Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin-induced lung fibrosis

Zhao, Hui; Qin, Hou-Ying; Cao, Linfeng; Chen, Yuan-Hua; Tan, Zhu-Xia; Zhang, Cheng; D, Xu

doi:10.1016/j.toxlet.2014.10.013

Cited by 47 publications

(38 citation statements)

References 29 publications

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“…Although 4-PBA has multiple activities -including inhibiting HDACs and scavenging ammonia -it also acts as an osmolyte chemical chaperone to rescue conformational abnormalities of proteins 177 . 4-PBA is reported to improve bleomycininduced lung fibrosis and to decrease the expression of ER stress markers, collagen and αSMA 178 . Although targeting the ER stress response seems promising as a future therapy for lung diseases, there is limited knowledge of how to specifically control UPR pathways that activate both pro-survival adaptive responses and cell death.…”

Section: Targets and Therapeutic Interventions For Insufficient Protementioning

confidence: 98%

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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Section: Targets and Therapeutic Interventions For Insufficient Protementioning

confidence: 98%

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

Mora

Rojas

Pardo

et al. 2017

Nat Rev Drug Discov

290

212

View full text Add to dashboard Cite

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“…ER stress develops in airway cells in this model and is exacerbated by viral infection, and the UPR has been associated with the differentiation status of macrophages, and intrinsic ER stress within macrophages also occurs 16, 71, 75, 83, 84, 85, 86…”

Section: Oxidative and Er Stress In Chronic Inflammatory And Mucopurumentioning

confidence: 88%

“…4‐phenylbutyrate (4‐PBA) and tauroursodeoxycholic acid (TUDCA) are chemical chaperones which promote correct folding in the ER that have been used widely in animal models of ER stress. 4‐PBA reduced ER stress, inflammation and fibrosis in the bleomycin model in mice,84 attenuated symptoms of asthma in the house dust mite allergen model in mice90 and also reduced ER stress and autophagy in LPS‐induced acute lung injury 104. Similarly, TUDCA has also been demonstrated to alleviate ER stress and associated pathology in the bleomycin fibrosis model and in asthma models in mice 83, 92.…”

Section: Therapeutic Approaches To Resolve Oxidative and Er Stress Inmentioning

confidence: 97%

Oxidative and endoplasmic reticulum stress in respiratory disease

2018

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Oxidative stress and endoplasmic reticulum (ER) stress are related states that can occur in cells as part of normal physiology but occur frequently in diseases involving inflammation. In this article, we review recent findings relating to the role of oxidative and ER stress in the pathophysiology of acute and chronic nonmalignant diseases of the lung, including infections, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. We also explore the potential of drugs targeting oxidative and ER stress pathways to alleviate disease.

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“…Recent investigations suggested that ER stress could also be involved (Zhao et al. 2014a,b; Tanaka et al. 2015).…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin-induced lung fibrosis

Cited by 47 publications

References 29 publications

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

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

Oxidative and endoplasmic reticulum stress in respiratory disease

Role of endoplasmic reticulum stress in drug‐induced toxicity

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