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Gian Marco Manzetti,1 Josuel Ora,1 Arianna Sepiacci,1 Mario Cazzola,1 Paola Rogliani,1 Luigino Calzetta2 1Department of Experimental Medicine, Unit of Respiratory Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, ItalyCorrespondence: Luigino Calzetta, Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy, Email luigino.calzetta@unipr.itPurpose: Clinically important deterioration (CID) is a composite endpoint developed to quantify the impact of pharmacological treatment in clinical trials for Chronic Obstructive Pulmonary Disease (COPD), also showing a prognostic value. CID is defined as any of the following condition: forced expiratory volume in 1 s decrease ≥ 100 mL from baseline, and/or St. George’s Respiratory Questionnaire total score increase ≥ 4-unit from baseline, and/or the occurrence of a moderate-to-severe exacerbation of COPD. Although most COPD patients experience a clinical worsening as they get older, to date, no specific studies assessed the correlation between ageing and CID in COPD. Therefore, the aim of this study was to investigate the impact of ageing on CID in COPD patients.Patients and Methods: Data obtained from 55219 COPD patients were extracted from 17 papers, mostly post-hoc analyses. A pairwise meta-analysis and a meta-regression analysis were performed according to PRISMA-P guidelines to quantify the impact of pharmacological therapy on CID and to determine whether ageing might modulate the risk of CID in COPD patients.Results: Inhaled treatments resulted generally effective in reducing the risk of CID in COPD (relative risk: 0.81, 95% confidence interval 0.79– 0.84; P < 0.001). The meta-regression analysis indicated a trend toward significance (P = 0.063) in the linear relationship between age and the risk of CID. Of note, age significantly (P < 0.05) increased the risk of CID when associated with lower post-bronchodilator FEV1. These results were not affected by a significant risk of bias.Conclusion: This quantitative synthesis suggests that inhaled therapy is effective in reducing the risk of CID in COPD, although such a protective effect may be affected in older patients with impaired lung function. Further studies specifically designed on CID in COPD are needed to confirm these results.Keywords: ageing, clinically important deterioration, chronic obstructive pulmonary disease, elderly, meta-analysis, inhaled therapy

Mario Cazzola,1 Paola Rogliani,1 Francesco Blasi2,3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Pulmonology and Cystic Fibrosis Unit, Internal Medicine Department, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan, Milan, Italy; 3Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyCorrespondence: Mario Cazzola, Email mario.cazzola@uniroma2.itAbstract: The complexity of COPD implies the need to identify groups of patients with similar clinical characteristics and prognosis or treatment requirements. This is why much attention has been paid to identifying the different clinical phenotypes by investigating the clinical expression of the disease, and endotypes by studying the biological networks that enable and limit reactions. However, this approach is complicated because one endotype gives rise to one or more clinical characteristics, and clinical phenotypes can be derived from several endotypes. To simplify the approach, a new taxonomic classification of COPD based on the different causes (or etiotypes) has been proposed, but these etiotypes have not yet been validated. A simpler method is the so-called tractable traits approach, which is free from any designation of the disorder to be treated and does not present the criticality of using etiotypes. A large randomised controlled trial on using the treatable traits approach in COPD is still lacking. Nevertheless, this approach is already applied by following the GOLD strategy. However, its application is complicated because several potentially treatable traits have been identified within the pulmonary domain, the extrapulmonary domain, and the behavioural/risk factor domain. In addition, the hierarchy of the dominant treatable traits has not yet been established, and they change over time both spontaneously and because of treatment. This means that the patients being treated according to the tractable traits approach must be constantly followed over time so that the therapy is focused on their temporal needs.Keywords: chronic obstructive pulmonary disease, phenotypes, endotypes, etiotypes, treatable traits

Mario Cazzola,1 Nicola A Hanania,2 Clive P Page,3 Maria Gabriella Matera4 1Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK; 4Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Mario Cazzola, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy, Email mario.cazzola@uniroma2.itAbstract: Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4+ and CD8+ T lymphocytes are key players in this process, although the extent of their participation varies according to the patient’s endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD.Keywords: anti-inflammatory drugs, COPD, inflammation, treatment

