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Profiling Lipid Mediators of Inflammation in Microenvironment of Chronic Venous Leg Ulcers

Profiling Lipid Mediators of Inflammation in Microenvironment of Chronic Venous Leg Ulcers. Jodi C. McDaniel, PhD Assistant Professor The Ohio State University College of Nursing. Agenda Background Current study Future direction Clinical relevance. Major Chronic Wound Types.

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Profiling Lipid Mediators of Inflammation in Microenvironment of Chronic Venous Leg Ulcers

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  1. Profiling Lipid Mediators of Inflammation in Microenvironment of Chronic Venous Leg Ulcers Jodi C. McDaniel, PhD Assistant Professor The Ohio State University College of Nursing

  2. Agenda • Background • Current study • Future direction • Clinical relevance

  3. Major Chronic Wound Types Pressure ulcers Venous leg ulcers Diabetic foot ulcers • Chronic wounds affect 6.5 million U.S. patients • $25 billion spent annually for treatment • Singer & Clark. N Engl J Med. 1999; Crovetti et al. Transfus Apher Sci. 2004; • Brem at al. Mol Med. 2007

  4. Chronic venous leg ulcers (CVLUs) • ~1.69% of U.S. population ≥ 65 years affected • ~ 600,000 cases annually • ~ 24 weeks to heal • ~ 15% never heal • up to 71% of cases recur • up to $5 billion annually for treatment expenses • significant social and economic cost • Valencia et al. J Am Acad Dermatol. 2001; Coleridge-Smith. Leg ulcers. Diagnosis and management. 2005; Abbade & Lastoria. Int J Dermatol. 2005; Heit et al. J Vasc Surg.2001.

  5. Stages of Wound Healing

  6. Key Players By Stage

  7. Neutrophils • Neutrophil influx into wound site & release of proteases important for healing, BUT prolonged, excessive levels detrimental: - destroy growth factors, receptors and extracellular matrix essential for healing • Majority of proteases associated with chronic wounds compared to healing wounds are primarily of neutrophil origin Moor et al. Wound Repair Regen. 2009; Yager et al. Int J Low Extrem Wounds.2007; Smith. Int J Low Extrem Wounds. 2006.

  8. Dressings have been designed to absorb excessive proteases. Topical Solutions

  9. Systemic Solutions? • Endogenously generated lipid mediators derived from n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic (EPA) & docosahexaenoic (DHA)neutrophil influx & activity • These lipid mediators include certain eicosanoids (e.g. PGE3), and resolvins & protectins. Norling & Serhan. J Intern Med. 2010; Arita et al. Journal of Immunology. 2007; Dona et al. Blood. 2008.

  10. N-6, N-3 Metabolic Pathways More inflammatory Less inflammatory

  11. Hypothesis  EPA + DHA  healing  lipid mediators that  excessive neutrophil activity

  12. EPA+DHA

  13. EPA+DHA • Balanced EPA:AA ratios associated with  risk of heart disease & improvements in inflammatory diseases (e.g. rheumatoid arthritis) • Minimal amts. synthesized in body, so require dietary sources - primarily from oily fish or fish oil supplements Calder. Eur J Pharmacol. 2011; Simopoulos. Exp Biol Med . 2008; Cleland et al. J Rheumatol. 2006.

  14. …But Genetic Variations Affect PUFA Metabolism • Activity of desaturases affected by genetic polymorphisms • Delta-5 & delta-6 desaturases encoded by fatty acid desaturase (FADS)1 & FADS2, respectively • Located on desaturase gene cluster on chromosome 11 (11q12-13.1) Rzehak et al. J Nutr. 2009; Martinelli et al. Am J Clin Nutr. 2008; Schaeffer et al. Hum Mol Genet. 2006; Tanaka et al. PLoS Genet. 2009.

  15. FADS2 FADS1

  16. FADS1,FADS2 gene cluster

  17. FADS Polymorphisms • Certain ancestry groups have ↑ frequency of alleles in FADS cluster associated with higher levels of AA • Genetically predisposed to more efficient conversion of LA to AA, systemic inflammation & inflammatory conditions • Individuals having genotypes associated with higher LA to AA conversion rates & diets high in LA & AA may be at ↑ risk of developing CVLUs Mathias et al. BMC Genet. 2011; Sergeant et al. Br J Nutr. 2011

  18. Current Study - CVLUs * CCTS funded project

  19. Current Study • Profiling lipid mediators in plasma & wound fluid of patients with CVLUs • Determining frequency of genetic variants in FADS gene The OSU Clinical Research Center

  20. Current Study • Determine dietary intake of PUFAs via food frequency questionnaire (FFQ)

  21. Current Study • Determine plasma levels of PUFAs • Determine lipid mediator levels in plasma and wound fluid

  22. Fluid Collection – Occlusive Dressing

  23. Current Study • Determine variants in FADS gene cluster

  24. Preliminary Data • Lipid mediators in chronic wound fluid exclusively products of n-6 PUFA metabolism • No detectable levels of products of n-3 PUFA metabolism • Suggesting that microenvironment of chronic leg wounds exhibits an n-6 PUFA lipid mediator profile N = 5

  25. Preliminary Data N=9 * Mathias, BMC Genet. 2011 ** UD = undetermined

  26. Preliminary Data

  27. Clinical Relevance EPA + DHA Supplementation ?

  28. Goal: Facilitate Wound Healing!

  29. Team • Sashwati Roy, PhD – OSU College of Medicine • Martha Belury, PhD – OSU College of Education and Human Ecology • Anna Nicolaou, PhD – University of Bradford, U.K. • Christopher Holloman, PhD – OSU Dept. of Stat. • OSU Clinical Research Center Staff

  30. Questions/Comments Conceptual model for diet–gene interactions

  31. Thank you

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