TAS-203, an oral phosphodiesterase 4 inhibitor, exerts anti-inflammatory activities in a rat airway inflammation model

Demizu, Shunsuke; Asaka, Naomasa; Kawahara, Hiroyuki; Sasaki, Eiji

doi:10.1016/j.ejphar.2019.01.068

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…Upregulation of MUC5AC genes has been demonstrated also in animal models of T2-low (neutrophilic) and obesity-related asthma [13,14], thus shifting the possibility of a therapeutic approach also for patients without a T2 signature. In this view, a novel PDE4 (TAS-203) has shown favorable results in animal models of asthma, suppressing EGF-induced mucin MUC5AC expression and reducing goblet cell hyperplasia and MUC5AC production in the bronchoalveolar lavage fluid [15]. Tiotropium, currently approved for the add-on therapy in patients with moderate to severe asthma, has demonstrated some in vivo regulatory effects on mucus production [16], but, to date, any conclusion on the clinical significance of these effects seems premature.…”

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confidence: 99%

Mucins and Asthma: Are We Headed to the Revolutionary Road?

Santus

Radovanovic

Chiumello

2019

JCM

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Mucus represents the first line of defense of our respiratory tract and mucociliary clearance is essential for maintaining the homeostasis of airway epithelium. The latter mechanisms are altered in asthma and mucus plugging of proximal and distal airways is the main cause of death in cases of fatal asthma. Starting from the influential review performed by Luke R. Bonser and David J. Erle in 2017, we discuss the latest evidence in terms of mucins regulation and potential treatment of mucus hypersecretion and tissue remodeling in severe asthma.

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confidence: 99%

Mucins and Asthma: Are We Headed to the Revolutionary Road?

Santus

Radovanovic

Chiumello

2019

JCM

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“…During the development of COPD, exposure to CS increases the expression of PDE4 in the lung tissue, thereby reducing the levels of cAMP. This eventually worsens inflammatory responses in the lung tissue and causes a decrease in lung function [32,33]. Thus, PDE4 inhibitors are recognized as very important drugs in the treatment of COPD, and many researchers are currently focused on discovering COPD drugs, with an emphasis on PDE4 inhibition of candidate drugs [34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

The Involvement of PDE4 in the Protective Effects of Melatonin on Cigarette-Smoke-Induced Chronic Obstructive Pulmonary Disease

et al. 2021

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Chronic obstructive pulmonary disease (COPD) is a significant disease threatening human health. Currently, roflumilast, a phosphodiesterase (PDE)4 inhibitor, is recommended as a therapeutic agent for COPD. In this study, we investigated the therapeutic effects of melatonin against COPD, focusing on determining whether it is a PDE4 inhibitor via in vivo and in vitro experiment using cigarette smoke (CS) and cigarette smoke condensate (CSC), respectively. In the in vivo experiments, melatonin treatment reduced inflammatory responses, including inflammatory cell counts. Melatonin treatment also suppressed the CS-exposure-induced upregulation of cytokine and matrix metalloproteinase (MMP)-9, reduced the PDE4B expression, and elevated cAMP levels. In addition, these effects were synergistic, as melatonin and roflumilast cotreatment eventually ameliorated the CS-exposure-induced worsening of lung function. In the CSC-stimulated NCI-H292 cells, melatonin inhibited elevation in the levels of inflammatory cytokines, MMP-9, and PDE4, and elevated cAMP levels. Furthermore, melatonin and roflumilast cotreatment was more effective on inflammatory responses than only melatonin or roflumilast treatment. Our results indicate that melatonin relieves inflammatory response and loss of lung function in COPD, which is associated with decreased PDE4 expression. Therefore, we suggest that melatonin is a putative candidate for the treatment of COPD.

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“…In addition, it showed some central nervous system related side effects, including nausea and vomiting [ 33 ]. However, another PDE4 inhibitor TAS203 that poses lower emetogenicity suppresses goblet cell hyperplasia of the airway epithelium in a cigarette smoke induced guinea pig model [ 247 ]. The continuous inflammation caused by cigarette smoke is assumed to be the cause of structural alterations in lungs that contributes to COPD [ 194 ].…”

Section: The Effect Of Pde Inhibitors On Different Cells In Copdmentioning

confidence: 99%