Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD

Lazaar, Aili L.; Miller, Bruce E.; Tabberer, Maggie; Yonchuk, John; Leidy, Nancy Kline; Ambery, Claire; Bloomer, Jackie C.; Watz, Henrik; Tal‐Singer, Ruth

doi:10.1183/13993003.01020-2018

Cited by 48 publications

(37 citation statements)

References 14 publications

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“…Although, greater treatment response was observed in smokers versus ex-smokers (NCT01006616). Even though no difference was observed in the number of HCRU-defined exacerbations experienced by participants in both groups, the data raise the possibility that Danirixin may reduce the duration of COPD exacerbation ( 63 ) (NCT02130193). We must highlight that inflammatory exacerbation in COPD patients is responsible for most hospitalizations, and enhances disease mortality, with no effective treatment to control them ( 64 , 65 ).…”

Section: Discussionmentioning

confidence: 78%

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

et al. 2020

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Rationale Increased IL-8 levels and neutrophil accumulation in the airways are common features found in patients affected by pulmonary diseases such as Asthma, Idiopathic Pulmonary Fibrosis, Influenza-A infection and COPD. Chronic neutrophilic inflammation is usually corticosteroid insensitive and may be relevant in the progression of those diseases. Objective To explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component. Findings Ladarixin was able to reduce the acute and chronic neutrophilic influx, also attenuating the Th2 eosinophil-dominated airway inflammation, tissue remodeling and airway hyperresponsiveness. Correspondingly, Ladarixin decreased bleomycin-induced neutrophilic inflammation and collagen deposition, as well as attenuated the corticosteroid resistant Th17 neutrophil-dominated airway inflammation and hyperresponsiveness, restoring corticosteroid sensitivity. Finally, Ladarixin reduced neutrophilic airway inflammation during cigarette smoke-induced corticosteroid resistant exacerbation of Influenza-A infection, improving lung function and mice survival. Conclusion CXCR1/2 antagonist Ladarixin offers a new strategy for therapeutic treatment of acute and chronic neutrophilic airway inflammation, even in the context of corticosteroid-insensitivity.

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Section: Discussionmentioning

confidence: 78%

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

et al. 2020

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“…Unfortunately, to date, there are few effective treatments for neutrophilic in ammation since NE inhibitors, CXCR2 antagonists and other neutrophil speci c therapies have not yet been shown to improve outcomes in broad populations of COPD patients. 30,31 Nevertheless, there is an established precedent for blood biomarkers being used to guide treatment of in ammatory endotypes, as in the case of blood eosinophil counts and anti-IL-5 therapy. It is theoretically possible that BNCs could serve a similar function for anti-neutrophil therapies.…”

Section: Discussionmentioning

confidence: 99%

Blood Neutrophil Counts are Associated with Exacerbation Frequency and Mortality in COPD

Lonergan

Dicker

Crichton

et al. 2020

Preprint

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Abstract Background: Identifying patients with COPD at increased risk of poor outcomes is challenging due to disease heterogeneity. Potential biomarkers need to be readily available in real-life clinical practice. Blood eosinophil counts are widely studied but few studies have examined the prognostic value of blood neutrophil counts (BNC).Methods: In a large population-based COPD registry in the East of Scotland (TARDIS: Tayside Allergic and Respiratory Disease Information System), BNC were compared to measures of disease severity and mortality for up to 15 years follow-up. Potential mechanisms of disease modification by BNC were explored in a nested microbiome substudy. Results: 178120 neutrophil counts were obtained from 7220 people (mean follow up 9 years) during stable disease periods. Median BNC was 5200cells/µL (IQR 4000-7000cells/µL). Mortality rates among the 34% of patients with elevated BNCs (defined as 6000-15000cells/µL) at the study start were 80% higher (14.0/100 person years v 7.8/100py, P<0.001) than those with BNC in the normal range (2000-6000cells/µL). People with elevated BNC were more likely to be classified as GOLD D (46% v 33% P<0.001), have more exacerbations (mean 2.3 v 1.3/year, P<0.001), and were more likely to have severe exacerbations (13% vs. 5%, P<0.001) in the following year. Eosinophil counts were much less predictive of these outcomes. In a sub-cohort (N=276), patients with elevated BNC had increased relative abundance of Proteobacteria and reduced microbiome diversity.Conclusion: High BNC may provide a useful indicator of risk of exacerbations and mortality in COPD patients.

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“…Unfortunately, to date, there are few effective treatments for neutrophilic inflammation since NE inhibitors, CXCR2 antagonists and other neutrophil specific therapies have not yet been shown to improve outcomes in broad populations of COPD patients. 30,31 Nevertheless, there is an established precedent for blood biomarkers being used to guide treatment of inflammatory endotypes, as in the case of blood eosinophil counts and anti-IL-5 therapy. It is theoretically possible that BNCs could serve a similar function for anti-neutrophil therapies.…”

Section: Discussionmentioning

confidence: 99%

Blood Neutrophil Counts are Associated with Exacerbation Frequency and Mortality in COPD

Lonergan

Dicker

Crichton

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Abstract Background Identifying patients with COPD at increased risk of poor outcomes is challenging due to disease heterogeneity. Potential biomarkers need to be readily available in real-life clinical practice. Blood eosinophil counts are widely studied but few studies have examined the prognostic value of blood neutrophil counts (BNC). Methods In a large population-based COPD registry in the East of Scotland (TARDIS: Tayside Allergic and Respiratory Disease Information System), BNC were compared to measures of disease severity and mortality over up to 15 years follow-up. Potential mechanisms of disease modification by BNC were explored in a nested microbiome substudy. Results 178120 neutrophil counts were obtained from 7220 people (mean follow up 9 years) during stable disease periods. Median BNC was 5200cells/µL (IQR 4000-7000cells/µL). Mortality rates among those 34% with elevated BNCs (defined as 6000-15000cells/µL) at the study start were 80% higher (14.0/100 person years v 7.8/100py, P<0.001) than those with BNC in the normal range (2000-6000cells/µL). People with elevated BNC were more likely to be classified as GOLD D (46% v 33% P<0.001), have more exacerbations (mean 2.3 v 1.3/year, P<0.001), and were more likely to have severe exacerbations (13% vs. 5%, P<0.001) in the following year. Eosinophil counts were much less predictive of these outcomes. In a sub-cohort (N=276), patients with elevated BNC had increased relative abundance of Proteobacteria and reduced microbiome diversity. Conclusion High BNC may provide a useful indicator of risk of exacerbations and mortality in COPD patients.

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Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD

Cited by 48 publications

References 14 publications

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

Blood Neutrophil Counts are Associated with Exacerbation Frequency and Mortality in COPD

Blood Neutrophil Counts are Associated with Exacerbation Frequency and Mortality in COPD

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