Histone Deacetylase Inhibitor Reduces Hypertrophic Scarring in a Rabbit Ear Model

Diao, Jian-Sheng; Xia, Wensen; Yi, Chengla; Yang, Yang; Zhang, Xi; Xia, Wei; Shu, Maoguo; Wang, Yingmei; Gui, Lin; Guo, Shuzhong

doi:10.1097/prs.0b013e318290f698

Cited by 16 publications

(12 citation statements)

References 42 publications

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“…TSA also inhibited mesangial cell proliferation and the synthesis of collagen and α‐SMA in renal fibrosis (Freidkin et al , ). Furthermore, a recent study using a rabbit ear model showed that TSA led to decreased Col1 and fibronectin synthesis and that it inhibited hypertrophic scar formation (Diao et al , ). These results indicate that HDAC inhibitors could be used to treat fibrotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars

Bai

Liu

Yang

et al. 2016

British J Pharmacology

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*These authors contributed equally to this work. BACKGROUND AND PURPOSESirtuin1 (SIRT1), the founding member of mammalian class III histone deacetylases, is reported to be a drug target involved in fibrotic diseases. However, whether it is an effective drug target in hypertrophic scar treatment is still not known. EXPERIMENTAL APPROACHIn the present study, we observed that SIRT1 localized to both the epidermis and the dermis of skin tissues by immunohistochemistry. After knock-down of SIRT1 by shRNA or up-regulating SIRT1 by resveratrol, the expression of α-SMA, Col1 and Col3 in fibroblasts were detected by western blots. A mouse excision wound healing model was used to observe the changes in collagen fibre associated with the different expression levels of SIRT1. KEY RESULTSSIRT1 expression was inhibited in hypertrophic scar tissue. The down-regulation of SIRT1 resulted in an increased expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts. In contrast, the up-regulation of SIRT1 not only inhibited the expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts but also blocked the activation of TGFβ1-induced normal skin-derived fibroblasts. In the mouse model of wound healing, the deletion of SIRT1 resulted in denser collagen fibres and a more disordered structure, whereas resveratrol treatment led to a more organized and thinner collagen fibre, which was similar to that observed during normal wound healing. CONCLUSIONS AND IMPLICATIONSThe results revealed that SIRT1 negatively regulates TGFβ1-induced fibroblast activation and inhibits excessive scar formation and is, therefore, a promising drug target for hypertrophic scar formation. IntroductionHypertrophic scars are characterized by the excessive production and deposition of extracellular matrix (ECM) proteins. They usually develop after burn injury, trauma and surgery, and cause not only cosmetic but also functional problems (Gurtner et al., 2008;Hsu et al., 2010;Gauglitz et al., 2011;Tyack et al., 2012). Although extensively studied, the mechanism of hypertrophic scar formation is still currently unclear, and treatment remains a great challenge. It is widely accepted that the major characteristic of hypertrophic scars is the excessive deposition of collagen-based ECM proteins. Under normal conditions, the dynamic balance between the synthesis and degradation of collagen is regulated by matrix metalloproteinase, tissue inhibitor of metalloproteinase and various cytokines, such as TGFβ1. The balance is broken after skin injuries, which leads to increased synthesis and deposition of collagen, and the skin then recovers and becomes normal after wound healing (Sternlicht and Werb, 2001;Park et al., 2004;Armour et al., 2007). However, prolonged inflammation and other chronic stimuli may result in the overproduction of collagen, finally leading to hypertrophic scar formation (Armour et al., 2007;van der Veer et al., 2009).Among the various cell types in skin, fibroblasts are responsible for the synthesis of collagen and othe...

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Section: Discussionmentioning

confidence: 99%

Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars

Bai

Liu

Yang

et al. 2016

British J Pharmacology

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“…Furthermore, Russell et al found that epigenetic alteration in keloid fibroblasts was normalized after treatment with TSA [110]. Diao et al injected TSA in hypertrophic scars and observed regression of a pre-established scar [111]. Taken together, these data indicate that topical administration of HDACI could be an effective method to control the overgrowth of skin fibroblasts.…”

Section: Experimental Outcomes Of Hdac Inhibitors In Animal Modelsmentioning

confidence: 99%

HDAC Inhibitors: Therapeutic Potential in Fibrosis-Associated Human Diseases

Yoon

Kang

Eom

2019

IJMS

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Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models.

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“…Typically, these therapies are designed to decrease collagen synthesis (Yamaguchi et al, 2012; Beyer et al, 2013; Diao et al, 2013; Tomcik et al, 2013). …”

Section: Possibilities For Therapeutic Interventionmentioning

confidence: 99%

“…A number of other therapeutic targets have shown promise for the mitigation of mechanically induced fibrosis in preclinical models, including the hedgehog pathway (Horn et al, 2012), extracellular cross-linking enzymes (transglutaminases, lysyl oxidases, and prolyl hydroxylases) (Barry-Hamilton et al, 2010; Kolb and Gauldie, 2011; Olsen et al, 2011), early growth response gene-1 (Yamaguchi et al, 2012), canonical Wnt (Beyer et al, 2013), heat shock protein 90 (Tomcik et al, 2013), histone deacetylase (Diao et al, 2013) and IL-10, which modulates fibrosis by intercepting specific but varied intracellular signaling pathways (Reitamo et al, 1994; Yamamoto et al, 2001; Yuan and Varga, 2001; Nakagome et al, 2006, Occleston et al, 2008; Shi et al, 2013). Although remarkable progress has been made in targeting pro-fibrotic pathways experimentally, clinical translation of these therapies remains an ongoing challenge.…”

Section: Possibilities For Therapeutic Interventionmentioning

confidence: 99%

Mechanotransduction and fibrosis

Duscher

Maan

Wong

et al. 2014

Journal of Biomechanics

168

146

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Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.

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Histone Deacetylase Inhibitor Reduces Hypertrophic Scarring in a Rabbit Ear Model

Abstract: The introduction of trichostatin A can result in the decreased formation of hypertrophic scars in a rabbit ear model, which is corroborated by evidence of decreased collagen I and fibronectin synthesis.

Cited by 16 publications

References 42 publications

Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars

Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars

HDAC Inhibitors: Therapeutic Potential in Fibrosis-Associated Human Diseases

Mechanotransduction and fibrosis

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