Katherine J Baines1, John W Upham2, Stephanie T Yerkovich3, Anne B Chang4, Julie M Marchant5, Melanie Carroll2, Jodie L Simpson6, Peter G Gibson6. 1. The Priority Research Centre for Asthma and Respiratory Diseases, Callaghan, NSW; The University of Newcastle, Callaghan, NSW. Electronic address: katherine.baines@newcastle.edu.au. 2. Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, NSW. 3. Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, NSW; Hunter Medical Research Institute, John Hunter Hospital, New Lambton Heights, NSW. 4. School of Medicine, The University of Queensland, Brisbane, QLD; Qld Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD; Department of Respiratory Medicine, Queensland Children's Medical Research Institute, Royal Children's Hospital, Brisbane, QLD; Child Health Division, Menzies School of Health Research, Darwin, NT, Australia. 5. Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, NSW; School of Medicine, The University of Queensland, Brisbane, QLD. 6. The Priority Research Centre for Asthma and Respiratory Diseases, Callaghan, NSW; The University of Newcastle, Callaghan, NSW.
Abstract
BACKGROUND: Protracted bacterial bronchitis (PBB) is a common and treatable cause of chronic wet cough in children in which the mechanisms are not understood. This study investigates the IL-1 pathway and a neutrophil gene expression signature in PBB. METHODS: BAL was collected from children in an experimental cohort (n = 21, PBB; n = 33, control subjects), and a second validation cohort (n = 36, PBB; n = 11, control subjects). IL-1β, IL-1 receptor antagonist (IL-1RA), and α-defensins 1-3 were assayed by enzyme-linked immunosorbent assay, western blot, and quantitative real-time polymerase chain reaction, together with selected IL-1 pathway members and neutrophil-related molecules. RESULTS: In the experimental cohort, children with symptomatic PBB had significantly higher levels of IL-1β and α-defensin gene and protein expression. Expression of the neutrophil chemokine receptor C-X-C motif receptor 2 was also higher in PBB. IL-1RA protein was higher, however, the IL-1RA:IL-1β ratio was lower in children with PBB than control subjects. In the validation cohort, protein and gene expression of IL-1β and α-defensins 1-3 were confirmed higher, as was gene expression of IL-1 pathway members and C-X-C motif receptor 2. IL-1β and α-defensin 1-3 levels lowered when PBB was treated and resolved. In children with recurrent PBB, gene expression of the IL-1β signaling molecules pellino-1 and IL-1 receptor-associated kinase 2 was significantly higher. IL-1β protein levels correlated with BAL neutrophilia and the duration and severity of cough symptoms. IL-1β and α-defensin 1-3 levels were highly correlated. CONCLUSIONS: PBB is characterized by increased IL-1β pathway activation. IL-1β and related mediators were associated with BAL neutrophils, cough symptoms, and disease recurrence, providing insight into PBB pathogenesis.
BACKGROUND: Protracted bacterial bronchitis (PBB) is a common and treatable cause of chronic wet cough in children in which the mechanisms are not understood. This study investigates the IL-1 pathway and a neutrophil gene expression signature in PBB. METHODS: BAL was collected from children in an experimental cohort (n = 21, PBB; n = 33, control subjects), and a second validation cohort (n = 36, PBB; n = 11, control subjects). IL-1β, IL-1 receptor antagonist (IL-1RA), and α-defensins 1-3 were assayed by enzyme-linked immunosorbent assay, western blot, and quantitative real-time polymerase chain reaction, together with selected IL-1 pathway members and neutrophil-related molecules. RESULTS: In the experimental cohort, children with symptomatic PBB had significantly higher levels of IL-1β and α-defensin gene and protein expression. Expression of the neutrophil chemokine receptor C-X-C motif receptor 2 was also higher in PBB. IL-1RA protein was higher, however, the IL-1RA:IL-1β ratio was lower in children with PBB than control subjects. In the validation cohort, protein and gene expression of IL-1β and α-defensins 1-3 were confirmed higher, as was gene expression of IL-1 pathway members and C-X-C motif receptor 2. IL-1β and α-defensin 1-3 levels lowered when PBB was treated and resolved. In children with recurrent PBB, gene expression of the IL-1β signaling molecules pellino-1 and IL-1 receptor-associated kinase 2 was significantly higher. IL-1β protein levels correlated with BAL neutrophilia and the duration and severity of cough symptoms. IL-1β and α-defensin 1-3 levels were highly correlated. CONCLUSIONS:PBB is characterized by increased IL-1β pathway activation. IL-1β and related mediators were associated with BAL neutrophils, cough symptoms, and disease recurrence, providing insight into PBB pathogenesis.
Authors: Ahmad Kantar; Anne B Chang; Mike D Shields; Julie M Marchant; Keith Grimwood; Jonathan Grigg; Kostas N Priftis; Renato Cutrera; Fabio Midulla; Paul L P Brand; Mark L Everard Journal: Eur Respir J Date: 2017-08-24 Impact factor: 16.671
Authors: Alice C-H Chen; Yang Xi; Melanie Carroll; Helen L Petsky; Samantha J Gardiner; Susan J Pizzutto; Stephanie T Yerkovich; Katherine J Baines; Peter G Gibson; Sandra Hodge; Ian B Masters; Helen M Buntain; Anne B Chang; John W Upham Journal: ERJ Open Res Date: 2017-10-02