Neutrophil extracellular trap formation is regulated by CXCR2 in COPD neutrophils

Pedersen, Frauke; Waschki, Benjamin; Marwitz, Sebastian; Goldmann, Torsten; Kirsten, Anne; Malmgren, Anna; Rabe, Klaus F.; Uddin, Mohib; Watz, Henrik

doi:10.1183/13993003.00970-2017

Cited by 50 publications

(50 citation statements)

References 12 publications

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“…Small molecule CXCR2 antagonists have been extensively tested in clinical trials for asthma, chronic obstructive pulmonary disease (COPD) and influenza. AZD5069 (AstraZeneca) is a selective CXCR2 antagonist that has been tested for safety and efficacy in pre-clinical and clinical studies of COPD and asthma (O'Byrne et al, 2016;Pedersen et al, 2018). AZD5069 was able to block neutrophil trafficking while preserving neutrophilmediated host immunity (Jurcevic et al, 2015;Uddin et al, 2017).…”

Section: Inhibitors Of Neutrophil Migration and Activationmentioning

confidence: 99%

“…AZD5069 was able to block neutrophil trafficking while preserving neutrophilmediated host immunity (Jurcevic et al, 2015;Uddin et al, 2017). The administration of AZD5069 reduced NETopathic inflammation of sputum neutrophils from patients with COPD (Pedersen et al, 2018;Uddin et al, 2019). Similarly, the CXCR2 inhibitor Danirixin (GlaxoSmithKline) has been tested in phase 2 clinical trials in patients with COPD and influenza, where it reduced neutrophilia (Madan et al, 2019;Roberts et al, 2019).…”

Section: Inhibitors Of Neutrophil Migration and Activationmentioning

confidence: 99%

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Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

et al. 2020

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There is an urgent need for new therapeutic strategies to contain the spread of the novel coronavirus disease 2019 (COVID-19) and to curtail its most severe complications. Severely ill patients experience pathologic manifestations of acute respiratory distress syndrome (ARDS), and clinical reports demonstrate striking neutrophilia, elevated levels of multiple cytokines, and an exaggerated inflammatory response in fatal COVID-19. Mechanical respirator devices are the most widely applied therapy for ARDS in COVID-19, yet mechanical ventilation achieves strikingly poor survival. Many patients, who recover, experience impaired cognition or physical disability. In this review, we argue the need to develop therapies aimed at inhibiting neutrophil recruitment, activation, degranulation, and neutrophil extracellular trap (NET) release. Moreover, we suggest that currently available pharmacologic approaches should be tested as treatments for ARDS in COVID-19. In our view, targeting host-mediated immunopathology holds promise to alleviate progressive pathologic complications of ARDS and reduce morbidities and mortalities in severely ill patients with COVID-19.

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Section: Inhibitors Of Neutrophil Migration and Activationmentioning

confidence: 99%

Section: Inhibitors Of Neutrophil Migration and Activationmentioning

confidence: 99%

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

et al. 2020

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“…However, neutropenia was also observed in a large proportion of COPD patients in that study, raising potential safety concerns. CXCR2 antagonist (AZD5069) has recently been shown to stabilize NET formation in neutrophils derived from COPD (Pedersen et al, ). The most effective and novel drug delivery systems currently in development for COPD involve the use of nanoparticles.…”

Section: Neutrophil‐targeted Drug Delivery In Respiratory Diseasesmentioning

confidence: 99%

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

Chellappan

Yee

Xuan

et al. 2020

Drug Development Research

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Neutrophils are essential effector cells of immune system for clearing the extracellular pathogens during inflammation and immune reactions. Neutrophils play a major role in chronic respiratory diseases. In respiratory diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, lung cancer and others, there occurs extreme infiltration and activation of neutrophils followed by a cascade of events like oxidative stress and dysregulated cellular proteins that eventually result in apoptosis and tissue damage. Dysregulation of neutrophil effector functions including delayed neutropil apoptosis, increased neutrophil extracellular traps in the pathogenesis of asthma, and chronic obstructive pulmonary disease enable neutrophils as a potential therapeutic target. Accounting to their role in pathogenesis, neutrophils present as an excellent therapeutic target for the treatment of chronic respiratory diseases. This review highlights the current status and the emerging trends in novel drug delivery systems such as nanoparticles, liposomes, microspheres, and other newer nanosystems that can target neutrophils and their molecular pathways, in the airways against infections, inflammation, and cancer. These drug delivery systems are promising in providing sustained drug delivery, reduced therapeutic dose, improved patient compliance, and reduced drug toxicity. In addition, the review also discusses emerging strategies and the future perspectives in neutrophil-based therapy. K E Y W O R D S nanoparticle, neutrophils, novel drug delivery, pulmonary, respiratory diseases

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“…AZD8999, a novel muscarinic acetylcholine receptor antagonist and β2adrenoceptor agonist (MABA), was shown to inhibit IL-8, IL-1β and MMP-9 release from human peripheral blood neutrophils stimulated with LPS [133]. AZD5069, a chemokine (C-X-C motif) receptor 2 (CXCR2) antagonist, was shown to reduce NET formation and levels of IL-8/CXCL-8 in sputum and blood neutrophils isolated from COPD patients [134]. Galectin (Gal)-9, a beta-galactoside lectin protein, was able to reduce the number of neutrophils and the levels of MMP-2 and MMP-9 in the bronchoalveolar lavage fluid (BALF) in a porcine pancreatic elastase (PPE)-induced emphysema model.…”

Section: Granulocyte-targeted Therapies For Copdmentioning

confidence: 99%

Granulocyte-targeted therapies for airway diseases

Tavares

Peh

Tan

et al. 2020

Pharmacological Research

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The average respiration rate for an adult is 12-20 breaths per minute, which constantly exposes the lungs to allergens and harmful particles. As a result, respiratory diseases, which includes asthma, chronic obstructive pulmonary disease (COPD) and acute lower respiratory tract infections (LTRI), are a major cause of death worldwide. Although asthma, COPD and LTRI are distinctly different diseases with separate mechanisms of disease progression, they do share a common featureairway inflammation with intense recruitment and activation of granulocytes and mast cells. Neutrophils, eosinophils, basophils, and mast cells are crucial players in host defense against pathogens and maintenance of lung homeostasis. Upon contact with harmful particles, part of the pulmonary defense mechanism is to recruit these cells into the airways. Despite their protective nature, overactivation or accumulation of granulocytes and mast cells in the lungs results in unwanted chronic airway inflammation and damage. As such, understanding the bright and the dark side of these leukocytes in lung physiology paves the way for the development of therapies targeting this important mechanism of disease. Here we discuss the role of granulocytes in respiratory diseases and summarize therapeutic strategies focused on granulocyte recruitment and activation in the lungs.

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Neutrophil extracellular trap formation is regulated by CXCR2 in COPD neutrophils

Cited by 50 publications

References 12 publications

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

Granulocyte-targeted therapies for airway diseases

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