NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma

Abstract

Neutrophils play a central role in innate immunity, inflammation, and resolution. Unresolving neutrophilia features as a disrupted inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD) and severe asthma. The extent to which this may be linked to disease pathobiology remains obscure and could be further confounded by indication of glucocorticoids or concomitant respiratory infections. The formation of neutrophil extracellular traps (NETs) represents a specialized host defense mechanism that entrap and eliminate invading microbes. NETs are web-like scaffolds of extracellular DNA in complex with histones and neutrophil granular proteins, such as myeloperoxidase and neutrophil elastase. Distinct from apoptosis, NET formation is an active form of cell death that could be triggered by various microbial, inflammatory, and endogenous or exogenous stimuli. NETs are reportedly enriched in neutrophil-dominant refractory lung diseases, such as COPD and severe asthma. Evidence for a pathogenic role for respiratory viruses (e.g., Rhinovirus), bacteria (e.g., Staphylococcus aureus) and fungi (e.g., Aspergillus fumigatus) in NET induction is emerging. Dysregulation of this process may exert localized NET burden and contribute to NETopathic lung inflammation. Disentangling the role of NETs in human health and disease offer unique opportunities for therapeutic modulation. The chemokine CXCR2 receptor regulates neutrophil activation and migration, and small molecule CXCR2 antagonists (e.g., AZD5069, danirixin) have been developed to selectively block neutrophilic inflammatory pathways. NET-stabilizing agents using CXCR2 antagonists are being investigated in proof-of-concept studies in patients with COPD to provide mechanistic insights. Clinical validation of this type could lead to novel therapeutics for multiple CXCR2-related NETopathologies. In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes.

Aerobic Exercise Attenuates Acute Lung Injury Through NET Inhibition

“…Although NETs have potentially beneficial anti-pathogenic functions in respiratory host defenses, protection can easily turn to injury when extensive, unbalanced NET formation occurs. NETs are embedded with potent granule proteins that are capable of killing pathogens but may also, under the right conditions, induce cell death of lung epithelial and endothelial cells (27) and contribute to certain lung diseases such as asthma (28), cystic fibrosis (29), and COPD (30). Little is known regarding the interaction between NETs and specific cells, including AMs.…”

In vivo evidence for extracellular DNA trap formation

“…NETs have also been visualized in induced sputum from patients with asthma and COPD, which compared with control sputum, exhibited higher levels of extracellular DNA and other NET components, such as cathelicidin LL-37, alphadefensin 1-3, NE, IL-1β, and CXCL8 correlating with decreased lung function 101 . In stable COPD patients, extensive NET formation was observed in all sputum samples irrespective of purulence or smoking status 102,103 . Moreover, the presence of NETs is associated with disease severity and microbiota diversity in patients with COPD 104 .…”

Necrostatin-1 Ameliorates Neutrophilic Inflammation in Asthma by Suppressing MLKL Phosphorylation to Inhibiting NETs Release

“…This difference is likely due to the fact that in neutrophilic asthma, especially in its severe form, neutrophil apoptosis is delayed, and clearance of the cell debris dysfunctioned, leading to an extensive accumulation of NETs (10,11,21). High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma (22,23). NETs are generally believed critical for killing bacteria, Abbreviations: NETs, neutrophil extracellular traps; EETs, eosinophil extracellular traps; Nec-1, necrostatin-1; RIP1, receptor-interacting protein 1; PMA, phorbol 12-myristate 13-acetate; PBNs, peripheral blood neutrophils; LDH, lactate dehydrogenase; OVA, ovalbumin; CFA, complete Freund's adjuvant; BAL, bronchoalveolar lavage; RIP1, receptor-interacting protein 1; kinase; MPO, myeloperoxidase; AHR, airway hyperresponsiveness; PAF, platelet-activating factor; RIPK3/MLKL, receptor-interacting protein 3 kinase/mixed-lineage kinase domain-like protein; DAMPs, damage-associated molecular patterns.…”