2024 |
Liu Z, Baines KJ, Niessen NM, Heer MK, Clark D, Bishop GA, Trevillian PR, 'Characterizing Foxp3+ and Foxp3- T cells in the homeostatic state and after allo-activation: resting CD4+Foxp3+ Tregs have molecular characteristics of activated T cells.', Front Immunol, 15 1292158 (2024) [C1]
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Nova |
2024 |
Huang D, Zhang L, Liu Y, Wang J, Zhang J, Baines KJ, et al., 'Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma.', Ann Allergy Asthma Immunol, (2024) [C1]
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2023 |
Negewo NA, Gibson PG, Simpson JL, McDonald VM, Baines KJ, 'Severity of Lung Function Impairment Drives Transcriptional Phenotypes of COPD and Relates to Immune and Metabolic Processes', International Journal of Chronic Obstructive Pulmonary Disease, Volume 18 273-287 [C1]
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Nova |
2022 |
Pinkerton JW, Kim RY, Brown AC, Rae BE, Donovan C, Mayall JR, et al., 'Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 149 1270-1280 (2022) [C1]
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Nova |
2022 |
Pathinayake PS, Waters DW, Nichol KS, Brown AC, Reid AT, Hsu AC-Y, et al., 'Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma', THORAX, 77 443-451 (2022) [C1]
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Nova |
2022 |
Robijn AL, Bokern MP, Jensen ME, Barker D, Baines KJ, Murphy VE, 'Risk factors for asthma exacerbations during pregnancy: a systematic review and meta-analysis', EUROPEAN RESPIRATORY REVIEW, 31 (2022) [C1]
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Nova |
2022 |
Twaddell SH, Baines KJ, 'The Unknown Sequential Behavior of Neutrophil Extracellular Traps in Parapneumonic Effusions Response', CHEST, 161 E251-E251 (2022)
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2022 |
Frossing L, Silberbrandt A, Von Bulow A, Klein DK, Ross Christensen M, Backer V, et al., 'Airway gene expression identifies subtypes of type 2 inflammation in severe asthma', CLINICAL AND EXPERIMENTAL ALLERGY, 52 59-69 (2022) [C1]
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Nova |
2022 |
Williams EJ, Guilleminault L, Berthon BS, Eslick S, Wright T, Karihaloo C, et al., 'Sulforaphane reduces pro-inflammatory response to palmitic acid in monocytes and adipose tissue macrophages.', J Nutr Biochem, 104 108978 (2022) [C1]
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Nova |
2022 |
Bokern MP, Robijn AL, Jensen ME, Barker D, Baines KJ, Murphy VE, 'Risk factors for asthma exacerbation during pregnancy: protocol for a systematic review and meta-analysis', SYSTEMATIC REVIEWS, 11 (2022)
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2022 |
Hosseini B, Berthon BS, Jensen ME, McLoughlin RF, Wark PAB, Nichol K, et al., 'The Effects of Increasing Fruit and Vegetable Intake in Children with Asthma on the Modulation of Innate Immune Responses', Nutrients, 14 3087-3087 (2022) [C1]
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Nova |
2022 |
Fricker M, Qin L, Sánchez-Ovando S, Simpson JL, Baines KJ, Riveros C, et al., 'An altered sputum macrophage transcriptome contributes to the neutrophilic asthma endotype.', Allergy, 77 1204-1215 (2022) [C1]
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Nova |
2022 |
Sánchez-Ovando S, Pavlidis S, Kermani NZ, Baines KJ, Barker D, Gibson PG, et al., 'Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts.', Respirology (Carlton, Vic.), 27 730-738 (2022) [C1]
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Nova |
2021 |
