Beyond corticosteroids: future prospects in the management of inflammation in COPD

Roche, N.; Marthan, Roger; Berger, Patrick; Chambellan, Arnaud; Chanez, Pascal; Aguilaniu, B.; Brillet, P.Y.; Burgel, Pierre‐Régis; Chaouat, Ari; Devillier, P.; Escamilla, R.; Louis, Renaud; Mal, Hervé; Muir, J F; Pérez, Thierry; Similowski, Thomas; Wallaert, B.; Aubier, Michel

doi:10.1183/09059180.00004211

Cited by 36 publications

(39 citation statements)

References 82 publications

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“…Corticosteroid treatment is used in COPD patients to reduce exacerbations and improve health outcomes (49). Unfortunately, this treatment option is immunosuppressive and is associated with increased bacterial-mediated pneumonia (50).…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

Lugade

Bogner

Thatcher

et al. 2014

The Journal of Immunology

109

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The detrimental impact of tobacco on human health is clearly recognized and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease (COPD) are susceptible to recurrent respiratory infections with pathogens, including non-typeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. As mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study to investigate chronic infection and the generation of adaptive immune responses to NTHI following chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells produced reduced levels of antibodies against outer membrane lipoprotein P6, with impaired IgG1, IgG2a and IgA class-switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke exposed mice exhibited a similar defect in the generation of adaptive immunity following immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes COPD patients to recurrent infections, leading to exacerbations and contributing to mortality.

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Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

Lugade

Bogner

Thatcher

et al. 2014

The Journal of Immunology

109

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“…In the specific context of oxidative and/or nitrative stress, such as cigarette smoke, in chronic obstructive pulmonary disease (COPD), HDAC2 phosphorylation or nitration was linked to its ubiquitination and degradation by proteasome [115-117]. Corticosteroids are used to reduce inflammation in the airways of patients with COPD.…”

Section: Introductionmentioning

confidence: 99%

Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors

2012

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The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to a link between misregulated HDAC activity and many oncologic and nononcologic diseases. Thus the development of HDAC inhibitors for therapeutic treatment garners a lot of interest from academic researchers and biotechnology entrepreneurs. Numerous studies of HDAC inhibitor specificities and molecular mechanisms of action are ongoing. In one of these studies, mass spectrometry was used to characterize the affinities and selectivities of HDAC inhibitors toward native HDAC multiprotein complexes in cell extracts. Such a novel approach reproduces in vivo molecular interactions more accurately than standard studies using purified proteins or protein domains as targets and could be very useful in the isolation of inhibitors with superior clinical efficacy and decreased toxicity compared to the ones presently tested or approved. HDAC inhibitor induced-transcriptional reprogramming, believed to contribute largely to their therapeutic benefits, is achieved through various and complex mechanisms not fully understood, including histone deacetylation, transcription factor or regulator (including HDAC1) deacetylation followed by chromatin remodeling and positive or negative outcome regarding transcription initiation. Although only a very low percentage of protein-coding genes are affected by the action of HDAC inhibitors, about 40% of noncoding microRNAs are upregulated or downregulated. Moreover, a whole new world of long noncoding RNAs is emerging, revealing a new class of potential targets for HDAC inhibition. HDAC inhibitors might also regulate transcription elongation and have been shown to impinge on alternative splicing.

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“…The current first-line maintenance treatment for COPD involves the use of bronchodilators, including long-acting muscarinic antagonists (LAMAs) and long-acting beta agonists (LABAs). Inhaled corticosteroids (ICS), despite their good activity in asthma, are much less effective in improving lung function and have little or no effect in controlling the underlying chronic inflammation in COPD [1]. Combined therapies, consisting of ICS + LABAs, LABA + LAMA, as well as LAMA monotherapy are common options for COPD patients at increased risk of an exacerbation of moderate symptoms [2–4].…”

Section: Introductionmentioning

confidence: 99%

Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients

et al. 2016

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BackgroundInhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect.MethodsHuman sputum and blood neutrophils were isolated from healthy individuals (n = 37), patients with stable COPD (n = 52) and those with exacerbated COPD (n = 16). The cells were incubated with corticosteroid fluticasone propionate (0.1 nM–1 μM), aclidinium bromide (0.1 nM–1 μM) or a combination thereof and stimulated with 1 μg of lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1β were measured and the mechanisms of corticosteroid resistance evaluated at the end of the incubation.ResultsThe non-neuronal cholinergic system was over-expressed in neutrophils from COPD patients, as evidenced by increases in the expression of muscarinic receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine transporter. Aclidinium bromide demonstrated anti-inflammatory effects on neutrophils from COPD patients, reversing their resistance to corticosteroids. Additive effects of combined aclidinium bromide and fluticasone propionate in blocking M2 receptor levels, inhibiting phosphoinositide 3-kinase-δ and enhancing the glucocorticoid response element transcription factor were demonstrated and were accompanied by an increase in the corticosteroid-induced expression of anti-inflammatory-related genes.ConclusionsLAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0467-8) contains supplementary material, which is available to authorized users.

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Beyond corticosteroids: future prospects in the management of inflammation in COPD

Cited by 36 publications

References 82 publications

Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors

Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients

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