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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. - PowerPoint PPT Presentation
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Profiling Lipid Mediators of Inflammation in Microenvironment of Chronic Venous Leg Ulcers
Jodi C. McDaniel, PhD Assistant ProfessorThe Ohio State University College of Nursing
Agenda
BackgroundCurrent study Future directionClinical relevance
Major Chronic Wound Types
Venous leg ulcers
Pressure 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
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.
Stages of Wound Healing
Key Players By Stage
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.
Topical Solutions
•Dressings have been designed to absorb excessive proteases.
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.
N-6, N-3 Metabolic Pathways
EPA & DHA from fish, fish oil, fish oil
supplementation
Omega-6 Fatty Acids
Omega-3 fatty Acids
Linoleic Acid (LA) 18:2n6 (Corn, Soy, Safflower oils)
AA 20: 4n-6
COX
AT-LXs LXA4 LXB4
LO
4 series leukotrienes
2 series prostaglandins;
2 series thromboxanes
LO COX
COX
Alpha-Linolenic Acid (ALA)18:3n3 (Flaxseed, walnuts, green
vegetables)
DHA 22: 6n-3
LO EPA
20: 5n-3
Δ6 desaturase
Δ5 desaturase
18: 3n-6
20: 3n-6
18: 4n-3
20: 4n-3
RvE1; RvE2; 5 series leukotrienes
COX
RvD1 PD1
AT- RvDs
LO
AT- RvEs; 3 series
prostaglandins; 3 series
thromboxanes
DIET
More inflammatory Less inflammatory
Hypothesis
EPA + DHA
lipid mediators that excessive neutrophilactivity
healing
EPA+DHA
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.
…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.
EPA & DHA from fish, fish oil, fish oil
supplementation
Omega-6 Fatty Acids
Omega-3 fatty Acids
Linoleic Acid (LA) 18:2n6 (Corn, Soy, Safflower oils)
AA 20: 4n-6
COX
AT-LXs LXA4 LXB4
LO
4 series leukotrienes
2 series prostaglandins;
2 series thromboxanes
LO COX
COX
Alpha-Linolenic Acid (ALA)18:3n3 (Flaxseed, walnuts, green
vegetables)
DHA 22: 6n-3
LO EPA
20: 5n-3
Δ6 desaturase
Δ5 desaturase
18: 3n-6
20: 3n-6
18: 4n-3
20: 4n-3
RvE1; RvE2; 5 series leukotrienes
COX
RvD1 PD1
AT- RvDs
LO
AT- RvEs; 3 series
prostaglandins; 3 series
thromboxanes
DIET
FADS2
FADS1
FADS1,FADS2 gene cluster
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
Current Study - CVLUs
* CCTS funded project
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
Current Study
•Determine dietary intake of PUFAs via food frequency questionnaire (FFQ)
Current Study
•Determine plasma levels of PUFAs
•Determine lipid mediator levels in plasma and wound fluid
Fluid Collection – Occlusive Dressing
Current Study
• Determine variants in FADS gene cluster
Preliminary DataLipid Mediators pg/µl fluidPGE2 6.30 (3.67)
PGD2 0.52 (0.55)
PGF2α 2.78 (0.60)
PGE1 1.29 (0.53)
PGF1α 1.30 (0.82)
TXB2 4.87 (3.92)
LTB4 0.45 (0.41)
9-HODE 2.47 (2.40)13-HODE 10.83 (15.36)5-HETE 6.03 (7.00)8-HETE 0.18 (0.08)11-HETE 0.25 (0.23)15-HETE 6.68 (11.74)12-HETE 2.35 (2.11)15-HETrE 0.82 (1.29)
• 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
Preliminary Data
SNPs
Allele
associated with increased
PUFA*
Genotype% Frequency
rs174537 GGG GT TT UD**0.22 0.56 0.22 0
rs102275 ACC CT TT UD0.56 0.33 0 0.11
rs174546 CCC CT TT UD0.11 0.56 0 0.33
rs174556 CCC CT TT UD0.11 0 0.22 0.67
rs1535 AAA AG GG UD0.78 0 0.11 0.11
rs174576 CAA AC CC UD0.67 0.22 0 0.1
rs174579 CCC CT TT UD0 0 0.22 0.78
N=9 * Mathias, BMC Genet. 2011** UD = undetermined
Preliminary Data
Clinical Relevance
EPA + DHA Supplementation ?
Goal: Facilitate Wound Healing!
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
Questions/Comments
Conceptual model for diet–gene interactions
Thank you
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