aberrant intestinal inflammation. The broad and long-term objectives of this application are to elucidate endogenous pathways that block PMN mediated injury to promote resolution of inflammation. Results from this project may provide novel anti-inflammatory tools for controlling inflammatory diseases such as Ulcerative Colitis and Chron's Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK060583-01
Application #
6418751
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2002-02-15
Project End
2004-12-31
Budget Start
2002-02-15
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$98,280
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Sims, Emily K; Hatanaka, Masayuki; Morris, David L et al. (2013) Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains. Am J Physiol Endocrinol Metab 305:E1495-511
Vance, Russell E; Hong, Song; Gronert, Karsten et al. (2004) The opportunistic pathogen Pseudomonas aeruginosa carries a secretable arachidonate 15-lipoxygenase. Proc Natl Acad Sci U S A 101:2135-9
Bannenberg, Gerard; Moussignac, Rose-Laure; Gronert, Karsten et al. (2004) Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration. Br J Pharmacol 143:43-52
Gronert, Karsten; Kantarci, Alpdogan; Levy, Bruce D et al. (2004) A molecular defect in intracellular lipid signaling in human neutrophils in localized aggressive periodontal tissue damage. J Immunol 172:1856-61
Devchand, Pallavi R; Arita, Makoto; Hong, Song et al. (2003) Human ALX receptor regulates neutrophil recruitment in transgenic mice: roles in inflammation and host defense. FASEB J 17:652-9
Marcheselli, Victor L; Hong, Song; Lukiw, Walter J et al. (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278:43807-17
Hong, Song; Gronert, Karsten; Devchand, Pallavi R et al. (2003) Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J Biol Chem 278:14677-87
Serhan, Charles N; Hong, Song; Gronert, Karsten et al. (2002) Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 196:1025-37
Levy, B D; Clish, C B; Schmidt, B et al. (2001) Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2:612-9