Berthon BS, McLoughlin RF, Jensen ME, Hosseini B, Williams EJ, Baines KJ, et al., 'The effects of increasing fruit and vegetable intake in children with asthma: A randomized controlled trial', CLINICAL AND EXPERIMENTAL ALLERGY, 51 1144-1156 (2021) [C1]
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Nova |
2021 |
Hosseini B, Berthon BS, Starkey MR, Collison A, McLoughlin RF, Williams EJ, et al., 'Children With Asthma Have Impaired Innate Immunity and Increased Numbers of Type 2 Innate Lymphoid Cells Compared With Healthy Controls', FRONTIERS IN IMMUNOLOGY, 12 (2021) [C1]
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Nova |
2021 |
Niessen NM, Gibson PG, Baines KJ, Barker D, Yang IA, Upham JW, et al., 'Sputum TNF markers are increased in neutrophilic and severe asthma and are reduced by azithromycin treatment', ALLERGY, 76 2090-2101 (2021) [C1]
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Nova |
2021 |
Williams EJ, Negewo NA, Baines KJ, 'Role of the NLRP3 inflammasome in asthma: Relationship with neutrophilic inflammation, obesity, and therapeutic options', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 147 2060-2062 (2021)
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2021 |
Niessen NM, Gibson PG, Simpson JL, Scott HA, Baines KJ, Fricker M, 'Airway monocyte modulation relates to tumour necrosis factor dysregulation in neutrophilic asthma', ERJ OPEN RESEARCH, 7 (2021) [C1]
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Nova |
2021 |
Ruffles TJC, Marchant JM, Masters IB, Yerkovich ST, Wurzel DF, Gibson PG, et al., 'Outcomes of protracted bacterial bronchitis in children: A 5-year prospective cohort study', Respirology, 26 241-248 (2021) [C1]
Background and objective: Long-term data on children with PBB has been identified as a research priority. We describe the 5-year outcomes for children with PBB to ascertain the pr... [more]
Background and objective: Long-term data on children with PBB has been identified as a research priority. We describe the 5-year outcomes for children with PBB to ascertain the presence of chronic respiratory disease (bronchiectasis, recurrent PBB and asthma) and identify the risk factors for these. Methods: Prospective cohort study was undertaken at the Queensland Children's Hospital, Brisbane, Australia, of 166 children with PBB and 28 controls (undergoing bronchoscopy for symptoms other than chronic wet cough). Monitoring was by monthly contact via research staff. Clinical review, spirometry and CT chest were performed as clinically indicated. Results: A total of 194 children were included in the analysis. Median duration of follow-up was 59 months (IQR: 50¿71 months) post-index PBB episode, 67.5% had ongoing symptoms and 9.6% had bronchiectasis. Significant predictors of bronchiectasis were recurrent PBB in year 1 of follow-up (ORadj = 9.6, 95% CI: 1.8¿50.1) and the presence of Haemophilus influenzae in the BAL (ORadj = 5.1, 95% CI: 1.4¿19.1). Clinician-diagnosed asthma at final follow-up was present in 27.1% of children with PBB. A significant BDR (FEV1 improvement >12%) was obtained in 63.5% of the children who underwent reversibility testing. Positive allergen-specific IgE (ORadj = 14.8, 95% CI: 2.2¿100.8) at baseline and bronchomalacia (ORadj = 5.9, 95% CI: 1.2¿29.7) were significant predictors of asthma diagnosis. Spirometry parameters were in the normal range. Conclusion: As a significant proportion of children with PBB have ongoing symptoms at 5 years, and outcomes include bronchiectasis and asthma, they should be carefully followed up clinically. Defining biomarkers, endotypes and mechanistic studies elucidating the different outcomes are now required.
