Interference with Transforming Growth Factor-β/ Smad3 Signaling Results in Accelerated Healing of Wounds in Previously Irradiated Skin

Flanders, Kathleen C.; Major, Christopher; Arabshahi, Alidad; Aburime, Ekinadese; Okada, Miya H.; Fujii, Makiko; Blalock, Timothy D.; Schultz, Gregory S.; Sowers, Anastasia L.; Anzano, Mario A.; Mitchell, James B.; Russo, Angelo; Roberts, Anita B.

doi:10.1016/s0002-9440(10)63582-1

Cited by 158 publications

(143 citation statements)

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“…This procedure can be associated with less edema and fibrosis. Conversely, higher rates of wound healing complications have been reported when irradiation is delivered before surgery (15,16). In this experimental research, the longer delay in wound healing observed from the specimens in IG2 can be explained on the basis of Wang et al (8) and Qu et al (13,14) findings.…”

Section: Discussionmentioning

confidence: 61%

“…Furthermore, the main components of the extracellular matrix, GAGs and collagen fibers, are synthesized by fibroblasts (7,10,11,13,14). Wound healing can be considered complete when, after reaching maturation, the newly formed collagen reestablishes the integrity of the damaged tissue (11,16). Since fibroblasts originate from cells of the surrounding undamaged connective tissue and the irradiated area comprised only an approximately 1-cm-wide zone around the wounds, it would be reasonable to assume that the observed delay in tissue repair can be attributed to direct damages in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the great number of previous investigations in radiobiology (4,5,7,8,10,(13)(14)(15)(16)(17), few studies have focused on the quantitative analysis of glycosaminoglycans (GAGs) in the granulation tissue of locally irradiated skin. Scientific evidences indicate that the influence of irradiation on connective tissue leads to the degradation of ground substance and produces severe disturbances in the metabolism of GAGs (10).…”

Section: Introductionmentioning

confidence: 99%

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Effect of low-dose electron radiation on rat skin wound healing

Almeida

Cruz

Ferreira³

et al. 2007

Braz. Dent. J.

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The aim of this study was to assess the effect of low-dose electron irradiation on morphological features of the wound healing process in rat skin. Surgical wounds were inflicted with a 2.3 x 1.4 cm template on 84 male rats that were assigned to 4 groups: IG1, immediately irradiated; IG2, irradiated 3 days after inflicting the wound; CG1 and CG2, control groups. Rats in IG1 and IG2 groups had their wounds exposed to 1 Gy of 6 MeV electron beam radiation, immediately after surgery and on the third postoperative day, respectively. Qualitative and histophotometric evaluations of tissue repair structures were carried out. Data were analyzed by ANOVA and Tukey's test (α = 0.05) and regression analysis. The repair process was delayed since the first sacrifice time in both irradiated groups, but in IG1, wound healing was closer to that of CG1; whereas in IG2, the delay was more pronounced. Based on the histological findings, it is possible to conclude that a low-dose of electron radiation delayed tissue repair in rat skin. The delay was longer in the skin irradiated 3 days after the beginning of tissue repair. However, the low-energy electron irradiation did not prevent wound healing.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of low-dose electron radiation on rat skin wound healing

Almeida

Cruz

Ferreira³

et al. 2007

Braz. Dent. J.

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“…In cutaneous wounding, the number of myofibroblasts was less in Smad3 knockout mice compared to wildtype mice. However, treatment of primary neonatal dermal fibroblasts from Smad3 knockout mice with 5 ng/ml TGF-β1 for 4 days induced α-SMA protein at the same level as fibroblasts from wild-type mice [Flanders et al, 2003]. Furthermore, lung fibroblasts transfected with Smad2, but not Smad3 had up-regulated α-SMA mRNA expression and altered cell phenotypes [Evans et al, 2003].…”

Section: Discussionmentioning

confidence: 93%

Nicotine inhibits myofibroblast differentiation in human gingival fibroblasts

Fang

Svoboda

2005

J of Cellular Biochemistry

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Cigarette smoking has been suggested as a risk factor for several periodontal diseases. It has also been found that smokers respond less favorably than non-smokers to periodontal therapy. Previous work in our lab has shown that nicotine inhibits human gingival cell migration. Since myofibroblasts play an important role in wound closure, we asked if nicotine affects gingival wound healing process by regulating myofibroblast differentiation. Human gingival fibroblasts (HGFs) from two patients were cultured in 10% fetal bovine serum cell culture medium. Cells were pretreated with different doses of nicotine (0, 0.01, 0.1, and 1 mM) for 2 h, and then incubated with transforming growth factor beta (TGF-β1) (0, 0.25, 0.5, and 1 ng/ml) with or without nicotine for 30 h. The expression level of α-smooth muscle actin (α-SMA), a specific marker for myofibroblasts, was analyzed by Western blots, immunocytochemistry, and real-time polymerase chain reaction (real-time PCR). Phosphorylated p38 mitogen-activated protein kinase (Phospho-p38 MAPK) activity was analyzed by Western blots. TGF-β1 induced an increase of α-SMA protein and mRNA expression, while nicotine (1 mM) inhibited the TGF-β1-induced expression of α-SMA but not β-actin. Nicotine treatment down-regulated TGF-β1-induced p38 MAPK phosphorylation. Our results demonstrated for the first time that nicotine inhibits myofibroblast differentiation in human gingival fibroblasts in vitro; supporting the hypothesis that delayed wound healing in smokers may be due to decreased wound contraction by myofibroblasts. Keywordshuman gingival fibroblasts; myofibroblasts; α smooth muscle actin; TGFβ; p38 MAP kinase Myofibroblasts are contractile cells that share characteristics of fibroblasts and smooth muscle cells [Tomasek et al., 2002]. One of the major features of myofibroblast differentiation is the expression of smooth muscle cell markers. These markers include α-SMA, γ-SMA, smooth muscle 22 (SM22), calponin, smoothelin, meta-vinculin, h-caldesmon [Halayko and Solway, 2001]. Among these, α-SMA has been suggested as the most reliable marker of myofibroblast differentiation [Gabbiani, 2003]. Also, Dr. Masur's lab demonstrated that myofibroblast differentiation was cell density dependent in corneal fibroblasts. They found that the lower the cell density when cells were seeded in culture, the more cells differentiated into myofibroblasts. However, the myofibroblast phenotype was not terminal. The cells lost the myofibroblast

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“…51,52 Expression of a-smooth muscle actin (aSMA), important in fibroblast-myofibroblast conversion, is mediated by Smad2. [53][54][55] However, expression of Snail, the master transcription factor involved in the earlier step of the epithelialmesenchymal transition (EMT), as an important step in the process of tissue fibrosis in the eye, is controlled by Smad3. 56 The expression of the majority of the extracellular matrix components and enzymes involved in matrix reorganization/ maturation depends on Smad3, whereas expression of matrix metalloproteinase-2 is Smad2 dependent.…”

Section: Tgfb Signal Transduction and Tissue Fibrosismentioning

confidence: 99%