Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways

Fang, Qing‐Qing; Wang, Xiaofeng; Zhao, Wan‐Yi; Ding, Shi-Li; Shi, Bang-Hui; Xia, Ying; Yang, Hu; Wu, Lie; Li, Caiyun; Tan, Wei‐Qiang

doi:10.1038/s41598-018-21600-w

Cited by 48 publications

(43 citation statements)

References 52 publications

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“…As an upper reaching signal molecule, TGF-β regulates the expression of multiple downstream signaling molecules involved in scar formation via both canonical and noncanonical pathways 25 . The TGF-β1/Smad2/3 pathway is considered as one of the most important signaling pathways in scar formation because it supports the overproduction of ECM components and the over-proliferation of fibroblasts, which was confirmed in our previous study 26,27 . Thus, down-regulating the expression of the TGF-β1/Smad2/3 pathway is a promising strategy in scar management.…”

Section: Discussionsupporting

confidence: 80%

Potential effect of non-thermal plasma for the inhibition of scar formation: a preliminary report

Fang

Jia

et al. 2020

Sci Rep

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Non-thermal plasma (NTP) is a promising biomedical tool for application to wound healing. However, there is limited scientific evidence that confirms its efficacy to inhibit scar formation. This study aims to investigate the role of non-thermal plasma in scar formation. Two full-thickness dorsal cutaneous wounds of rats were treated with either a non-thermal helium plasma jet or helium. It was determined that the non-thermal plasma jet accelerated the wound healing process from 5 days after surgery (day 5: 41.27% ± 2.351 vs 54.7% ± 5.314, p < 0.05; day 7: 56.05% ± 1.881 vs 75.28% ± 3.914, p < 0.01; day 14: 89.85% ± 2.991 vs 98.07% ± 0.839, p < 0.05). The width of the scars for the NTP group was narrower than those of control group (4.607 ± 0.416 mm vs 3.260 ± 0.333 mm, p < 0.05). In addition, a lower level of TGF-β1, p-Smad2 and p-Smad3 were detected in the NTP treated wounds (p < 0.05, p < 0.01 and p < 0.01). As expected, α-SMA was also significantly decreased in the NTP treatment group (p < 0.01). Moreover, the expression of type I collagen and the proportion of type I to III collagen were lower in the NTP group (p < 0.05). The results of the study suggest that NTP may play a potential role in scar formation by inhibiting the TGF β1 signal pathway and reducing the levels of α-SMA and type I collagen, and may have clinical utility in the future. Scar formation is an inevitable outcome after physical, biological, and chemical injury of the skin, The phenomenon is characterized by excessive deposition and irregular distribution of extracellular matrices (ECM), in addition to an overproduction of fibroblasts 1-3. Patients with severe scars caused by burns, scalds or serious traumas, experience physical and mental anguish that is typically associated with the dysfunction and disfigurement caused by tissue hypertrophy or severe contraction 4. Therefore, even incremental improvements in scar management could result in significant benefits to patients. To date, numerous therapeutic approaches have been developed for the treatment of scars including surgical excision, corticosteroid injection, and laser therapy 5,6. However, in many cases these treatments do not result in satisfactory outcomes. The treatment of scars is still a formidable task, and advanced treatments or techniques for the minimization of scarring are needed. Plasma medicine, a rapidly developing interdisciplinary field, has already developed as a new innovative approach for biomedical and clinical applications 7. Emerging evidence suggests that non-thermal plasma (NTP) is potentially beneficial for bacteria disinfection, blood coagulation, and cancer therapy 8-12. NTP has also been shown to play a role in wound healing 13. However, there are limited experimental studies on the application of NTP to inhibit scar formation. In this study, we aimed to investigate the efficacy of non-thermal plasma in the inhibition of scar formation in a rat model. Based on histological observation and immunohistochemistry quantitative analysis, we concluded that plasma e...

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Section: Discussionsupporting

confidence: 80%

Potential effect of non-thermal plasma for the inhibition of scar formation: a preliminary report

Fang

Jia

et al. 2020

Sci Rep

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“…It is possible that high level of ACE and chymase enzyme activity and subsequently high concentration of angiotensin II is involved in scar formation . Angiotensin II causes increase in collagen synthesis but losartan is an AT 1 receptor antagonist that inhibits collagen production . Our results showed that losartan reduces pliability significantly in keloids and hypertrophic scars probably by antifibrotic effects.…”

