Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications.

SummaryBackground
Hypertrophic scars (HPSs) are characterized by excessive fibrosis associated with aberrant function of fibroblasts. Currently no satisfactory treatment has been developed.

Objectives
To investigate the effect of baicalein on HPSs and its underlying mechanisms.

Methods
Baicalein was administered intradermally (10 μmol L−1 in 100 μL sterile saline plus 10% dimethylsulfoxide) to mechanical-load-induced scars in mice once a day for 14 or 28 days. Histological and immunohistochemical studies were performed to evaluate scar hypertrophy and the function of fibroblasts. Human HPS-derived fibroblasts (HSFs) were determined by immunofluorescence study, collagen gel contraction assay and wound-healing assay. Also, protein expression of the transforming growth factor (TGF)-β signalling pathway was detected using Western blotting. Lastly, a molecular docking study and kinase binding assay were conducted in search of the potential interaction between baicalein and activin receptor-like kinase (ALK)5.

Results
Baicalein treatment significantly attenuated HPS formation and collagen deposition in a mechanical-load-induced mouse model. Baicalein also inhibited the proliferation and activation of fibroblasts in vitro and in vivo. Furthermore, baicalein impaired the contractile and migration ability of HSFs. Protein expression investigation revealed that baicalein had an inhibitory effect on TGF-β/Smad2/3 signalling. Such bioactivity of baicalein may result from its selective binding to the ATP-binding pocket of ALK5, as suggested by the molecular docking study and kinase binding assay.

Conclusions
Baicalein could serve as a promising agent for treatment of HPSs and a selective ALK5 inhibitor.

Baicalein attenuates hypertrophic scar formation via inhibition of the transforming growth factor‐β/Smad2/3 signalling pathway

LncRNA COL1A2-AS1 inhibits the scar fibroblasts proliferation via regulating miR-21/Smad7 pathway.

The dramatic alteration in the appearance of the skin with aging is related to both intrinsic (genetic) and exogenous factors. While intrinsic aging is an insidious degenerative process predictable in outcome, the superposition of environmental factors is neither universal nor inevitable. There are distinct morphologic and histological features differentiating intrinsic and extrinsic aging of the skin. The most well appreciated environmental factors affecting skin aging are sun exposure and smoking. Recent advances in molecular biology have increased our understanding of the mechanisms by which exogenous factors contribute to the cutaneous aging. The skin is equipped with numerous inherent mechanisms that protect and defend against accelerating aging. But the efficacy of these mechanisms decreases significantly over a lifetime. In this review, we summarize the features of extrinsic aging and biochemical steps involved in this process. Copyright © 2007 S. Karger AG, Basel

Current Problems in Dermatology

Hypertrophic scar (HPS) presents as excessive extracellular matrix deposition and abnormal function of fibroblasts. However, there is no single satisfactory method to prevent HPS formation so far. Here, we found that honokiol (HKL), a natural compound isolated from Magnolia tree, had an inhibitory effect on HPS both in vitro and in vivo. Firstly, HKL could dose-dependently down-regulate the mRNA and protein levels of type I collagen, type III collagen, and α-smooth muscle actin (α-SMA) in hypertrophic scar-derived fibroblasts (HSFs). Secondly, HKL suppressed the proliferation, migration abilities of HSFs and inhibited HSFs activation to myofibroblasts, but had no effect on cell apoptosis. Besides, the in vivo rabbit ear scar model further affirmed the inhibitory effects of HKL on collagen deposition, proliferating cell nuclear antigen and α-SMA. Finally, Western blot results showed that HKL reduced the phosphorylation status of Smad2/3, as well as affected the protein levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase1. Taken together, this study demonstrated that HKL alleviated HPS by suppressing fibrosis-related molecules and inhibiting HSFs proliferation, migration as well as activation to myofibroblasts via Smad-dependent pathway. Therefore, HKL could be used as a potential agent for treating HPS and other fibrotic diseases.

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Honokiol Alleviates Hypertrophic Scar by Targeting Transforming Growth Factor-β/Smad2/3 Signaling Pathway.

Background: To study the effect of abnormal savda munziq (ASMq) on TGF-β1 and Smad7 expression in hypertrophic scar fibroblasts (HSFs) and to preliminarily assess the function of abnormal savda munziq in hypertrophic scar formation at the molecular biology level. Methods: HSFs were cultured in vitro. RT-PCR and Western-blot were used to investigate the influence of 48-h treatment with ASMq at different concentrations (0 mg/mL, 0.1 mg/mL, 0.4 mg/mL, and 0.7 mg/mL) on TGF-β1 and Smad7 mRNA and protein expression levels. Results: After 48-h treatment with ASMq, the expression of TGF-β1 mRNA and protein gradually decreased in HSFs as the concentration increased. In contrary, Smad7 mRNA and protein expression were positively correlated with ASMq concentration. Conclusions: ASMq reduces TGF-β1, increases Smad7 mRNA and protein expression through regulating TGFβ-1/Smad signaling pathway, inhibiting HSFs proliferation and reducing extracellular collagen deposition.

Preliminary study of the effect of abnormal savda munziq on TGF-β1 and Smad7 expression in hypertrophic scar fibroblasts.

Background. To explore the effect of ASMq on proliferation and migration ability of the fibroblast derived from HS of donor (HSFbs) in vitro. Methods. The HSFbs were cultured from tissue specimens and passaged to the 3~4 generation, which were treated with the different concentrations of ASMq and 5-Fu from 1 to 11 days. The difference of HSFbs proliferation activity was analyzed by the CCK-8 method. The HSFbs migration ability in ASMq (0.4 mg/mL) was analyzed by the Cell Scratch method. Results. Transmission electron microscope result shows ASMq concentration significantly increases and fibroblast cell structure markedly change in the experimental group. The proliferation activity of the HSFbs was obviously weakened in ASMq groups than those of the group A () at seven days. The group C (0.4 mg/mL) is better suitable than other three ASMq treatment groups. Cell Migration Assay shows that the migration ability HSFbs was significantly reduced in ASMq (0.4 mg/mL) treatment group compared with those of blank control group at both 24 h and 48 h (). Conclusions. These results suggest that ASMq effectively restrains the proliferation and migration ability of the HTSFbs in vitro, which can be one of the mechanisms for the prevention and treatment of HS.

https://downloads.hindawi.com/journals/ecam/2015/870514.pdf

Nan Li

Papers

Preliminary study of the effect of abnormal savda munziq on TGF-β1 and Smad7 expression in hypertrophic scar fibroblasts.

Effects of Abnormal Savda Munzip on the Proliferation Activity and Migration Ability of Fibroblasts Derived from Hypertrophic Scar In Vitro