Peter MA Calverley,1 Alberto Papi,2 Clive Page,3 Paola Rogliani,4 Roberto W Dal Negro,5 Mario Cazzola,4 Arrigo F Cicero,6 Jadwiga A Wedzicha7 1Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; 2Respiratory Medicine, University of Ferrara, Ferrara, Italy; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London, UK; 4Respiratory Medicine Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 5National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 6Medical and Surgical Department, University of Bologna, Bologna, Italy; 7Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: Peter MA Calverley, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK, Tel +44 1515295886, Fax +44 1515295888, Email pmacal@liverpool.ac.ukPurpose: To explore the effect of erdosteine on COPD exacerbations, health-related quality of life (HRQoL), and subjectively assessed COPD severity.Patients and methods: This post-hoc analysis of the RESTORE study included participants with COPD and spirometrically moderate (GOLD 2; post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted; n = 254), or severe airflow limitation (GOLD 3; post-bronchodilator FEV1 30‒49% predicted; n = 191) who received erdosteine 300 mg twice daily or placebo added to usual maintenance therapy for 12 months. Antibiotic and oral corticosteroid use was determined together with patient-reported HRQoL (St George’s Respiratory Questionnaire, SGRQ). Patient and physician subjective COPD severity scores (scale 0‒4) were rated at baseline, 6 and 12 months. Data were analyzed using descriptive statistics for exacerbation severity, COPD severity, and treatment group. Comparisons between treatment groups used Student’s t-tests or ANCOVA as appropriate.Results: Among GOLD 2 patients, 43 of 126 erdosteine-treated patients exacerbated (7 moderate-to-severe exacerbations), compared to 62 of 128 placebo-treated patients (14 moderate-to-severe exacerbations). Among those with moderate-to-severe exacerbations, erdosteine-treated patients had a shorter mean duration of corticosteroid treatment (11.4 days vs 13.3 days for placebo, P = 0.043), and fewer patients required antibiotic treatment with/without oral corticosteroids (71.4% vs 85.8% for placebo, P < 0.001). Erdosteine-treated GOLD 2 patients who exacerbated showed significant improvements from baseline in SGRQ total scores and subjective disease severity scores (patient- and physician-rated), compared with placebo-treated patients regardless of exacerbation severity. Among GOLD 3 patients, there were no significant differences between treatment groups on any of these measures.Conclusion: Adding erdosteine to the usual maintenance therapy of COPD patients with moderate airflow limitation reduced the number of exacerbations, the duration of treatment with corticosteroids and the episodes requiring treatment with antibiotics. Additionally, treatment with erdosteine improved HRQoL and patient-reported disease severity.Keywords: antibiotic, chronic obstructive pulmonary disease, erdosteine, COPD exacerbation, health-related quality of life, systemic corticosteroid

Paola Rogliani,1 Francesco Cavalli,1 Alfredo Chetta,2 Mario Cazzola,1 Luigino Calzetta2 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, ItalyCorrespondence: Paola Rogliani, Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy, Email paola.rogliani@uniroma2.itIntroduction: Inhaled corticosteroid/long-acting β2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) fixed-dose combination (FDC) is currently recommended as controller option at asthma Step 4 and as preferred treatment at asthma Step 5, but no research investigated the potential drawbacks of this therapeutic option in a large asthmatic population. Thus, the aim of this study was to quantify the potential drawbacks of triple FDC therapy in asthma.Methods: A pairwise meta-analysis was performed according to PRISMA-P guidelines to assess the risk of overall serious adverse events (SAEs), cardiovascular SAEs, and pneumonia reported as SAE in asthmatic patients treated with ICS/LABA/LAMA FDC vs ICS/LABA FDC. A pooled analysis was performed to calculate the frequency of SAEs.Results: Data from 7204 asthmatic patients were extracted from the CAPTAIN, IRIDIUM, TRIMARAN, and TRIGGER studies. Triple FDC vs ICS/LABA FDC did not increase the risk of total SAEs (RR 0.99 95% CI 0.83– 1.18) and cardiac SAEs (RR 0.74 95% CI 0.39– 1.40), whereas the sensitivity analysis performed to resolve heterogeneity resulted in increased risk of vascular SAEs (RR 3.23 95% CI 1.05– 9.90, P< 0.05). The level of ICS dose did not modulate the risk of pneumonia, in any case pneumonia was the most frequent SAE (0.57%). These results were not affected by significant risk of bias.Conclusion: Triple FDC is a safe pharmacological therapy in severe asthmatic patients; it is characterized by a favourable safety profile and few potential drawbacks, namely, the increased risk of vascular SAEs, that certainly are worthy of future investigations.Keywords: asthma, cardiovascular, meta-analysis, pneumonia, safety, triple combination

Mario Cazzola,1 Paola Rogliani,1 Rossella Laitano,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Unit of Respiratory Diseases and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.Keywords: dual bronchodilation, triple therapy, ICSs, LABs, LAMAs

Mario Cazzola,1 Josuel Ora,2 Francesco Cavalli,1 Paola Rogliani,1,2 Maria Gabriella Matera3 1Chair of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy; 3Chair of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: Several mAbs have been tested or are currently under clinical evaluation for the treatment of COPD. They can be subdivided into those that aim to block specific pro-inflammatory and pro-neutrophilic cytokines and chemokines, such as TNF-α, IL-1β, CXCL8 and IL-1β, and those that act on T2-mediated inflammation, respectively, by blocking IL-5 and/or its receptor, preventing IL-4 and IL-13 signaling, affecting IL-33 pathway and blocking TSLP. None of these approaches has proved to be effective, probably because in COPD there is no dominant cytokine or chemokine and, therefore, a single mAb cannot be effective on all pathways. With a more in-depth understanding of the numerous pheno/endotypic pathways that play a role in COPD, it may eventually be possible to identify those specific patients in whom some of these cytokines or chemokines might predominate. In this case, it will be possible to implement a personalized treatment, but the use of each mAb will only be reserved for a very limited number of subjects.Keywords: COPD, monoclonal antibodies, pheno/endotypic pathways, anti–T1-mediated inflammation mAbs, anti–T2-mediated inflammation mAbs

Maria Gabriella Matera,1 Josuel Ora,2 Francesco Cavalli,2 Paola Rogliani,2,3 Mario Cazzola3 1Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy; 2Respiratory Diseases Unit, “Tor Vergata” University Hospital, Rome, Italy; 3Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, ItalyCorrespondence: Mario CazzolaDipartimento di Medicina Sperimentale, Università di Roma Tor Vergata, Rome, ItalyEmail mario.cazzola@uniroma2.itIntroduction: Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease.Areas Covered: In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma.Expert Opinion: Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.Keywords: asthma, phosphodiesterases, phosphodiesterase inhibitors, bifunctional drugs, treatable traits therapeutic approach

Josuel Ora,1 Angelo Coppola,2 Mario Cazzola,3 Luigino Calzetta,4 Paola Rogliani1,3 1Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy; 2Division of Respiratory Medicine, San Filippo Neri Hospital, Rome, Italy; 3Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 4Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, ItalyCorrespondence: Josuel OraDivision of Respiratory Medicine, University Hospital Tor Vergata, Viale Oxford 81, Rome 00133, ItalyEmail josuel.ora@ptvonline.itIntroduction: Bronchodilators are the cornerstone of chronic obstructive pulmonary disease (COPD) therapy and long-acting muscarinic antagonists (LAMAs) as a mono or combination treatment play a pivotal role. Several LAMAs are already available on the market in different formulations, but developing a new compound with a higher M3 receptor selectivity and a lower affinity to M2 receptors to increase the therapeutic effect and minimize the adverse effects is still a goal. Moreover, new formulations could improve adherence to therapy.Areas Covered: This systematic review assesses investigational long-acting muscarinic antagonist in Phase I and II clinical trials over the last decade. It offers insights on whether LAMAs and/or their new formulations in clinical development can become effective treatments for COPD in the future.Expert Opinion: Research on LAMA seems to have come to a standstill, the few new molecules under study do not show distinctive characteristics compared to the previous ones. Muscarinic antagonist/β 2-agonist (MABAs) appear to be the major innovation currently under investigation, and they could theoretically open new research frontiers on the effect between adrenergic and muscarinic interaction in the same cell.Keywords: long-acting muscarinic antagonist, MABA, LAMA, Phase I, Phase II, efficacy, safety, COPD treatment, investigational drugs, chronic obstructive pulmonary disease

Paola Rogliani,1,2 Beatrice Ludovica Ritondo,1 Ermanno Puxeddu,2 Gloria Pane,2 Mario Cazzola,1 Luigino Calzetta3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Division of Respiratory Medicine, University Hospital “Tor Vergata”, Rome, Italy; 3Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, ItalyCorrespondence: Paola RoglianiDepartment of Experimental Medicine, Via Montpellier 1, Rome 00133, ItalyTel +39 06 2090 4656Email paola.rogliani@uniroma2.itAbstract: Inhaled corticosteroids (ICSs) are considered the cornerstone of asthma treatment. Despite the solid evidence documenting the efficacy and safety of ICSs at the level of the airways, their use can be affected by pulmonary and systemic adverse events (AEs) when administered chronically and/or at high doses. Thus, there is a pharmacological and medical need for new glucocorticoid (GC) receptor (GR) ligands with a more favorable therapeutic index, in order to overcome the shortcomings of currently available ICSs. The therapeutic profile of GCs can be improved by enhancing genomic mechanisms mediated by transrepression, which is assumed to be responsible for several anti-inflammatory and immunomodulatory actions, rather than transactivation, which causes most of the GC-associated AEs. It was assumed that an independent modulation of the molecular mechanisms underlying transactivation and transrepression could translate into the dissociation of beneficial effects from AEs. Therefore, current research is looking for GCs that are able to elicit prevalently transrepression with negligible transactivating activity. These compounds are known as selective glucocorticoid receptor agonists (SEGRAs). In this review, experimental GR agonists currently in pre-clinical and clinical development for the treatment of asthma have been systematically assessed. Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine.Keywords: asthma, glucocorticoid agonists, SEGRA, efficacy, safety

Mario Cazzola,1 Paola Rogliani,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Unit of Respiratory Disease and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: There is a large interindividual variability in response to ICSs in asthma. About 70% of the variance in ICS response is likely due at least partially to genetically determined characteristics of target genes. In this article, we examine the effects on the ICS response of gene variations in the corticosteroid pathway, and in the pharmacokinetics of corticosteroids, and also those outside the corticosteroid pathway, which have the potential to influence corticosteroid activity. Although the available evidence indicates that responses to ICSs in asthma are influenced by different genetic variants, there are still deep uncertainties as to whether a real association between these genetic variants and corticosteroid response could also possibly exist because there are difficulties in reproducing pharmacogenetic findings. This explains at least partly the insufficient use of pharmacogenomic data when treating asthmatic patients, which creates a real limitation to the proper use of ICSs in an era of precision medicine that links the right patient to the right treatment. Knowing and dealing with the genetic factors that influence the therapeutic ICS response is a fundamental condition for prescribing the right dose of ICS to the right patient at the right time.Keywords: asthma, inhaled corticosteroids, gene polymorphisms, genome-wide association studies, precision medicine

Peter MA Calverley,1 Clive Page,2 Roberto W Dal Negro,3 Giovanni Fontana,4 Mario Cazzola,5 Arrigo F Cicero,6 Edoardo Pozzi7,†, Jadwiga A Wedzicha8 1Department of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK; 2Faculty of Life Sciences and Medicine, King’s College, London, UK; 3Lung Unit, National Centre for Respiratory Pharmacoeconomics and Pharmacoepidemiology, Verona, Italy; 4Pulmonology Department, Cough Centre, Careggi University Hospital, Firenze, Italy; 5Department of Systems Medicine, Chair of Respiratory Medicine, University of Rome ‘Tor Vergata’, Rome, Italy; 6Medical and Surgical Department, University of Bologna, Bologna, Italy; 7Medical Affairs Department, Edmond Pharma, Paderno, Italy; 8Respiratory Division, National Heart And Lung Institute, Imperial College London, London, UK†Dr Pozzii passed away on 9th July, 2019Correspondence: Peter MA CalverleyDepartment of Medicine, University Hospital Aintree, Lower Lane, Liverpool, Merseyside, UKTel +44 1515295886Fax +44 1515295888Email pmacal@liverpool.ac.ukBackground: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine – a muco-active antioxidant that modulates bacterial adhesiveness – reduced the rate and duration of exacerbations in moderate and severe COPD with a history of exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear.Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted) examined exacerbation rate and duration, time to first exacerbation, and exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann–Whitney U-tests, or log rank tests.Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an exacerbation. There was a 47% reduction in the mean exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild exacerbation rate (0.23 vs 0.53 mild exacerbations per-patient per-year, P=0.001). Mean duration of exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe exacerbations. Mean time to first exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P

Paola Rogliani,1 Luigino Calzetta,1 Fulvio Braido,2 Mario Cazzola,1 Enrico Clini,3 Girolamo Pelaia,4 Andrea Rossi,5 Nicola Scichilone,6 Fabiano Di Marco7 1Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; 2Department of Internal Medicine, IRCCS San Martino Genoa University Hospital, Genoa, Italy; 3Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy; 4Department of Medical and Surgical Sciences, Section of Respiratory Diseases, Magna Græcia University, Catanzaro, Italy; 5Pulmonary Unit, University of Verona, Verona, Italy; 6Department of Internal Medicine, University of Palermo, Palermo, Italy; 7Department of Health Sciences, Università degli Studi di Milano, Respiratory Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy Objectives: The aim of this study was to assess the current evidence for long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the treatment of COPD.Materials and methods: A systematic literature search of randomized controlled trials published in English up to September 2017 of LABA/LAMA FDCs vs LABA or LAMA or LABA/inhaled corticosteroid (ICS) FDCs in COPD patients was performed using PubMed, Embase, Scopus, and Google Scholar. Outcomes including forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index (TDI) scores, St George’s Respiratory Questionnaire (SGRQ) scores, exacerbations, exercise tolerance (endurance time [ET]), inspiratory capacity (IC), and rescue medication use were evaluated.Results: In total, 27 studies were included in the review. LABA/LAMA FDCs significantly improved lung function (FEV1) at 12 weeks compared with LABA or LAMA or LABA/ICS. These effects were maintained over time. Significant improvements with LABA/LAMA FDCs vs each evaluated comparator were also observed in TDI and SGRQ scores, even if significant differences between different LABA/LAMA FDCs were detected. Only the LABA/LAMA FDC indacaterol/glycopyrronium has shown superiority vs LAMA and LABA/ICS for reducing exacerbation rates, while olodaterol/tiotropium and indacaterol/glycopyrronium have been shown to improve ET and IC vs the active comparators. Rescue medication use was significantly reduced by LABA/LAMA FDCs vs the evaluated comparators. LABA/LAMA FDCs were safe, with no increase in the risk of adverse events with LABA/LAMA FDCs vs the monocomponents.Conclusion: Evidence supporting the efficacy of LABA/LAMA FDCs for COPD is heterogeneous, particularly for TDI and SGRQ scores, exacerbation rates, ET, and IC. So far, indacaterol/glycopyrronium is the LABA/LAMA FDC that has the strongest evidence for superiority vs LABA, LAMA, and LABA/ICS FDCs across the evaluated outcomes. LABA/LAMA FDCs were safe; however, more data should be collected in a real-world setting to confirm their safety. Keywords: LABA, LAMA, fixed-dose combination, COPD, systematic review

Anthony D D’Urzo,1 Mario Cazzola,2 Nicola A Hanania,3 Roland Buhl,4 M Reza Maleki-Yazdi5 1Department of Family and Community Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy; 3Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 4Pulmonary Department, Mainz University Hospital, Mainz, Germany; 5Division of Respiratory Medicine, Women’s College Hospital, University of Toronto, Toronto, ON, Canada Abstract: COPD causes considerable health and economic burden worldwide, with incidence of the disease expected to continue to rise. Inhaled bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), are central to the maintenance treatment of patients with COPD. Clinical studies have demonstrated that combined LAMA + LABA therapies improve efficacy while retaining a safety profile similar to LAMA or LABA alone. This has led to the development of several LAMA/LABA fixed-dose combination (FDC) therapies, which provide patients with the convenience of two active compounds in a single inhaler. GFF MDI (Bevespi Aerosphere®) is an FDC of glycopyrrolate/formoterol fumarate 18/9.6 µg formulated using innovative co-suspension delivery technology for administration via metered dose inhaler (MDI). GFF MDI was developed to make a treatment option available for patients who have a requirement or preference to use an MDI, rather than a dry powder or soft mist inhaler. Now that several LAMA/LABA FDCs have been approved for use in COPD, we review the impact of dual-bronchodilator treatment on COPD therapy and discuss recent clinical studies that are helping to develop a more comprehensive understanding of how LAMA/LABA FDCs can improve patient outcomes. Keywords: long-acting bronchodilator, LAMA, LABA, chronic obstructive pulmonary disease, fixed-dose combination, GFF MDI

Paola Rogliani,1,2 Maria Gabriella Matera,3 Josuel Ora,2 Mario Cazzola,1 Luigino Calzetta1 1Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; 2Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy; 3Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy Objective: Long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are burdened by the potential risk of inducing cardiovascular serious adverse events (SAEs) in COPD patients. Since the risk of combining a LABA with a LAMA could be greater, we have carried out a quantitative synthesis to investigate the cardiovascular safety profile of LABA/LAMA fixed-dose combinations (FDCs).Methods: A pair-wise and network meta-analysis was performed by using the data of the repository database ClinicalTrials.gov concerning the impact of approved LABA/LAMA FDCs versus monocomponents and/or placebo on cardiovascular SAEs in COPD.Results: Overall, LABA/LAMA FDCs did not significantly (P>0.05) modulate the risk of cardiovascular SAEs versus monocomponents. However, the network meta-analysis indicated that aclidinium/formoterol 400/12 µg and tiotropium/olodaterol 5/5 µg were the safest FDCs, followed by umeclidinium/vilanterol 62.5/25 µg which was as safe as placebo, whereas glyco­pyrronium/formoterol 14.9/9.6, glycopyrronium/indacaterol 15.6/27.5 µg, and glycopyrronium/indacaterol 50/110 µg were the least safe FDCs. No impact on mortality was detected for each specific FDC.Conclusion: This meta-analysis indicates that LABA/LAMA FDC therapy is characterized by an excellent cardiovascular safety profile in COPD patients. However, the findings of this quantitative synthesis have been obtained from populations that participated in randomized clinical trials, and were devoid of major cardiovascular diseases. Thus, post-marketing surveillance and observational studies may help to better define the real impact of specific FDCs with regard to the cardiovascular risk. Keywords: COPD, LABA/LAMA FDC, cardiovascular safety, mortality, meta-analysis

Maria Gabriella Matera,1 Clive Page,2 Mario Cazzola3 1Department of Experimental Medicine, Unit of Pharmacology, University of Campania ‘Luigi Vanvitelli’, Naples, Italy; 2Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK; 3Department of Experimental Medicine and Surgery, Chair of Respiratory Medicine, University of Rome ‘Tor Vergata’, Rome, Italy Abstract: Doxofylline, which differs from theophylline in containing the dioxalane group at position 7, has comparable efficacy to theophylline in the treatment of respiratory diseases, but with an improved tolerability profile and a favorable risk-to-benefit ratio. Furthermore, it does not have significant drug–drug interactions as exhibited with theophylline, which make using theophylline more challenging, especially in elderly patients with co-morbidities receiving multiple classes of drug. It is now clear that doxofylline also possesses a distinct pharmacological profile from theophylline (no significant effect on any of the known phosphodiesterase isoforms, no significant adenosine receptor antagonism, no direct effect on histone deacetylases, interaction with β2-adrenoceptors) and therefore, should not be considered as just a modified theophylline. Randomized clinical trials of doxofylline to investigate the use of this drug to reduce exacerbations and hospitalizations due to asthma or COPD as an alternative to expensive biologics, and certainly as an alternative to theophylline are to be encouraged. Keywords: doxofylline, theophylline, mechanisms of action, therapeutic effects, adverse effects

Marco Mantero,1,2 Paola Rogliani,3 Marta Di Pasquale,1,2 Eva Polverino,4 Ernesto Crisafulli,5 Monica Guerrero,6 Andrea Gramegna,1,2 Mario Cazzola,3 Francesco Blasi1,2 1Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 2Internal Medicine Department, Respiratory Unit and Regional Adult Cystic Fibrosis Center, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan, 3Respiratory Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 4Respiratory Disease Department, Servei de Pneumologia, Hospital Universitari Vall d’Hebron (HUVH), Institut de Recerca Vall d’Hebron (VHIR), Barcelona, Spain; 5Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy; 6Hospital d’Igualada, Consorci Socisanitari de l’Anoia, Barcelona, Spain Abstract: Acute exacerbations are a leading cause of worsening COPD in terms of lung ­function decline, quality of life, and survival. They also have a relevant economic burden on the health care system. Determining the risk factors for acute exacerbation and early relapse could be a crucial element for a better management of COPD patients. This review analyzes the current knowledge and underlines the main risk factors for recurrent acute exacerbations. Comprehensive evaluation of COPD patients during stable phase and exacerbation could contribute to prevent treatment failure and relapses. Keywords: infections, prevention, treatment, COPD, exacerbations

Paola Rogliani, Josuel Ora, Ermanno Puxeddu, Mario Cazzola Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy Abstract: Despite the availability of guideline recommendations, diagnostic confusion between COPD and asthma appears common, and often it is very difficult to decide whether the obstruction is caused by asthma or COPD in a patient with airway obstruction. However, there are well-defined features that help in differentiating asthma from COPD in the presence of fixed airflow obstruction. Nonetheless, the presentations of asthma and COPD can converge and mimic each other, making it difficult to give these patients a diagnosis of either condition. The association of asthma and COPD in the same patient has been designated mixed asthma–COPD phenotype or overlap syndrome. However, since the absence of a clear definition and the inclusion of patients with different characteristics under this umbrella term, it may not facilitate treatment decisions, especially in the absence of clinical trials addressing this heterogeneous population. We are realizing that neither asthma nor COPD are single diseases, but rather syndromes consisting of several endotypes and phenotypes, consequently comprising a spectrum of diseases that must be recognized and adequately treated with targeted therapy. Therefore, we must treat patients by personalizing therapy on the basis of those treatable traits present in each subject. Keywords: airway obstruction, asthma, ACOS, chronic obstructive pulmonary disease

Paul W Jones,1 Henrik Watz,2 Emiel FM Wouters,3 Mario Cazzola4 1Division of Clinical Science, St George’s, University of London, London, UK; 2Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 3CIRO+, Department of Respiratory Medicine, Maastricht University, Maastricht, the Netherlands; 4Unit of Respiratory Clinical Pharmacology, Department of Systemic Medicine, University of Rome ‘Tor Vergata,’ Rome, Italy Abstract: Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease characterized by nonreversible airway obstruction. Well-characterized symptoms such as exertional dyspnea and fatigue have a negative impact on patients’ quality of life (QoL) and restrict physical activity in daily life. The impact of COPD symptoms on QoL is often underestimated; for example, 36% of patients who describe their symptoms as being mild-to-moderate also admit to being too breathless to leave the house. Additionally, early morning and nighttime symptoms are a particular problem. Methods are available to allow clinicians to accurately assess COPD symptoms, including patient questionnaires. Integrated approaches to COPD management, particularly pulmonary rehabilitation, are effective strategies for addressing symptoms, improving exercise capacity and, potentially, also increasing physical activity. Inhaled bronchodilators continue to be the mainstay of drug therapy in COPD, where options can be tailored to meet patients’ needs with careful selection of the inhaled medication and the device used for its delivery. Overall, an integrated approach to disease management should be considered for improving QoL and subsequent patient outcomes in COPD. Keywords: COPD, patients, physical actiity levels, pulmonary rehabilitation

Maria Gabriella Matera,1 Alessandro Sanduzzi,2 Mario Cazzola3 1Department of Experimental Medicine, Second University of Naples, 2Department of Respiratory Diseases, Monaldi Hospital, University Federico II, Naples, 3Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Abstract: Co-administration of a long-acting β2-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice-daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β2-agonist fixed-dose combination that has been studied for this therapeutic indication. Keywords: aclidinium, formoterol, fixed-dose combination, COPD, symptoms

Maria Gabriella Matera,1 Josuel Ora,2 Mario Cazzola2,3 1Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, 2Division of Respiratory Medicine, University Hospital Tor Vergata, 3Department of Systems Medicine, Respiratory Pharmacology Research Unit, University of Rome Tor Vergata, Rome, Italy Abstract: Olodaterol (BI 1744 CL) is a novel, once-daily long-acting β2-agonist (LABA) designed with the aim of improving β2-adrenoreceptor selectivity and intrinsic activity. Phase III pivotal trials have documented that olodaterol Respimat Soft Mist inhaler 5 µg induces fast onset of bronchodilation, comparable with formoterol at day 1. Moreover, significant lung function improvements have been documented up to 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Olodaterol was generally well tolerated and had an acceptable cardiovascular and respiratory adverse event profile. Regrettably, the clinical development of olodaterol is however still too partial to draw any firm conclusions on the positioning of this ultra-LABA as monotherapy in the management of COPD. Waiting for further data on the impact of olodaterol on different patient-reported outcomes, which however are widely available for indacaterol, and mainly for a head-to-head comparison between these two ultra-LABAs and between olodaterol long-acting antimuscarinic antagonists other than tiotropium, we believe it is correct to follow the clinical indications of indacaterol also for olodaterol. In any case, the parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The results from the ongoing large TOviTO Phase III trial program have documented the efficacy and safety of olodaterol/tiotropium fixed-dose combination as maintenance therapy in patients with moderate to very severe COPD. In particular, olodaterol/tiotropium fixed-dose combination provides a convincing alternative for patients remaining symptomatic with olodaterol monotherapy. Keywords: olodaterol, β2-agonists, once-daily dose, chronic obstructive pulmonary disease

Rogliani P, Matera MG, Ora J, Cazzola M, Calzetta L. International Journal of Chronic Obstructive Pulmonary Disease. 2017; 12:3469—3485. Page 3481, right column, last paragraph, line 3, the text “(fromoterol and indacaterol)” should read “(formoterol and indacaterol)”. Read the original article

Andrea Rossi,1 Erika Zanardi,2 Venerino Poletti,3 Mario Cazzola4 1Pulmonary Unit, University of Verona, Verona, 2Department of Respiratory and General Rehabilitation, ULSS 20, Verona, 3Pulmonary Unit, GB Morgani Hospital, AUSL 20, Forli, 4Pulmonary Unit, University of Rome, Tor Vergata, Italy Abstract: Chronic obstructive pulmonary disease (COPD) is the result of persistent and progressive pathologic abnormalities in the small airways, most often associated with alveolar loss. Smoking cessation is the most effective intervention to slow down the progression of COPD. Long-acting inhaled bronchodilators are prescribed for the symptomatic relief at any stage of disease severity. For patients whose COPD cannot be not sufficiently controlled with long-acting bronchodilator monotherapy, international guidelines suggest the possibility of associating a long-acting beta2 agonist (LABA) with a long-acting muscarinic antagonist (LAMA), ie, dual bronchodilation. This is not a new concept as the combination of short-acting agents has been popular in the past. In recent years, several fixed-dose combinations containing a LAMA and a LABA in a single inhaler have been approved by regulatory authorities in several countries. Among the new LAMA/LABA combinations, the fixed-dose combination of indacaterol 110 µg/glycopyrronium 50 µg (QVA149) has been shown in a series of clinical trials to be as safe as the single components and placebo, and more effective than placebo and the single components with regard to lung function, symptoms, and patient-oriented outcomes. Furthermore, QVA149 achieved better bronchodilation than salmeterol 50 µg/fluticasone 500 µg twice daily. Compared with tiotropium, a well-recognized treatment for COPD, the percentage of patients that exceed the minimal clinical important difference for dyspnea and health-related quality of life measurements was superior with QVA149. Other patient-oriented outcomes, such as daily symptoms, night-time awakening, and use of rescue medication consistently favored QVA149. Finally, QVA149 was significantly superior to LAMAs for reducing all types of exacerbation. In conclusion, several years after introduction of dual bronchodilation, the fixed-dose combination of indacaterol 110 µg/glycopyrronium 50 µg in a single inhaler for once-daily administration via the Breezhaler® device (QVA149) has been demonstrated to be a safe and effective treatment for COPD patients. Keywords: chronic obstructive pulmonary disease, long-acting bronchodilators, dual bronchodilation, indacaterol, glycopyrronium, patient-oriented outcomes

Mario Cazzola,1 Nicola Alexander Hanania,2 William MacNee,3 Katja Rüdell,4 Claire Hackford,4 Nihad Tamimi4 1University of Rome ‘Tor Vergata’, Department of Medicine of Systems, Unit of Respiratory Clinical Pharmacology, Rome, Italy; 2Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA; 3University of Edinburgh/MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh, United Kingdom; 4Patient Reported Outcome Center of Excellence, Global Market Access, Primary Care Business Unit, Pfizer, Tadworth, United Kingdom Abstract: Patient-reported outcome (PRO) measures that quantify disease impact have become important measures of outcome in COPD research and treatment. The objective of this literature review was to comprehensively evaluate psychometric properties of available PRO instruments and the ability of each of them to characterize pharmaceutical treatment effects from published clinical trial evidence. Identified in this study were several PRO measures, both those that have been used extensively in COPD clinical trials (St George’s Respiratory Questionnaire and Chronic Respiratory Questionnaire) and new instruments whose full value is still to be determined. This suggests a great need for more information about the patient experience of treatment benefit, but this also may pose challenges to researchers, clinicians, and other important stakeholders (eg, regulatory agencies, pharmaceutical companies) who develop new treatment entities and payers (including but not limited to health technology assessment agencies such as the National Institute for Health and Care Excellence and the Canadian Agency for Drugs and Technologies in Health). The purpose of this review is to enable researchers and clinicians to gain a broad overview of PRO measures in COPD by summarizing the value and purpose of these measures and by providing sufficient detail for interested audiences to determine which instrument may be the most suitable for evaluating a particular research purpose. Keywords: COPD, patient reported outcome, health related quality of life, quality of life, psychometric properties

Roberto Lipsi,1 Paola Rogliani,1 Luigino Calzetta,2 Andrea Segreti,1 Mario Cazzola1 1Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 2Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Rome, Italy Abstract: Regenerative or stem cell therapy is an emerging field of treatment based on stimulation of endogenous resident stem cells or administration of exogenous stem cells to treat diseases or injury and to replace malfunctioning or damaged tissues. Current evidence suggests that in the lung, these cells may participate in tissue homeostasis and regeneration after injury. Animal and human studies have demonstrated that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for the activation of endogenous stem/progenitor cells may be a potent next-generation therapy for chronic obstructive pulmonary disease. The use of bone marrow-derived stem cells could allow repairing and regenerate the damaged tissue present in chronic obstructive pulmonary disease by means of their engraftment into the lung. Another approach could be the stimulation of resident stem cells by means of humoral factors or photobiostimulation. Keywords: chronic obstructive pulmonary disease, stem cells, regenerative therapy, all-trans retinoic acid, photobiostimulation

Mario Cazzola,1 Andrea Segreti,1 Maria Gabriella Matera2 1Department of System Medicine, University of Rome 'Tor Vergata', Rome, Italy; 2Department of Experimental Medicine, Second University, Naples, Italy Abstract: An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients. Keywords: muscarinic antagonist, dual bronchodilation, COPD

Abstract Background Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-κB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1β. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1β and airway hyperresponsiveness. Methods We have examined the effect of passive sensitization on IL-1β mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 μM), were used to quantify IL-1β mRNA. Other tissues were used to study the effect of EFS (3–10–25 Hz). Results Mean IL-1β mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1β mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues. Conclusion Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1β mRNA expression and responsiveness to EFS of passively sensitized bronchi.