Section: Discussionmentioning

confidence: 54%

“…Stimulation of human fibroblasts isolated from keloid, hypertrophic scar, and normal tissues by TGF‐β leads to the increment of CTGF expression and CTGF may be a fibrogenic mediator of angiotensin II . It is reported that losartan can reduce TGF‐β, phosphorylated SMAD2/3, phosphorylated TAK‐1, and CTGF signaling …”

Section: Introductionmentioning

confidence: 99%

Losartan ointment relieves hypertrophic scars and keloid: A pilot study

Hedayatyanfard

Ziai

Niazi

et al. 2018

Wound Repair Regeneration

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Keloid and hypertrophic scars are two types of fibrosis caused by extracellular matrix overexpression, and angiotensin II via AT receptor is known to play a key role in stimulation of fibrosis. A pilot placebo controlled single blind study was carried out on patients with hypertrophic scars and keloids. A total of 37 adult volunteers were randomly assigned into losartan 5% or placebo treatment groups. The treatment was performed twice a day for three months and a 6-month follow-up. The treatment was evaluated using Vancouver scar scale method. Totally, 30 participants were analyzed (Losartan ointment n = 20; placebo ointment n = 10; seven placebo volunteers left the study because they thought the treatment was not effective for them). In the losartan group, VSS scores dropped significantly (p < 0.01) both in keloid and hypertrophic scar patients. Vascularity and pliability were significantly reduced by losartan treatment (p < 0.05). It can be concluded that losartan potassium ointment (5%) can alleviate the keloid and hypertrophic scar.

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“…Many articles have concluded that inhibiting broblast proliferation can effectively reduce epidural brosis and reduce scar tissues hyperplasia. Some articles show that the TGF-β1 / Smad2/3 axis is extensively participated in the formation of brosis, and repression of the channel can inhibit the proliferation of broblasts [11,12]. In addition, many studies have indicated that inhibition of broblasts migration and differentiation can also achieve better anti-brotic effects [13,14].…”

Section: Introductionmentioning

confidence: 99%

Mycophenolate mofetil reduces epidural fibrosis by regulating TGF-β1/Smad2/3 axis to repress the proliferation, migration and differentiation of fibroblasts

Zhu¹,

Zhang²,

Zhang³

et al. 2020

Preprint

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Background Excessive fibroblasts proliferation is believed as a major reason in the process of epidural fibrosis, which is known as a troublesome complication of lumbar laminectomy clinically. Mycophenolate mofetil (MMF) is a kind of immunosuppressant, previous studies had shown that it has the function of preventing fibrosis, but the role and mechanism are still unclear. In this study, we determined the repressed effect of MMF on fibroblasts proliferation, migration and differentiation in surgical-induced epidural fibrosis and the underlying mechanism. Methods In vitro, the impacts of MMF on cell viability were measured by cell counting kit-8 (CCK-8) assay and the fibroblasts proliferation rates were determined by using EdU incorporation, cell cycle assays and western blot. Additionally, the impacts of MMF on fibroblasts migration and differentiation were analyzed by cell wound scratch assay, transwell assay, immunofluorescence analysis and western blot. In vivo, we built epidural fibrosis models in rats and locally applied MMF. Histological and immunohistochemical staining were used to determine the effect of MMF on reducing epidural fibrosis and fibroblasts functions. Results CCK-8 assay demonstrated that MMF repressed fibroblasts proliferation in a time- and a dose-dependent manner. EdU incorporation assay and cell cycle analysis proved the inhibition effect of MMF on the proliferation of fibroblasts. Cell wound scratch assay, transwell assay and immunofluorescence proved the inhibition effect of MMF on the migration and differentiation of fibroblasts. Western blotting analysis proved that MMF inhibited the expression of TGF-β1, p-Smad2 and p-Smad3. The expression of proliferation proteins, migration proteins and differentiation proteins were downregulated. In addition, histological and immunohistochemical stain showed that MMF reduces epidural fibrosis by repressing the proliferation, migration and differentiation of fibroblasts. Conclusion MMF could inhibit the proliferation, migration and differentiation of fibroblasts, it reduced surgical-induced epidural fibrosis as well. TGF-β1/Smad2/3 axis may be the latent mechanism in MMF reduced epidural fibrosis. It might provide a new notion for mitigating surgery-induced epidural fibrosis.

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Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways

Cited by 48 publications

References 52 publications

Potential effect of non-thermal plasma for the inhibition of scar formation: a preliminary report

Potential effect of non-thermal plasma for the inhibition of scar formation: a preliminary report

Losartan ointment relieves hypertrophic scars and keloid: A pilot study

Mycophenolate mofetil reduces epidural fibrosis by regulating TGF-β1/Smad2/3 axis to repress the proliferation, migration and differentiation of fibroblasts

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