Suberoylanilide hydroxamic acid attenuates paraquat-induced pulmonary fibrosis by preventing Smad7 from deacetylation in rats

Rao, Shanshan; Zhang, Xiangyan; Shi, Mingjun; Xiao, Ying; Zhang, Yingying; Wang, Yuan‐Yuan; Chang-zhi, Zhang; Shao, Songjun; Liu, Xinmei; Guo, Bing

doi:10.21037/jtd.2016.08.08

Cited by 27 publications

(26 citation statements)

References 27 publications

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“…In addition, in this study, using in vitro experiments with lung fibroblast cell line MRC5, we confirmed the central role of histone deacetylates in fibrogenesis, highlighting the possible use of histone deacetylase inhibitor to directly inhibit myofibroblast formation. Our data are in line with other groups that demonstrated that SAHA is able to attenuate the TGF-β1 effects on proliferation and differentiation 20 , 58 , 59 .…”

Section: Discussionsupporting

confidence: 93%

Lung resident mesenchymal cells isolated from patients with the Bronchiolitis Obliterans Syndrome display a deregulated epigenetic profile

Vella

Conaldi

Cova

et al. 2018

Sci Rep

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Bronchiolitis Obliterans Syndrome is the major determinant of the graft function loss after lung transplantation, but its pathogenesis is still incompletely understood and currently available therapeutic strategies are poorly effective. A deeper understanding of its pathogenic mechanisms is crucial for the development of new strategies to prevent and treat this devastating complication. In this study, we focused on the mesenchymal stromal cells, recently recognized as BOS key effectors, and our primary aim was to identify their epigenetic determinants, such as histone modifications and non-coding RNA regulation, which could contribute to their differentiation in myofibroblasts. Interestingly, we identified a deregulated expression of histone deacetylases and methyltransferases, and a microRNA-epigenetic regulatory network, which could represent novel targets for anti-fibrotic therapy. We validated our results in vitro, in a cell model of fibrogenesis, confirming the epigenetic involvement in this process and paving the way for a new application for epigenetic drugs.

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Section: Discussionsupporting

confidence: 93%

Lung resident mesenchymal cells isolated from patients with the Bronchiolitis Obliterans Syndrome display a deregulated epigenetic profile

Vella

Conaldi

Cova

et al. 2018

Sci Rep

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“…For example, vorinostat (suberoylanilide hydroxamic acid; SAHA), a pan-histone deacetylase inhibitor with FDA approval for the treatment of cutaneous T cell lymphoma, has been shown to induce the apoptosis of myofibroblasts from lungs with IPF in vitro, and to reduce the fibrotic response, thus improving lung function, in a murine model of bleomycin-induced pulmonary fibrosis 155 . More recently, it was found that vorinostat represses paraquatinduced lung fibrosis in rats by preventing the deacetylation of SMAD7 (a strong inhibitor of TGFβ1 signalling), highlighting the importance of non-histone targets of HDACs 156 . 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 .…”

Section: Targets and Therapeutic Interventions For Epigenetic Changesmentioning

confidence: 99%

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

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

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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.Fibrosis as a pathogenic mechanism occurs in numerous organs and diseases. Fibrosis results from abnormal tissue repair and is associated with persistent and/or severe tissue damage and cellular stress. Epithelial and/or endothelial injury caused by various insults triggers interrelated wound-healing pathways to restore homeostasis 1 . Failure to adequately contain or eliminate inciting factors can exacerbate inflammation and chronic woundCorrespondence to A.L.M. anamora@pitt.edu. Competing interests statementThe authors declare competing interests: see Web version for details. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript healing responses, resulting in continued tissue damage and inadequate regeneration and, ultimately, fibrosis 2 . Although their aetiology and causative mechanisms differ, the various fibrotic diseases all have abnormal and exaggerated accumulation of extracellular matrix (ECM) components, mainly fibrillar collagens. The resulting fibrosis disturbs the normal architecture of affected organs, which ultimately leads to their dysfunction and failure. Nearly 45% of deaths in the developed world are attributable to some type of chronic fibroproliferative disease, including idiopathic pulmonary fibrosis (IPF) and end-stage fibrotic liver, kidney and heart disease 2 . The progressive nature of these diseases and the absence of effective treatments mean that a better understanding of the cellular and molecular mechanisms that contribute to the development of fibrosis is needed.Although IPF was originally thought to be an inflammation-driven disorder, clinical trials with a combination of anti-inflammatory drugs (prednisone, azathioprine and N-acetyl-Lcysteine (NAC)), failed to improve outcomes and instead increased mortality 3 . In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF ...

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“…The continuous redox cycling of PQ, given adequate amounts of NAD(P)H and O 2 , allows for a concentration-dependent generation of ROS. Thus, in experimental models, PQ has been utilized to generate low levels of intracellular ROS to study the mechanisms of redox-dependent signaling [ 16 ], or it has been used to generate high levels of ROS to initiate toxicity and cause neurodegeneration and pulmonary fibrosis [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

A CRISPR screen identifies a pathway required for paraquat-induced cell death

et al. 2017

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Paraquat, a herbicide linked to Parkinson’s disease, generates reactive oxygen species (ROS) to cause cell death. Because the source of paraquat-induced ROS production remains unknown, we conducted a CRISPR-based positive selection screen to identify metabolic genes essential for paraquat-induced cell death. Our screen uncovered three genes, POR (cytochrome P450 oxidoreductase), ATP7A (copper transporter), and SLC45A4 (sucrose transporter), required for paraquat–induced cell death. Furthermore, our results revealed POR as the source of paraquat-induced ROS production. Thus, our study highlights the use of functional genomic screens to uncover redox biology.

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Suberoylanilide hydroxamic acid attenuates paraquat-induced pulmonary fibrosis by preventing Smad7 from deacetylation in rats

Abstract: SAHA repressed PQ-induced lung fibrosis via preventing Smad7 from deacetylation.

Cited by 27 publications

References 27 publications

Lung resident mesenchymal cells isolated from patients with the Bronchiolitis Obliterans Syndrome display a deregulated epigenetic profile

Lung resident mesenchymal cells isolated from patients with the Bronchiolitis Obliterans Syndrome display a deregulated epigenetic profile

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

A CRISPR screen identifies a pathway required for paraquat-induced cell death

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