Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease

Milara, Javier; Serrá, Juan Antonio Monsoriu; Almudever, Patricia; Freire, Jose; Xiaozhong, Qian; Cortijo, Julio

doi:10.1016/j.jaci.2014.02.001

Cited by 74 publications

(74 citation statements)

References 57 publications

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“…We believe our study gives a more representative view of MIF levels in patients with COPD, both because of its size and additional adjustment for important covariates such as body composition, comorbidities (CCS), and use of inhaled steroids. More recently, Milara et al (25) analyzed MIF mRNA expression in peripheral neutrophils and found an increase in 15 patients with COPD compared with 15 control individuals, which is in accordance with our findings (25). Russell et al (32) found increased MIF in sputum and bronchial alveolar lavage, but not serum, in 25 patients with COPD compared with nonsmoking control individuals (32).…”

Section: Discussionsupporting

confidence: 90%

“…Yet only a few studies have examined the relationship between MIF and COPD. Contrary to the conditions listed above, some studies have associated COPD with decreased values of MIF (15,36), although two more recent studies indicated the opposite (25,32). COPD exacerbations are often triggered by infections in which MIF potentially mediates both beneficial (antimicrobial) and harmful (sustained or overwhelming inflammation) effects.…”

mentioning

confidence: 99%

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Macrophage migration inhibitory factor, a role in COPD

Husebø

Bakke

Grønseth

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Macrophage migration inhibitor factor (MIF) is a pluripotent cytokine associated with several different inflammatory conditions, but its role within lung inflammation and chronic obstructive pulmonary disease (COPD) is unclear. This study aimed to examine MIF in both stable COPD and during acute exacerbations (AECOPD). The study included 433 patients with COPD aged 41–76 and 325 individuals from the Bergen COPD cohort study who served as controls. All patients had an FEV1 of <80% predicted, FEV1/FVC ratio of <0.7, and a smoking history >10 pack-years. Serum levels of MIF were compared between the two groups at baseline, and for 149 patients, measurements were also carried out during AECOPD. Linear regression models were fitted with MIF as the outcome variable and adjusted for sex, age, body composition, smoking, and Charlson Comorbidity Score (CCS). Median MIF (interquartile range) in patients with COPD was 20.1 ng/ml (13.5–30.9) compared with 14.9 ng/ml (11.1–21.6) in controls ( P < 0.01). MIF was bivariately associated with sex, body composition, and CCS ( P < 0.05 for all). In the regression analyses, MIF was significantly higher in patients with COPD, coefficient 1.32 ( P < 0.01) and 1.30 ( P < 0.01) unadjusted and adjusted, respectively. In addition, in 149 patients during episodes of AECOPD, MIF was significantly elevated, with a median of 23.2 ng/ml (14.1–42.3) compared with measurements at stable disease of 19.3 ng/ml (12.4–31.3, P < 0.01). Serum levels of MIF were significantly higher in patients with COPD compared with controls. We also identified an additional increase in MIF levels during episodes of AECOPD.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Macrophage migration inhibitory factor, a role in COPD

Husebø

Bakke

Grønseth

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Milara et al (34,35) have demonstrated the influence of RNO in improving the effect of corticosteroids. In bronchial epithelial cells from patients with COPD, RNO, when combined with dexamethasone, increased the expression of MKP-1 and enhanced the inhibitory effects on phospho-p38 MAPK and activity of transcription factors AP-1 and NF-κB (35).…”

Section: Discussionmentioning

confidence: 99%

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

Patel¹,

Rahman²,

Baehring

et al. 2017

Am J Respir Cell Mol Biol

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Roflumilast is an orally active phosphodiesterase 4 (PDE4) inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has demonstrated anti-inflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMPdependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation. RNO (0.001-1000 nM) alone had no effect on AMP production from ASM cells, and significant potentiation of the long-acting β2-agonist formoterol-induced cAMP could only be achieved at the highest concentration of RNO tested (1000 nM). At this concentration, RNO exerted a small, but not significantly different, potentiation of formoterolinduced expression of anti-inflammatory mitogen-activated protein kinase phosphatase 1 (MKP-1). Consequently, tumor necrosis factor (TNF)-induced IL-8 secretion was unaffected by RNO in combination with formoterol. However, as there was the potential for PDE4 inhibitors and LABAs to interact with corticosteroids to achieve superior anti-inflammatory efficacy, we examined whether RNO, alone or in combination with formoterol, enhanced the antiinflammatory effect of dexamethasone by measuring the impact on IL-8 secretion. While RNO alone did not significantly enhance cytokine repression achieved with steroids; RNO in combination with formoterol significantly enhanced the anti-inflammatory effect of dexamethasone in ASM cells. This was linked to increased MKP-1 expression in ASM cells, suggesting a molecular mechanism responsible for augmented anti-inflammatory actions of combination therapeutic approaches that include RNO.

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“…Low-dose theophylline increases corticosteroid sensitivity, as its molecular mechanism enhances HDAC activity in PBMCs in cases of severe asthma and COPD (79,85). However, the effects of roflumilast on HDAC activation and reversal corticosteroid resistance in COPD require further investigation (78,86). Despite that roflumilast was approved for COPD, its potential beyond inflammatory lung diseases such as bronchiectasis, pulmonary fibrosis and ACOS is promising.…”

Section: Future Direction Of Pde4 Inhibitorsmentioning

confidence: 99%

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

Kawamatawong

2017

J. Thorac. Dis.

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Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease

Cited by 74 publications

References 57 publications

Macrophage migration inhibitory factor, a role in COPD

Macrophage migration inhibitory factor, a role in COPD

Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

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