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Nova |
2021 |
Twaddell SH, Gibson PG, Grainge C, Baines KJ, 'Parapneumonic Effusions Are Characterized by Elevated Levels of Neutrophil Extracellular Traps', CHEST, 160 1645-1655 (2021) [C1]
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Nova |
2021 |
Niessen NM, Baines KJ, Simpson JL, Scott HA, Qin L, Gibson PG, Fricker M, 'Neutrophilic asthma features increased airway classical monocytes', CLINICAL AND EXPERIMENTAL ALLERGY, 51 305-317 (2021) [C1]
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Nova |
2021 |
Zounemat Kermani N, Saqi M, Agapow P, Pavlidis S, Kuo C, Tan KS, et al., 'Type 2-low asthma phenotypes by integration of sputum transcriptomics and serum proteomics', ALLERGY, 76 380-383 (2021)
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2021 |
Winter NA, Qin L, Gibson PG, McDonald VM, Baines KJ, Faulkner J, et al., 'Sputum mast cell/basophil gene expression relates to inflammatory and clinical features of severe asthma', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 148 428-438 (2021) [C1]
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Nova |
2021 |
Fricker M, McDonald VM, Winter NA, Baines KJ, Wark PAB, Simpson JL, Gibson PG, 'Molecular markers of type 2 airway inflammation are similar between eosinophilic severe asthma and eosinophilic COPD', ALLERGY, 76 2079-2089 (2021) [C1]
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Nova |
2021 |
Sanchez-Ovando S, Simpson JL, Barker D, Baines KJ, Wark PAB, 'Transcriptomics of biopsies identifies novel genes and pathways linked to neutrophilic inflammation in severe asthma', CLINICAL AND EXPERIMENTAL ALLERGY, 51 1279-1294 (2021) [C1]
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Nova |
2020 |
Fricker M, Qin L, Niessen N, Baines KJ, McDonald VM, Scott HA, et al., 'Relationship of sputum mast cells with clinical and inflammatory characteristics of asthma', CLINICAL AND EXPERIMENTAL ALLERGY, 50 696-707 (2020) [C1]
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Nova |
2020 |
Baines KJ, Fricker M, McDonald VM, Simpson JL, Wood LG, Wark PAB, et al., 'Sputum transcriptomics implicates increased p38 signalling activity in severe asthma', Respirology, 25 709-718 (2020) [C1]
Background and objective: Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. This study analyses sputum transcriptomics to... [more]
Background and objective: Severe asthma is responsible for a disproportionate burden of illness and healthcare costs spent on asthma. This study analyses sputum transcriptomics to investigate the mechanisms and novel treatment targets of severe asthma. Methods: Induced sputum samples were collected in a cross-sectional study from participants with severe asthma (n = 12, defined as per GINA criteria), non-severe uncontrolled (n = 21) and controlled asthma (n = 21) and healthy controls (n = 15). Sputum RNA was extracted and transcriptomic profiles were generated (Illumina HumanRef-8 V2) and analysed (GeneSpring). Sputum protein lysates were analysed for p38 activation in a validation study (n = 24 asthma, n = 8 healthy) by western blotting. Results: There were 2166 genes differentially expressed between the four groups. In severe asthma, the expression of 1875, 1308 and 563 genes was altered compared to healthy controls, controlled and uncontrolled asthma, respectively. Of the 1875 genes significantly different to healthy controls, 123 were >2-fold change from which four networks were identified. Thirty genes (>2-fold change) were significantly different in severe asthma compared to both controlled asthma and healthy controls. There was enrichment of genes in the p38 signalling pathway that were associated with severe asthma. Phosphorylation of p38 was increased in a subset of severe asthma samples, correlating with neutrophilic airway inflammation. Conclusion: Severe asthma is associated with substantial differences in sputum gene expression that underlie unique cellular mechanisms. The p38 signalling pathway may be important in the pathogenesis of severe asthma, and future investigations into p38 inhibition are warranted as a ¿non-Th2¿ therapeutic option.
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Nova |
2020 |
Frøssing L, Kjærsgaard Klein D, Backer V, Baines KJ, Porsbjerg C, 'The six-gene expression signature in whole sampled sputum provides clinically feasible inflammatory phenotyping of asthma.', ERJ open research, 6 1-9 (2020) [C1]
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Nova |
2020 |
Sánchez-Ovando S, Baines KJ, Barker D, Wark PA, Simpson JL, 'Six gene and TH2 signature expression in endobronchial biopsies of participants with asthma', Immunity, Inflammation and Disease, 8 40-49 (2020) [C1]
