CXCL-8-dependent and -independent neutrophil activation in COPD: experiences from a pilot study of the CXCR2 antagonist danirixin

Keir, Holly R.; Richardson, Hollian; Fillmore, Christina; Shoemark, Amelia; Lazaar, Aili L.; Miller, Bruce E.; Tal‐Singer, Ruth; Chalmers, James D.; Mohan, Divya

doi:10.1183/23120541.00583-2020

Cited by 24 publications

(22 citation statements)

References 14 publications

(19 reference statements)

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“… 134 However, further investigation of this drug demonstrated an increase in the incidence of exacerbations in patients with chronic mucus secretion. 135 These observations have now led to the suggestion that such therapies targeting neutrophils will be of benefit in a subset of patients, 136 but identification of these is not clear.…”

Section: Implications For Therapymentioning

confidence: 99%

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

Baker

Donnelly

2021

COPD

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Chronic obstructive pulmonary disease (COPD) is a progressive lung condition affecting 10% of the global population over 45 years. Currently, there are no disease-modifying treatments, with current therapies treating only the symptoms of the disease. COPD is an inflammatory disease, with a high infiltration of leukocytes being found within the lung of COPD patients. These leukocytes, if not kept in check, damage the lung, leading to the pathophysiology associated with the disease. In this review, we focus on the main leukocytes found within the COPD lung, describing how the release of chemokines from the damaged epithelial lining recruits these cells into the lung. Once present, these cells become active and may be driven towards a more pro-inflammatory phenotype. These cells release their own subtypes of inflammatory mediators, growth factors and proteases which can all lead to airway remodeling, mucus hypersecretion and emphysema. Finally, we describe some of the current therapies and potential new targets that could be utilized to target aberrant leukocyte function in the COPD lung. Here, we focus on old therapies such as statins and corticosteroids, but also look at the emerging field of biologics describing those which have been tested in COPD already and potential new monoclonal antibodies which are under review.

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Section: Implications For Therapymentioning

confidence: 99%

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

Baker

Donnelly

2021

COPD

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“… 42 Keir et al demonstrated that there was a subset of individuals with COPD in whom neutrophil activation was independent of CXCR2. 43 Another study found that specific CXC chemokines resulted in enhanced migration of PBMCs/monocytes from patients with COPD, which was mediated via CXCR1 and CXCR2. 44 CXCR2 was significantly increased in patients with severe/very severe COPD compared with patients with mild/moderate COPD and control healthy smokers.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Key Immune-Related Genes in Chronic Obstructive Pulmonary Disease Based on Immune Infiltration Analysis

Meng¹,

Long²,

Wang³

et al. 2022

COPD

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Purpose: Chronic obstructive pulmonary disease (COPD) is a major cause of death and morbidity worldwide. A better understanding of new biomarkers for COPD patients and their complex mechanisms in the progression of COPD are needed. Methods: An algorithm was conducted to reveal the proportions of 22 subsets of immune cells in COPD samples. Differentially expressed immune-related genes (DE-IRGs) were obtained based on the differentially expressed genes (DEGs) of the GSE57148 dataset, and 1509 immunerelated genes (IRGs) were downloaded from the ImmPort database. Functional enrichment analyses of DE-IRGs were conducted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and Ingenuity Pathway Analysis (IPA). We defined the DE-IRGs that had correlations with immune cells as hub genes. The potential interactions among the hub genes were explored by a protein-protein interaction (PPI) network. Results:The CIBERSORT results showed that lung tissue of COPD patients contained a greater number of resting NK cells, activated dendritic cells, and neutrophils than normal samples. However, the fractions of follicular helper T cells and resting dendritic cells were relatively lower. Thirty-eight DE-IRGs were obtained for further analysis. Functional enrichment analysis revealed that these DE-IRGs were significantly enriched in several immunerelated biological processes and pathways. Notably, we also observed that DE-IRGs were associated with the coronavirus disease COVID-19 in the progression of COPD. After correlation analysis, six DE-IRGs associated with immune cells were considered hub genes, including AHNAK, SLIT2 TNFRRSF10C, CXCR1, CXCR2, and FCGR3B. Conclusion:In the present study, we investigated immune-related genes as novel diagnostic biomarkers and explored the potential mechanism for COPD based on CIBERSORT analysis, providing a new understanding for COPD treatment.

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“…In a double-blind RCT (NCT03250689) [ 16 ], participants were randomised (3:1) to receive danirixin 35 mg twice daily or placebo for 14 days.…”

Section: Methodsmentioning

confidence: 99%

“…We conducted pilot RCT primarily to study the effects of a CXCR2 antagonist, danirixin, the primary results for which have been published [ 16 ]. In this pilot RCT, our exploratory objectives were feasibility of measuring VOCs via multiple techniques, assessing relationships between VOCs and Haemophilus colonisation, and whether CXCR2 antagonism with danirixin altered lung microbiome composition in individuals with COPD.…”

Section: Introductionmentioning

confidence: 99%

Exhaled volatile organic compounds and lung microbiome in COPD: a pilot randomised controlled trial

et al. 2021

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BackgroundBreath analyses in a burgeoning field, with interest in volatile organic compounds (VOCs) as a non-invasive diagnostic tool or an outcome measure, but no randomised clinical trials (RCT) have yet evaluated this technology in a clinical trial longitudinally. In a pilot RCT, our exploratory objectives were feasibility of measuring VOCs via multiple techniques, assessing relationships between VOCs and Haemophilus colonisation, and whether CXCR2 antagonism with danirixin altered lung microbiome composition in individuals with chronic obstructive pulmonary disease (COPD).Method43 participants had VOCs and sputum biomarkers evaluated. VOCs and induced sputum were collected after 6 h of fasting at screening, Days 1, 7 and 14. VOCs were analysed via gas chromatography mass spectrometry (GCMS), field asymmetric ion mobility spectrometry and eNose. The primary outcome for these analyses was the relationship between VOCs and Haemophilus abundance determined by 16S rRNA sequencing.ResultsA joint effects model demonstrated a modest relationship between 4 exhaled VOCs and Haemophilus relative abundance (R2=0.55) measured only by GCMS, but not as measured GC FAIMs or eNose. There was considerable variability in absolute quantities of individual VOCs longitudinally.ConclusionsVOC measurement in clinical trials to identify subsets of COPD is feasible but assessment of new VOC technologies must include concurrent GCMS validation. Further work to standardise collection of VOCs and measuring a background or “housekeeper” VOC is required to understand and normalise individual VOC quantities.

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CXCL-8-dependent and -independent neutrophil activation in COPD: experiences from a pilot study of the CXCR2 antagonist danirixin

Cited by 24 publications

References 14 publications

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

Identification of the Key Immune-Related Genes in Chronic Obstructive Pulmonary Disease Based on Immune Infiltration Analysis

Exhaled volatile organic compounds and lung microbiome in COPD: a pilot randomised controlled trial

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