Journal Club Presentation

1
Journal Club Presentation

• by Paul Liu, MD

2
PERMISSIVE ENVIRONMENT IN POSTNATAL WOUNDS
INDUCED BY ADENOVIRAL-MEDIATED OVEREXPRESSION OF
THE ANTI-INFLAMMATORY CYTOKINE INTERLEUKIN-10
PREVENTS SCAR FORMATION

• Ashley Gordon, MD, Elliott Kozin, MD, Sundeep
  Keswani, MD, Sachin Vaikunth, MD, Anna Katz, MD,
  Philip Zoltick, MD, Michele Favata, PhD, Antoneta
  Radu, MS, Louis Soslowsky, PhD, Meenhard Herlyn,
  DVM, Timothy Crombleholme, MD
• Wound Repair and Regeneration (2008) 1670-79

3
BACKGROUND

• Early and midgestational fetal wounds heal via
  regeneration rather than scar
• Efforts to recapitulate the fetal environment in
  adult organisms have hitherto failed
• Three characteristics of fetal wounds seem
  special
• Decreased or absent inflammation
• ECM composition rich in HA and decorin
• Reversed ratio of TGF-b3TGF-b1

4
IL-10

• 35 kDa protein produced by Th2, B-cells, and
  Mfs., thought to be important in preventing
  maternal rejection of the fetus
• Decreases the production of proinflammatory
  cytokines IL-6 and -8
• In post-natal scarring, inversely correlated with
  fibrosis

5
HYPOTHESIS

• Overexpression of IL-10 in post-natal wounds may
  replicate the permissive fetal environment
  allowing scarless wound repair

6
METHODS

• IL-10 expression compared in fetal and neonatal
  skin in IHC sections from human tissue
• Ad-IL-10 constructed in E1 and E3-deleted
  serotype 5 adenovirus
• CMV promoter
• Animal model- C57BL/six depilated and injected on
  their backs with either Ad-lacz or Ad-IL-10 mixed
  with India ink to track the sites
• 48 hours later, 2 cm-paired incisional wounds
  created
• Wounds harvested 3, 7, 10, 14, 21, 28, 60, and 90
  days post-wounding
• Optimal dose determined empirically to be 109 PFU

7
METHODS

• Inflammatory response measured by IHC for CD-45
  and Mac-3
• Biomechanics assessed using tensiometry of a
  dumbell-shaped wound section

8
RESULTS

• IL-10 expression is greater in fetal skin than in
  neonatal skin
• Ad-IL-10 results in over-expression of IL-10
• Ad-IL-10 diminishes scar formation
• Scarless healing seen at 90 days at 109 dose
• Dermal appendages present
• Ad-lacz doesnt do this
• Ad-IL-10 decreases CD45 and Mac-3 cells
• IL-10-treated wounds and unwounded skin have
  similar tensile strength and modulus of elasticity

9
DISCUSSION

• Effects are greatest at 60 and 90 day wounds
  long after Ad-IL10 expression had ceased
• Implies that the early expression of IL-10
  initiates a csacade of events culminating in the
  scarless phenotype
• Has implications for those conditions where scar
  is harmful cirrhosis, pulmonary fibrosis,
  keloids, intraabdominal adhesions