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Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation
Kathleen C Flanders1, Catherine D Sullivan, Makiko Fujii
1Laboratory of Cell Regulation and Carcinogenesis and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5055, USA. flanderk@dce41.nci.nih.gov
Abstract:
Transforming growth factor-beta (TGF-beta) plays a central role in the pathogenesis of inflammatory and fibrotic diseases, including radiation-induced fibrosis. We previously reported that mice null for Smad3, a key downstream mediator of TGF-beta, show accelerated healing of cutaneous incisional wounds with reduced inflammation and accumulation of matrix. To determine if loss of Smad3 decreases radiation-induced injury, skin of Smad3+/+ [wild-type (WT)] and -/- [knockout (KO)] mice was exposed to a single dose of 30 to 50 Gy of gamma-irradiation. Six weeks later, skin from KO mice showed significantly less epidermal acanthosis and dermal influx of mast cells, macrophages, and neutrophils than skin from WT littermates. Skin from irradiated KO mice exhibited less immunoreactive TGF-beta and fewer myofibroblasts, suggesting that these mice will have a significantly reduced fibrotic response. Although irradiation induced no change in the immunohistochemical expression of the TGF-beta type I receptor, the epidermal expression of the type II receptor was lost after irradiation whereas its dermal expression remained high. Primary keratinocytes and dermal fibroblasts prepared from WT and KO mice showed similar survival when irradiated, as did mice exposed to whole-body irradiation. These results suggest that inhibition of Smad3 might decrease tissue damage and reduce fibrosis after exposure to ionizing irradiation.
Insights
Loss of Smad3, a mediator of transforming growth factor-beta (TGF-beta), reduces radiation-induced skin fibrosis and inflammation. Smad3 knockout mice showed decreased tissue damage and fewer inflammatory cells after irradiation compared to wild-type mice.
Area of Science:
- Radiation oncology
- Dermatology
- Fibrosis research
Background:
- Transforming growth factor-beta (TGF-beta) is implicated in inflammatory and fibrotic diseases.
- Radiation-induced fibrosis is a significant clinical challenge.
- Smad3 is a key mediator of TGF-beta signaling.
Purpose of the Study:
- To investigate the role of Smad3 in radiation-induced skin injury and fibrosis.
- To determine if Smad3 deficiency mitigates radiation damage.
Main Methods:
- Smad3 wild-type (WT) and knockout (KO) mice were exposed to gamma-irradiation.
- Skin tissue was analyzed for histopathological changes, inflammatory cell infiltration, and TGF-beta expression.
- Immunohistochemistry was used to assess receptor expression and myofibroblast presence.
Main Results:
- Irradiated KO mice exhibited reduced epidermal acanthosis and dermal inflammatory cell infiltration (mast cells, macrophages, neutrophils) compared to WT mice.
- KO mice showed decreased TGF-beta immunoreactivity and fewer myofibroblasts in irradiated skin.
- Irradiation led to loss of epidermal TGF-beta type II receptor expression, while dermal expression remained high.
Conclusions:
- Smad3 deficiency significantly reduces radiation-induced skin damage and fibrosis.
- Inhibition of Smad3 signaling may be a therapeutic strategy to mitigate radiation-induced tissue injury and fibrosis.