Background: Both the six gene signature (6GS: CPA3, DNASE1L3, CLC, IL1B, ALPL, and CXCR2) and T-helper 2 signature (TH2S: CLCA1, SERPINB2, and POSTN) are proposed as biomarkers in... [more]
Background: Both the six gene signature (6GS: CPA3, DNASE1L3, CLC, IL1B, ALPL, and CXCR2) and T-helper 2 signature (TH2S: CLCA1, SERPINB2, and POSTN) are proposed as biomarkers in the identification of inflammatory phenotypes of asthma in induced sputum and epithelial brushings, respectively. The aim of this study was to explore patterns of gene expression of known signatures, 6GS and TH2S in endobronchial biopsies. Methods: This was an exploratory cross-sectional study of gene expression in endobronchial biopsies of 55 adults with asthma and 9 healthy controls (HC). The expression of the 6GS and TH2S was determined by quantitative polymerase chain reaction. Correlations with clinical and cellular characteristics were performed, and receiver operating characteristic was utilized to assess signatures' ability to predict asthma from HC and inflammatory phenotypes. Results: Gene expression of DNASE1L3 (P =.045) was upregulated in asthma compared with HC, and IL1B (P =.017) was upregulated in neutrophilic asthma compared with non-neutrophilic asthma. In asthma, the expression of CPA3 was negatively associated with ICS daily dose (r = -.339; P =.011), IL1B expression was positively associated with bronchial lavage fluid (BLF) total cell count (r =.340; P =.013) and both CLC and POSTN expression were associated with lymphocytes percentage in BLF (r = -.355, P =.009; r = -.300, P =.025, respectively). Both 6GS (area under curve [AUC] = 86.3%; P =.017) and TH2S (AUC = 72.7%; P =.037) could significantly predict asthma from HC. In addition, 6GS can identify neutrophilic (AUC = 93.2%; P =.005) and TH2S identifies eosinophilic (AUC = 62.7%; P =.033) asthma. Conclusions and Clinical Relevance: There was increased expression of DNASE1L3 in asthma and IL1B in neutrophilic asthma. These results show similar upregulated patterns of expression in two genes of the 6GS in endobronchial biopsies, previously identified in sputum. The upregulation of DNASE1L3 and IL1B suggests that common mechanisms may be at play throughout the airway.
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Nova |
2020 |
Baines KJ, Negewo NA, Gibson PG, Fu JJ, Simpson JL, Wark PAB, et al., 'A Sputum 6 Gene Expression Signature Predicts Inflammatory Phenotypes and Future Exacerbations of COPD', International Journal of COPD, 15 1577-1590 (2020) [C1]
Background: The 6 gene expression signature (6GS) predicts in¿ammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, patterns of airway in¿am... [more]
Background: The 6 gene expression signature (6GS) predicts in¿ammatory phenotype, exacerbation risk, and corticosteroid responsiveness in asthma. In COPD, patterns of airway in¿ammation are similar, suggesting the 6GS may be useful. This study determines the diagnostic and prognostic ability of 6GS in predicting in¿ammatory phenotypes and exacerbation risk in COPD. Methods: We performed 2 studies: a cross-sectional phenotype prediction study in stable COPD (total N=132; n=34 eosinophilic (E)-COPD, n=42 neutrophilic (N)-COPD, n=39 paucigranulocytic (PG)-COPD, n=17 mixed-granulocytic (MG)-COPD) that assessed 6GS ability to discriminate phenotypes (eosinophilia=3%; neutrophilia=61%); and a prospective cohort study (total n=54, n=8 E-COPD; n=18 N-COPD; n=20 PG-COPD; n=8 MG-COPD, n=21 exacerbation prone (=2/year)) that investigated phenotype and exacerbation prediction utility. 6GS was measured by qPCR and evaluated using multiple logistic regression and area under the curve (AUC). Short-term reproducibility (intra-class correlation) and phenotyping method agreement (¿ statistic) were assessed. Results: In the phenotype prediction study, 6GS could accurately identify and discriminate patients with E-COPD from N-COPD (AUC=96.4%; p<0.0001), PG-COPD (AUC=88.2%; p<0.0001) or MG-COPD (AUC=86.2%; p=0.0001), as well as N-COPD from PG-COPD (AUC=83.6%; p<0.0001) or MG-COPD (AUC=87.4%; p<0.0001) and was reproducible. In the prospective cohort study, 6GS had substantial agreement for neutrophilic in¿ammation (82%, ¿=0.63,p<0.001)and moderate agreement foreosinophilici n¿ammation(78%, ¿=0.42,p<0.001). 6GS could signi¿cantly discriminate exacerbationprone patients (AUC=77.2%; p=0.034). Higher IL1B levels were associated with poorer lung function and increased COPD severity. Conclusion: 6GS can signi¿cantly and reproducibly discriminate COPD in¿ammatory phenotypes and predict exacerbation prone patients and may become a useful molecular diagnostic tool assisting COPD management..
