Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

Cecilia K. Andersson; Alexandra Adams; Prasad Nagakumar; Cara Bossley; Atul Gupta; Daphne De Vries; Afiqah Adnan; Andrew Bush; Sejal Saglani; Clare M Lloyd

doi:10.1016/j.jaci.2016.09.022

Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

Cecilia K. Andersson, Alexandra Adams, Prasad Nagakumar, Cara Bossley, Atul Gupta, Daphne De Vries, Afiqah Adnan, Andrew Bush, Sejal Saglani, Clare M Lloyd

Imperial College London

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

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BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown.

OBJECTIVES: We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA).

METHODS: Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA-expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide.

RESULTS: Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted (r = 0.43; P = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A-positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA-positive cells in the submucosa and epithelium in children with STRA compared with controls (P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide.

CONCLUSIONS: A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.

Originalspråk	engelska
Sidor (från-till)	1819-1829.e11
Tidskrift	Journal of Allergy and Clinical Immunology
Volym	139
Nummer	6
DOI	https://doi.org/10.1016/j.jaci.2016.09.022
Status	Published - 2017 juni
Externt publicerad	Ja

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10.1016/j.jaci.2016.09.022

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@article{3a111f394a3445bfbefac9196f7391a1,

title = "Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function",

abstract = "BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown.OBJECTIVES: We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA).METHODS: Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA-expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide.RESULTS: Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted (r = 0.43; P = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A-positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA-positive cells in the submucosa and epithelium in children with STRA compared with controls (P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide.CONCLUSIONS: A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.",

keywords = "Adolescent, Asthma, Biopsy, Bronchoalveolar Lavage Fluid, Bronchoscopy, Child, Child, Preschool, Female, Humans, Infant, Interleukin-17, Interleukins, Lung, Male, Neutrophils, Receptors, Interleukin-17, Respiratory Mucosa, Journal Article",

author = "Andersson, {Cecilia K.} and Alexandra Adams and Prasad Nagakumar and Cara Bossley and Atul Gupta and {De Vries}, Daphne and Afiqah Adnan and Andrew Bush and Sejal Saglani and Lloyd, {Clare M}",

year = "2017",

month = jun,

doi = "10.1016/j.jaci.2016.09.022",

language = "English",

volume = "139",

pages = "1819--1829.e11",

journal = "Journal of Allergy and Clinical Immunology",

issn = "1097-6825",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

AU - Andersson, Cecilia K.

AU - Adams, Alexandra

AU - Nagakumar, Prasad

AU - Bossley, Cara

AU - Gupta, Atul

AU - De Vries, Daphne

AU - Adnan, Afiqah

AU - Bush, Andrew

AU - Saglani, Sejal

AU - Lloyd, Clare M

PY - 2017/6

Y1 - 2017/6

N2 - BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown.OBJECTIVES: We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA).METHODS: Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA-expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide.RESULTS: Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted (r = 0.43; P = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A-positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA-positive cells in the submucosa and epithelium in children with STRA compared with controls (P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide.CONCLUSIONS: A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.

AB - BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown.OBJECTIVES: We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA).METHODS: Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA-expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide.RESULTS: Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted (r = 0.43; P = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A-positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA-positive cells in the submucosa and epithelium in children with STRA compared with controls (P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide.CONCLUSIONS: A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.

KW - Adolescent

KW - Asthma

KW - Biopsy

KW - Bronchoalveolar Lavage Fluid

KW - Bronchoscopy

KW - Child

KW - Child, Preschool

KW - Female

KW - Humans

KW - Infant

KW - Interleukin-17

KW - Interleukins

KW - Lung

KW - Male

KW - Neutrophils

KW - Receptors, Interleukin-17

KW - Respiratory Mucosa

KW - Journal Article

U2 - 10.1016/j.jaci.2016.09.022

DO - 10.1016/j.jaci.2016.09.022

M3 - Article

C2 - 27746241

SN - 1097-6825

VL - 139

SP - 1819-1829.e11

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -

Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

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