Valproic acid suppresses collagen by selective regulation of Smads in conjunctival fibrosis

Seet, Li‐Fong; Toh, Li Zhen; Finger, Sharon N.; Chu, Stephanie; Stefanovic, Branko; Wong, Tina

doi:10.1007/s00109-015-1358-z

Cited by 28 publications

(32 citation statements)

References 54 publications

(68 reference statements)

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“…The post-operative response of this experimental surgery model closely mimicked that of patients with GFS [15] and consists of an early inflammatory phase that precedes repair or fibrosis [16]. At the same dosage previously shown to be effective for inhibiting collagen deposition [13], we demonstrate in this study that subconjunctival injection of VPA modulated tissue macrophage composition and chemokine/cytokine levels, as well as repressed specific NF-kB expression. In conjunctival fibroblasts, which we have shown previously to faithfully replicate in vivo responses when exposed to proinflammatory or profibrotic stimulus [16], VPA not only reduced specific cytokine production in uninduced cells but also has the capacity to suppress TNF-α induction of multiple cytokines.…”

Section: Introductionsupporting

confidence: 58%

“…The dosage of VPA used in the experimental model was previously determined based on effective inhibition of collagen expression in mouse conjunctival fibroblasts while remaining within safe limits, causing less than 10% loss in cell density or viability [13]. We further show here that VPA is likely to be safe for treatment of conjunctival inflammation as it did not induce any overt adverse tissue response, such as visually conspicuous increase in vascularity or inflammation.…”

Section: Discussionmentioning

confidence: 53%

“…Taken together, our data suggest that VPA will be beneficial as pre-operative and intra-operative therapy to reduce conjunctival inflammation. Since VPA appears to be relatively safe and also has the capacity to reduce collagen production [13], the potential use of this drug in post-operative management of inflammation and fibrosis should be considered.…”

Section: Discussionmentioning

confidence: 99%

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Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva

et al. 2018

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Valproic acid (VPA) is a histone deacetylase inhibitor used clinically for neurological disorders. It is also potentially useful as anti-fibrotic therapy as it reduced collagen deposition in the post-operative conjunctiva. In this study, we further evaluated the effects of VPA on post-operative inflammation using the mouse model of conjunctival scarring. VPA, injected into the subconjunctiva immediately after surgery, did not cause any adverse tissue response when examined by live microscopy and produced an apparent reduction of proinflammatory and proangiogenic markers in immunohistological examinations. In-depth analyses of the treated operated tissues revealed that VPA selectively inhibited the CD45highF4/80low macrophage subset as well as the production of specific proinflammatory cytokines/ chemokines, including CXCL1, IL-5, IL-6, and IL-10 which were reduced by ≥ 2.0-fold. VPA also specifically reduced tissue NF-кB2 p100 protein by mean 3.87-fold. On conjunctival fibroblasts, VPA treatment resulted in decreased secretion of specific cytokines, including CCL2, VEGF-A, and IL-15. In the presence of TNF-α, VPA inhibited the induction of specific cytokines/chemokines, notably CCL5 and VEGF-A, as well as NF-кB2 p100. In corroboration, VPA suppressed TNF-α stimulation of NF-кB reporter transcription by 1.51-fold. These data indicate that VPA can modulate both proinflammatory cellular and molecular targets in a selective manner and may therefore attenuate surgery-induced conjunctival inflammation. These and previous findings suggest that, by suppressing key mediators of both inflammation and fibrosis, VPA is a useful therapeutic for improving surgical outcome involving the conjunctiva.Key messages VPA inhibited recruitment of a CD45highF4/80low macrophage subset. VPA reduced chemokine and cytokine levels in treated tissues.VPA selectively suppressed tissue NF-кB2 p100 levels.VPA suppressed TNF-α induction of chemokines, cytokines and NF-кB2 p100 expression.VPA suppressed TNF-α stimulation of NF-кB reporter.

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Section: Introductionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva

et al. 2018

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“…In addition, anti-fibrotic effects of valproic acid, an inhibitor of class I HDACs, have been reported in experimental models of numerous fibrotic conditions 157 . This drug suppresses TGFβ1-stimulated αSMA expression, probably by modulating SMAD expression, and is a potent inducer of autophagy 158,159 . More recently, several compounds with selectivity for individual HDACs, including HDAC1, HDAC3, HDAC6 and HDAC8, have been described 160 .…”

Section: Ageing Mechanisms and Novel Therapiesmentioning

confidence: 99%

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora¹,

Rojas²,

Pardo³

et al. 2017

Nat Rev Drug Discov

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.

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“…21 In conjunctival fibrosis, valproic acid decreases collagen expression by up-regulating the expression of Smad6. 22 Both Foxf2 and Smad6 are related to the production of collagen, and Foxf2 and Smad6 expression were correlated with the degree of IUA ( Figure 1B). Therefore, we speculated that Foxf2 and Smad6 are important for the pathogenesis of IUA.…”

mentioning

confidence: 92%

Foxf2 and Smad6 co‐regulation of collagen 5A2 transcription is involved in the pathogenesis of intrauterine adhesion

Chen

Liu

Sun

et al. 2020

J Cellular Molecular Medi

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The replacement of normal endometrial epithelium by fibrotic tissue is the pathological feature of intrauterine adhesion (IUA), which is caused by trauma to the basal layer of the endometrium. COL5A2 is a molecular subtype of collagen V that regulates collagen production in fibrotic tissue. Here, we investigated the roles of Foxf2 and Smad6 in regulating the transcription of COL5A2 and their involvement in the pathogenesis of IUA. Small interference‐mediated Foxf2 (si‐Foxf2) silencing and pcDNA3.1‐mediated Smad6 (pcDNA3.1‐Smad6) up‐regulation were performed in a TGF‐β1‐induced human endometrial stromal cell line (HESC) fibrosis model. Assessment of collagen expression by Western blotting, immunofluorescence and qRT‐PCR showed that COL5A2, COL1A1 and FN were significantly down‐regulated in response to si‐Foxf2 and pcDNA3.1‐Smad6. Transfection of lentivirus vector‐Foxf2 (LV‐Foxf2) and pcDNA3.1‐Smad6 into HESCs and qRT‐PCR showed that Foxf2 promoted COL5A2 expression and Smad6 inhibited Foxf2‐induced COL5A2 expression. Co‐immunoprecipitation, chromatin immunoprecipitation and dual‐luciferase reporter assays to detect the interaction between Foxf2 and Smad6 and their role in COL5A2 transcription showed that Foxf2 interacted with Smad6 and bond the same promoter region of COL5A2. In a rat IUA model, injection of ADV2‐Foxf2‐1810 and ADV4‐Smad6 into the uterine wall showed that Foxf2 down‐regulation and Smad6 up‐regulation decreased fibrosis and the expression of COL5A2 and COL1A1, as detected by haematoxylin/eosin, Masson trichrome staining and immunohistochemistry. Taken together, these results suggested that Foxf2 interacted with Smad6 and co‐regulated COL5A2 transcription in the pathogenesis of IUA, whereas they played opposite roles in fibrosis.

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Valproic acid suppresses collagen by selective regulation of Smads in conjunctival fibrosis

Cited by 28 publications

References 54 publications

Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva

Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Foxf2 and Smad6 co‐regulation of collagen 5A2 transcription is involved in the pathogenesis of intrauterine adhesion

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