Simvastatin Increases the Ability of Roflumilast N-oxide to Inhibit Cigarette Smoke-Induced Epithelial to Mesenchymal Transition in Well-differentiated Human Bronchial Epithelial Cells<i>in vitro</i>

Milara, Javier; Peiró, Teresa; Serrano, Adela; Artigues, Enrique; Aparicio, Jesús; Tenor, Herman; Sanz, Celia; Cortijo, Julio

doi:10.3109/15412555.2014.948995

Cited by 20 publications

(20 citation statements)

References 40 publications

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“…However, pretreatment of airway epithelial cells with dexamethasone was not sufficient to reverse TGFb-induced EMT (148). In addition to corticosteroids, Milara and colleagues (34,149,150) showed that treatment with cAMP-elevating compounds successfully restores airway epithelial barrier dysfunction induced by either cigarette smoke extract or TGF-b in vitro. Therefore, it will be of interest to study effects of PDE4 inhibitors on epithelial barrier dysfunction in COPD.…”

Section: Recent Developments In Therapeutic Approaches Based On the Rmentioning

confidence: 99%

Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure

Aghapour¹,

Raee

Moghaddam

et al. 2018

Am J Respir Cell Mol Biol

247

216

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The epithelial lining of the airway forms the first barrier against environmental insults, such as inhaled cigarette smoke, which is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). The barrier is formed by airway epithelial junctions, which are interconnected structures that restrict permeability to inhaled pathogens and environmental stressors. Destruction of the epithelial barrier not only exposes subepithelial layers to hazardous agents in the inspired air, but also alters the normal function of epithelial cells, which may eventually contribute to the development of COPD. Of note, disruption of epithelial junctions may lead to modulation of signaling pathways involved in differentiation, repair, and proinflammatory responses. Epithelial barrier dysfunction may be particularly relevant in COPD, where repeated injury by cigarette smoke exposure, pathogens, inflammatory mediators, and impaired epithelial regeneration may compromise the barrier function. In the current review, we discuss recent advances in understanding the mechanisms of barrier dysfunction in COPD, as well as the molecular mechanisms that underlie the impaired repair response of the injured epithelium in COPD and its inability to redifferentiate into a functionally intact epithelium.

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Section: Recent Developments In Therapeutic Approaches Based On the Rmentioning

confidence: 99%

Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure

Aghapour¹,

Raee

Moghaddam

et al. 2018

Am J Respir Cell Mol Biol

247

216

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“…We found that ROS generation was significantly elevated in NPC cells when GLRX3 was knocked down (Figure 6B, 6C). The effect of ROS on activating the Akt pathway remains controversial [20, 21]. To identify whether the hypergeneration of ROS by silencing GLRX3 in NPC cell lines contributes to inhibiting the Akt signaling cascade, we decreased the ROS level in shGLRX3 -HONE1/CNE2 cells by an ROS inhibitor N-acetyl cysteine (NAC) (Figure 6D, 6E).…”

Section: Resultsmentioning

confidence: 99%

Glutaredoxin 3 promotes nasopharyngeal carcinoma growth and metastasis via EGFR/Akt pathway and independent of ROS

Wei

Luo

et al. 2016

Oncotarget

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Glutaredoxin 3 (GLRX3) is antioxidant enzyme, maintaining a low level of ROS, thus contributing to the survival and metastasis of several types of cancer. However, the expression and functions of GLRX3 have not been addressed in nasopharyngeal carcinoma (NPC). In this study, we found that GLRX3 was overexpressed in NPC. Knockdown of GLRX3 in NPC cell lines inhibited proliferation in vitro, tumorignesis in vivo, and colony formation. In addition, GLRX3 knockdown decreased the migration and invasion capacity of NPC cells by reversing the epithelial-mesenchymal transition (EMT). Furthermore, stabilization of GLRX3 was positively related to with epidermal growth factor receptor (EGFR) expression and negatively with ROS generation. Phosphorylation of Akt, a key downstream effector, was induced by EGFR signaling but did not rely on increasing ROS level in NPC cells. GLRX3 might be an oncoprotein in NPC, playing important roles in increasing redox reaction and activating EGFR/ Akt signals, so it may be a therapeutic target for NPC.

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“…However, increased glutathione is not sufficient to overcome the increase of ROS in lung tissue [ 30 ]. In this regard, we and others showed that in different models relevant to pulmonary fibrosis roflumilast and its active metabolite roflumilast N-oxide reduce ROS generation in numerous types of lung cells and lung tissue [ 12 , 31 , 32 ]. Specifically, it has been shown that roflumilast inhibits the NADPH oxidase (NOX) activity by suppressing the interaction of rac1 with NADPH oxidase isoenzymes [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, we and others showed that in different models relevant to pulmonary fibrosis roflumilast and its active metabolite roflumilast N-oxide reduce ROS generation in numerous types of lung cells and lung tissue [ 12 , 31 , 32 ]. Specifically, it has been shown that roflumilast inhibits the NADPH oxidase (NOX) activity by suppressing the interaction of rac1 with NADPH oxidase isoenzymes [ 31 ]. Furthermore, roflumilast was able to reduce an enhanced expression of NADPH oxidase isoenzymes NOX1, NOX2 DUOX2 and NOX4 secondary to different stimuli in bronchial epithelial cells and lung fibroblast [ 11 , 32 ] which may contribute to the anti-fibrotic profile of roflumilast in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

et al. 2015

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Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (NMR) metabolic profiling of intact lung tissue. Metabolic profiling reveals strong differences between fibrotic and non-fibrotic tissue. These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids. In parallel, there was a loss in plasma BH4. This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others. Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.

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Simvastatin Increases the Ability of Roflumilast N-oxide to Inhibit Cigarette Smoke-Induced Epithelial to Mesenchymal Transition in Well-differentiated Human Bronchial Epithelial Cellsin vitro

Abstract: The PDE4 inhibitor roflumilast N-oxide acts (over)additively with simvastatin to prevent CSE-induced EMT in WD-HBEC in vitro.

Cited by 20 publications

References 40 publications

Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure

Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure

Glutaredoxin 3 promotes nasopharyngeal carcinoma growth and metastasis via EGFR/Akt pathway and independent of ROS

Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

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