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Radiation-induced skin fibrosis is mediated by IL-13 and mitigated by local IL-13 gene suppression
John Layliev, Denis Knobel, MD, Manisha Patel, BS, BA, Fabio Sagebin, BS, Andrew Weinstein, BS, Oriana Cohen, BA, Meredith Wetterau, MD, Jason Barr, BS, Raven Henderson, MD, Stephen M. Warren, MD, FACS, Pierre B. Saadeh, MD, FACS.
NYU Langone Medical Center, New York, NY, USA.

BACKGROUND:
Recent studies have implicated IL-13 as a potent mediator of tissue fibrosis in schistosomiasis, asthma, and scleroderma. We investigated whether IL-13 plays a role in the pathogenesis of radiation-induced skin fibrosis by using a transcutaneous delivery system to inhibit IL-13 gene expression with small interfering RNA (siRNA). Moreover, we attempted to mitigate the phenotypic effects of radiation on murine skin by inhibiting IL-13.
METHODS:
Using an isolated skin radiation model, the dorsal skin of C57 mice was radiated (45Gy). Prior to radiation, mice were separated into 3 groups and treated with IL-13 siRNA, nonsense siRNA, or no treatment (siRNA reapplied weekly). Non radiated mice were additional controls. Skin was harvested at 1, 2, and 4 wks. Expression of Col1A1, IL-13, TGFB1, SMAD3, profibrotic and angiogenic chemokines was assessed (RT-PCR). Epidermal thickness, dermal collagen density, and scarring were assessed using H&E and picrosirius red staining. Skin fibrosis was measured via tensiometry. Significance was via paired by One -Way ANOVA (p<0.05).
RESULTS:
Skin treated with topical IL-13 siRNA demonstrated effective inhibition at 1 wk and persistent suppression at 4 wks (67%). In this group, expression of Col1a1 and TGFB1 was suppressed (69% and 63%) while SMAD3 was not significantly decreased. Profibrotic chemokines CCL2, CCL3, and CCL11 were also inhibited (71%, 68%, and 78%) as were angiogenic chemokines CXCL1 and CXCR2. The epidermis was significantly thinner and picrosirius staining was markedly diminished compared to the control irradiated group, reflecting less scarring. Tensiometry confirmed less skin stiffness.
CONCLUSIONS:
This study strongly implicates IL-13 as a mediator of radiation-induced skin fibrosis, independent of the well described SMAD3 pathway. Genes responsible for the fibrotic phenotype were effectively suppressed by IL-13 knockdown. Histology and biomechanical testing in mice treated with topical IL-13 siRNA was more consistent with non-radiated mice. IL-13 may be an attractive target for local gene knockdown prior to radiation exposure of the skin.


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