Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents

Lv, Xin; Wang, Xiaoxing; Li, Ke-ke; Wang, Ziyan; Li, Zhe; Lv, Qi; Fu, Xiaoming; Hu, Zhuowei

doi:10.1371/journal.pone.0068631

“…Rupatadine, an antihistamine and inhibitor of PAF, has been shown to attenuate experimental lung fibrosis and improve lung function and survival, as well as reduce cellular senescence 135 . Rupatadine reduces the expression of CCAAT/enhancer-binding protein-β (C/EBPβ), IL-6, CXCL2 and other SASP factors 135 . These studies 135 also suggest that rupatadine decreases p53-dependent senescence in bleomycin-injured lung tissues.…”

mentioning

confidence: 99%

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

Mora

¹

,

Rojas

²

,

Pardo

³

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.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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“…A mouse model of bleomycin-induced lung injury and inflammation showed that repeated injury was accompanied by a loss of normal tissue architecture, a persistent increase in collagen deposition, increased collagen synthesis and increased number of myofibroblasts [37]. The fibrotic change in lung inflammation was associated with reduced total lung capacity, increased dynamic resistance and decreased dynamic compliance [38]. Subsequent studies showed that a variety of inflammatory cytokines and chemokines including TGFβ, CXCL6, IL-1, IL-5, IL-6, IL-17 modulate collagen deposition and the fibrotic effects of lung inflammation [39]–[44].…”

Section: Discussionmentioning

confidence: 99%

Prostatic Inflammation Induces Fibrosis in a Mouse Model of Chronic Bacterial Infection

Wong

¹

,

Hutson

²

,

Bushman

³

2014

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Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show–for the first time–that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process.

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“…Platelet-activating factor (PAF) is a SASP member that is secreted by senescent cells in lungs treated with bleomycin. Rupatadine, an antihistamine and inhibitor of PAF, has been shown to attenuate experimental lung fibrosis and improve lung function and survival, as well as reduce cellular senescence 135 . Rupatadine reduces the expression of CCAAT/enhancer-binding protein-β (C/EBPβ), IL-6, CXCL2 and other SASP factors 135 .…”

Section: Ageing Mechanisms and Novel Therapiesmentioning

confidence: 99%

“…Rupatadine, an antihistamine and inhibitor of PAF, has been shown to attenuate experimental lung fibrosis and improve lung function and survival, as well as reduce cellular senescence 135 . Rupatadine reduces the expression of CCAAT/enhancer-binding protein-β (C/EBPβ), IL-6, CXCL2 and other SASP factors 135 . These studies 135 also suggest that rupatadine decreases p53-dependent senescence in bleomycin-injured lung tissues.…”

Section: Ageing Mechanisms and Novel Therapiesmentioning

confidence: 99%

See 1 more Smart Citation

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

Mora¹,

Rojas²,

Pardo³

et al. 2017

Nat Rev Drug Discov

View full text Add to dashboard Cite

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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Rupatadine Protects against Pulmonary Fibrosis by Attenuating PAF-Mediated Senescence in Rodents

Cited by 48 publications

References 51 publications

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

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

Prostatic Inflammation Induces Fibrosis in a Mouse Model of Chronic Bacterial Infection

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

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