Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation.
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.
Flanders
Kathleen C
KC
Laboratory 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
Sullivan
Catherine D
CD
Fujii
Makiko
M
Sowers
Anastasia
A
Anzano
Mario A
MA
Arabshahi
Alidad
A
Major
Christopher
C
Deng
Chuxia
C
Russo
Angelo
A
Mitchell
James B
JB
Roberts
Anita B
AB
D000818:Animals; D002470:Cell Survival / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D011833:Radiation Injuries, Experimental / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D004268:DNA-Binding Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta