COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type‐2 and PDE4 gene expression in sputum

Singh, Dave; Bassi, Michele; Balzano, Deborah; Lucci, Germano; Emirova, Aida; Nandeuil, Marie Anna; Jellema, Gera L.; Afolabi, Ebenezer; Leaker, Brian; Kornmann, Oliver; Beeh, Kai Michael; Watz, Henrik; Govoni, Mirco

doi:10.1111/jcmm.16146

Cited by 17 publications

(14 citation statements)

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“…A recent study identifying SOCS2 and HDC as differentially expressed in E-COPD vs NE-COPD in sputum microarray analysis supports the positive association between MC/basophil genes and eosinophilic inflammation in COPD. 37 This study also reported increased IL9R in E-COPD compared to non-eosinophilic COPD. IL9 promotes MC growth and differentiation, and this further supports the role of MCs and basophils in T2 inflammation in COPD.…”

Section: Discussionsupporting

confidence: 58%

“…IL9 promotes MC growth and differentiation, and this further supports the role of MCs and basophils in T2 inflammation in COPD. 37 mRNA abundance of all MC/basophil genes was correlated in COPD sputum, supporting a common MC/basophil origin, with qPCR measures of MC/ basophil-related genes reflecting MC and basophil abundance in sputum. There were no significant clinical differences between E-COPD and NE-COPD and therefore the differences in MC/basophil gene expression between the groups demonstrate the importance of molecular biomarkers such as these to distinguish between COPD inflammatory phenotypes.…”

Section: Discussionmentioning

confidence: 62%

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Sputum Gene Expression Reveals Dysregulation of Mast Cells and Basophils in Eosinophilic COPD

Winter¹,

Gibson²,

McDonald³

et al. 2021

COPD

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The clinical and inflammatory associations of mast cells (MCs) and basophils in chronic obstructive pulmonary disease (COPD) are poorly understood. We previously developed and validated a qPCR-based MC/basophil gene signature in asthma to measure these cells in sputum samples. Here, we measured this gene signature in a COPD and control population to explore the relationship of sputum MCs/basophils to inflammatory and COPD clinical characteristics. Patients and Methods: MC/basophil signature genes (TPSAB1/TPSB2, CPA3, ENO2, GATA2, KIT, GPR56, HDC, SOCS2) were measured by qPCR in sputum from a COPD (n=96) and a non-respiratory control (n=17) population. Comparative analyses of gene expression between the COPD and the control population, and between eosinophilic COPD and non-eosinophilic COPD were tested. Logistic regression analysis and Spearman correlation were used to determine relationships of sputum MC/basophil genes to inflammatory (sputum eosinophil proportions, blood eosinophils) and clinical (age, body mass index, quality of life, lung function, past year exacerbations) characteristics of COPD. Results: MC/basophil genes were increased in COPD versus control participants (CPA3, KIT, GATA2, HDC) and between eosinophilic-COPD and non-eosinophilic COPD (TPSB2, CPA3, HDC, SOCS2). We found all MC/basophil genes were positively intercorrelated. In COPD, MC/basophil genes were associated with eosinophilic airway inflammation (GATA2, TPSB2, CPA3, GPR56, HDC, SOCS2), blood eosinophilia (all genes) and decreased lung function (KIT, GATA2, GPR56, HDC). Conclusion:We demonstrate associations of MCs and basophils with eosinophilic inflammation and lower lung function in COPD. These findings are consistent with prior results in asthma and may represent a new tool for endotyping eosinophilic-COPD.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 62%

Sputum Gene Expression Reveals Dysregulation of Mast Cells and Basophils in Eosinophilic COPD

Winter¹,

Gibson²,

McDonald³

et al. 2021

COPD

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“…In line with these observations the ability of tanimilast to reduce eosinophils and other key type-2 mediators in sputum (e.g. IL5RA, CLC, ALOX15, SMPD3, PTGDR2, and CEBPE) was most relevant to individuals with higher sputum eosinophil counts (≥3%) ( Singh et al, 2020d ; 2020b ). These data are in line with the reduction of sputum and bronchial mucosal eosinophils observed in patients treated with roflumilast ( Rabe et al, 2018 ) and support the rationale for PDE4 inhibition on top of inhaled corticosteroids and bronchodilators also in patients with higher eosinophil counts.…”

Section: Clinical Overviewsupporting

confidence: 62%

“…In patients with chronic bronchitis, tanimilast administered on top of ICS, a LABA and a LAMA consistently reduced a large number of key mediators associated to airways inflammation, remodeling and lung integrity ( Singh et al, 2019 ; Govoni et al, 2020 ). Notably, patients treated with triple therapy and having higher eosinophil counts at baseline (and thus patients known to respond better to ICS) showed increased levels of sputum cell inflammation associated to type-2 and PDE4 mediators ( Singh et al, 2020b ). These findings supported the potential for tanimilast to provide an additional beneficial effect in patients with chronic bronchitis who are still symptomatic despite regular use of ICS, LABA and LAMA, with a favorable systemic tolerability profile.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms responsible for these differential drug effects is unknown but may relate to an increased presence of type-2 inflammation in COPD patients with higher blood eosinophil counts causing different responses to anti-inflammatory drugs ( Higham et al, 2020 ). In a recent post-hoc analysis of the BIOMARKER study ( Table 4 ) focused on sputum gene expression it was shown that patients with chronic bronchitis and higher sputum eosinophil counts on treatment with triple therapy had increased expression of type-2 and PDE4 related genes ( Singh et al, 2020b ). In this investigation a large number of genes were differentially expressed ( p -FDR<0.05) between patients having different sputum eosinophil level (<3% or ≥3%); all genes were upregulated in patients with higher eosinophil counts and functionally enriched for type-2 and PDE4 inflammatory processes including interleukin 5 receptor alpha (IL5RA), interleukin 4 (IL4), chemokine (C-C motif) ligand 26 (CCL26), arachidonate 15-lipoxygenase (ALOX15), Interleukin 1-receptor-like 1 (IL1RL1), charcot-Leyden crystal galectin (CLC), GATA-binding protein 1 (GATA1), sphingomyelin phosphodiesterase 3 (SMPD3), cysteinyl leukotriene receptor 2 (CYSLTR2), prostaglandin D2 receptor 2 (PTGDR2) and CCAAT enhancer binding protein epsilon (CEBPE) and the cAMP-specific PDE4 isoform D (PDE4D).…”

Section: Clinical Overviewmentioning

confidence: 99%

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Tanimilast, A Novel Inhaled Pde4 Inhibitor for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

et al. 2021

Self Cite

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Chronic respiratory diseases are the third leading cause of death, behind cardiovascular diseases and cancer, affecting approximately 550 million of people all over the world. Most of the chronic respiratory diseases are attributable to asthma and chronic obstructive pulmonary disease (COPD) with this latter being the major cause of deaths. Despite differences in etiology and symptoms, a common feature of asthma and COPD is an underlying degree of airways inflammation. The nature and severity of this inflammation might differ between and within different respiratory conditions and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients. A precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success. Inhibitors of the phosphodiesterase 4 (PDE4) enzyme like the oral PDE4 inhibitor roflumilast have shown a potential to reduce inflammatory-mediated processes and the frequency of exacerbations in certain groups of COPD patients with a chronic bronchitis phenotype. However, roflumilast use is dampened by class related side effects as nausea, diarrhea, weight loss and abdominal pain, resulting in both substantial treatment discontinuation in clinical practice and withdrawal from clinical trials. This has prompted the search for PDE4 inhibitors to be given by inhalation to reduce the systemic exposure (and thus optimize the systemic safety) and maximize the therapeutic effect in the lung. Tanimilast (international non-proprietary name of CHF6001) is a novel highly potent and selective inhaled PDE4 inhibitor with proven anti-inflammatory properties in various inflammatory cells, including leukocytes derived from asthma and COPD patients, as well as in experimental rodent models of pulmonary inflammation. Inhaled tanimilast has reached phase III clinical development by showing promising pharmacodynamic results associated with a good tolerability and safety profile, with no evidence of PDE4 inhibitors class-related side effects. In this review we will discuss the main outcomes of preclinical and clinical studies conducted during tanimilast development, with particular emphasis on the characterization of the pharmacodynamic profile that led to the identification of target populations with increased therapeutic potential in inflammatory respiratory diseases.

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Inhaled Phosphodiesterase Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease

Singh

Lea

Mathioudakis

2021

Drugs

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COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type‐2 and PDE4 gene expression in sputum

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 17 publications

References 76 publications

Sputum Gene Expression Reveals Dysregulation of Mast Cells and Basophils in Eosinophilic COPD

Sputum Gene Expression Reveals Dysregulation of Mast Cells and Basophils in Eosinophilic COPD

Tanimilast, A Novel Inhaled Pde4 Inhibitor for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

Inhaled Phosphodiesterase Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease

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