VEGF-A modified mRNA in diabetic wound healing and future treatment opportunities
Mechanisms of diabetic wound healing - Saint Louis...
Transcript of Mechanisms of diabetic wound healing - Saint Louis...
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Mechanisms of diabeticwound healing
Phillip J. Finley, MSIntegrated & Applied Sciences
Program
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Normal Wound Healing• Body’s natural process of regenerating skin – Complex
• Inflammatory response• Formation of granulation tissue• Angiogenesis• Collagen deposition• Epithelialization• Remodeling
• All of these events are impaired during healing indiabetic wounds.
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Wound healingis impaired in diabetics
• Significant health problem• 80,000 amputations per year at
$45,000 per amputation.• Approximately 20.8 million people
with diabetes54 million Americans have pre-diabetes.
• ! in obesity = ! diabetes
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Background
• Neuropathy, prevents diabetic patients fromfeeling discomfort in their lower extremities.
• Thus, a minor abrasion can go unnoticed leadingto a very serious chronic wound
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Neutrophils• 1st inflammatory cells to respond to the
site of injury within hours1.Phagocytose debris and bacteria2.Release microbicidal compounds to kill
bacteria3.Secrete proteases that break down
damaged tissue4.Produce cytokines to promote
inflammatory response
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Macrophages• 2nd cell to migrate into wound.• Monocytes migrate from bloodstream and
become macrophage upon entering thetissue
1.Release microbicidal compounds to kill bacteria2.Phagocytose debris, bacteria, dead neutrophils3.Produce cytokines to promote inflammatory
response
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Macrophages & Wound Healing
• Normal Wound Healing– Depletion of macrophages resulted in
defective healing• Diabetic Wound Healing
– Depletion of macrophages significantlyimproved healing
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Macrophage Activation Classically Activated
Macs• Provide antimicrobial
protection by eliminatingvarious pathogens
• Clean the wound byremoving dead cells anddebris.
• Produce pro-inflammatorycytokines to sustainresponse
• Helps maintain inflammation
Alternatively ActivatedMacs
• Associated with theresolution of inflammation
• Promotes tissue remodelingand angiogenesis
• Produce anti-inflammatorycytokines
Differentiation depends on proteins in the microenvironment
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Hypotheses
• Macrophage activation will be differentbetween normal and diabetic wounds
• Cytokine expression will be differentbetween normal and diabetic wounds
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Mice Homozygous fordiabetes spontaneousmutation were used asdiabetic mice. C57BLCK6db/db
•Depletion of beta-cells
•Increased blood glucoseat 4 weeks
WT mice were C57BLCK6with the geneticbackground as diabeticmice
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Day 2 Day 5 Day 7
WT
Dia
betic
Neutrophil influx is delayed in diabetic wounds
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Day 2 Day 5 Day 7
WT
Dia
betic
YM1 expression is delayed in diabetic wounds
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1 3 5 7102
103
104
105
106
107
108Ym1 WTYm1 DB
Day
Ym1 expression is delayed in diabetic wounds
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1 3 5 7101
102
103
104
105
IL-20 WTIL-20 DB
PW Day
Interleukin-20 is increased in diabetic wounds
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Silver and Wound Healing
• Silver wound dressings improve woundhealing.– Due to reduced bacterial load?– Does silver have anti-inflammatory
properties?
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Delayed wound healing in wounds treated with a gauze dressing compared towounds treated with a silver nylon dressing across Diabetic and wild type mice.
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2 5100101102103104105106107108
WT GauzeWT SilverDB GauzeDB Silver
Day
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Silver dressings
• Normal wounds– Improved healing– Reduced bacterial load
• Diabetic Wounds– Improved healing– Did NOT reduce bacterial load in diabetic wounds– Altered cytokine expression