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Children with Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance.

ABSTRACT: BACKGROUND:Airway neutrophils are abundant in some children with severe asthma, but their functions are poorly understood. OBJECTIVE:To characterize that the inflammatory airway environment of children with neutrophil-predominant severe asthma promotes neutrophil survival and disrupts neutrophil-associated innate immune defenses. METHODS:Sixty-seven children with severe asthma refractory to high-dose inhaled corticosteroid treatment undergoing bronchoscopy with bronchoalveolar lavage (BAL) for clinical indications were stratified into neutrophil "high" versus "low" groups on the basis of BAL differential counts. Neutrophil activation markers, functional assays, and phenotyping studies were performed, as well as airway macrophage functional assays. Results were compared with those from children with moderate asthma treated with inhaled corticosteroids. RESULTS:Children with neutrophil-predominant severe asthma had increased markers of neutrophil activation/degranulation and a greater magnitude of airway proinflammatory cytokine and chemokine release. Primary neutrophils exposed to BAL of these children exhibited greater phagocytic capability and greater neutrophil extracellular trap formation, but a more impaired respiratory burst. Despite greater abundance of airway TGF-?1, the neutrophils were not more apoptotic. Instead, neutrophils had a highly proinflammatory phenotype associated with a number of surface markers that regulate neutrophil activation, recruitment/migration, and granule release. Airway macrophages from children with neutrophil-predominant severe asthma were also more proinflammatory with impaired phagocytosis and increased apoptosis. CONCLUSIONS:Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival. Airway macrophages are also proinflammatory and dysfunctional and may contribute to global innate immune impairment. Therapies that target neutrophils and related inflammation may be warranted in this subset of children.

SUBMITTER: Grunwell JR

PROVIDER: S-EPMC6363859 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Children with Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance.

Grunwell Jocelyn R JR Stephenson Susan T ST Tirouvanziam Rabindra R Brown Lou Ann S LAS Brown Milton R MR Fitzpatrick Anne M AM

The journal of allergy and clinical immunology. In practice 20180905 2

<h4>Background</h4>Airway neutrophils are abundant in some children with severe asthma, but their functions are poorly understood.<h4>Objective</h4>To characterize that the inflammatory airway environment of children with neutrophil-predominant severe asthma promotes neutrophil survival and disrupts neutrophil-associated innate immune defenses.<h4>Methods</h4>Sixty-seven children with severe asthma refractory to high-dose inhaled corticosteroid treatment undergoing bronchoscopy with bronchoalveo ...[more]

PMID: 30193935

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Project description:IntroductionSevere burns cause unique pathophysiological alterations especially on the immune system. A murine scald model was optimized as a basis for the understanding of immunological reactions in response to heat induced injury. The understanding of the roles of neutrophil extracellular traps (NETs) and DNases will support the development of new surgical or pharmacological strategies for the therapy of severe burns.MethodsWe studied C57BL/6 mice (n=30) and employed four scalding protocols with varying exposure times to hot water. An additional scald group with a shorter observational time was generated to reduce mortality and study the very early phase of pathophysiology. At 24h or 72h, blood was drawn and tissue (wound, liver, lung, spleen) was analyzed for the presence of NETs, oxidative stress, apoptosis, bacterial translocation, and extracellular matrix re-organization. In addition, we analyzed the transcriptome from lung and liver tissues.ResultsExposure to hot water for 7s led to significant systemic and local effects and caused considerable late mortality. Therefore, we used an observation time of 24h in this groups. To study later phases of burns (72h) an exposure time of 6s is optimal. Both conditions led to significant disorganization of collagen, increased oxidative stress, NET formation (by immunodetection of H3cit, NE, MPO), apoptosis (cC3) and alterations of the levels of DNase1 and DNase1L3. Transcriptome analysis revealed remarkable alterations in genes involved in acute phase signaling, cell cohesion, extracellular matrix organization, and immune response.ConclusionWe identified two scald models that allow the analysis of early (24h) or late (72h) severe burn effects, thereby generating reproducible and standardized scald injuries. The study elucidated the important involvement of neutrophil activity and the role of NETs in burns. Extensive transcriptome analysis characterized the acute phase and tissue remodeling pathways involved in the process of healing and may serve as crucial basis for future in-depth studies.

Dataset Information

Children with Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance.

Publications

Children with Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance.

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