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Nova |
2020 |
McDonald VM, Clark VL, Cordova-Rivera L, Wark PAB, Baines KJ, Gibson PG, 'Targeting treatable traits in severe asthma: a randomised controlled trial', EUROPEAN RESPIRATORY JOURNAL, 55 (2020) [C1]
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Nova |
2019 |
Fricker M, Gibson PG, Powell H, Simpson JL, Yang IA, Upham JW, et al., 'A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma', Journal of Allergy and Clinical Immunology, 144 51-60.e11 (2019) [C1]
Background: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene s... [more]
Background: Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). Objectives: We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. Methods: One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. Results: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. Conclusion: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.
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Nova |
2019 |
Erriah M, Pabreja K, Fricker M, Baines KJ, Donnelly LE, Bylund J, et al., 'Galectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma', RESPIRATORY RESEARCH, 20 (2019) [C1]
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Nova |
2019 |
Lokwani R, Wark PAB, Baines KJ, Barker D, Simpson JL, 'Hypersegmented airway neutrophils and its association with reduced lung function in adults with obstructive airway disease: An exploratory study', BMJ Open, 9 (2019) [C1]
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Nova |
2019 |
Qin L, Gibson PG, Simpson JL, Baines KJ, McDonald VM, Wood LG, et al., 'Dysregulation of sputum columnar epithelial cells and products in distinct asthma phenotypes', Clinical and Experimental Allergy, 49 1418-1428 (2019) [C1]
Background: Dysfunction of the bronchial epithelium plays an important role in asthma; however, its measurement is challenging. Columnar epithelial cells are often quantified, yet... [more]
Background: Dysfunction of the bronchial epithelium plays an important role in asthma; however, its measurement is challenging. Columnar epithelial cells are often quantified, yet rarely analysed, in induced sputum studies. Objective: We aimed to test whether sputum columnar epithelial cell proportion and count are altered in asthma, and whether they are associated with clinical and inflammatory variables. We aimed to test whether sputum-based measures could provide a relatively non-invasive means through which to monitor airway epithelial activation status. Methods: We examined the relationship of sputum columnar epithelial cells with clinical and inflammatory variables of asthma in a large retrospective cross-sectional cohort (901 participants with asthma and 138 healthy controls). In further studies, we used flow cytometry, microarray, qPCR and ELISA to characterize sputum columnar epithelial cells and their products. Results: Multivariate analysis and generation of 90th centile cut-offs (=11% or =18.1¿×¿104/mL) to identify columnar epithelial cell ¿high¿ asthma revealed a significant relationship between elevated sputum columnar cells and male gender, severe asthma and non-neutrophilic airway inflammation. Flow cytometry showed viable columnar epithelial cells were present in all sputum samples tested. An epithelial gene signature (SCGB3A1, LDLRAD1, FOXJ1, DNALI1, CFAP157, CFAP53) was detected in columnar epithelial cell-high sputum. CLCA1 mRNA and periostin protein, previously identified biomarkers of IL-13-mediated epithelial activation, were elevated in columnar epithelial cell-high sputum samples, but only when accompanied by eosinophilia. Conclusions & clinical relevance: Sputum columnar epithelial cells are related to important clinical and inflammatory variables in asthma. Measurement of epithelial biomarkers in sputum samples could allow non-invasive assessment of altered bronchial epithelium status in asthma.
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Nova |
2019 |
Wood LG, Li Q, Scott HA, Rutting S, Berthon BS, Gibson PG, et al., 'Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 143 305-315 (2019) [C1]
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Nova |
2019 |
Twaddell SH, Baines KJ, Grainge C, Gibson PG, 'The Emerging Role of Neutrophil Extracellular Traps in Respiratory Disease', Chest, 156 774-782 (2019) [C1]
Neutrophil extracellular traps (NETs) are extrusions of intracellular DNA and attached granular material that enable bacterial killing. NETs are increasingly recognized for their ... [more]
Neutrophil extracellular traps (NETs) are extrusions of intracellular DNA and attached granular material that enable bacterial killing. NETs are increasingly recognized for their role in the pathogenesis of respiratory disease. NETs are composed of a complex mix of intracellularly derived material that neutrophils organize within the cytoplasm and then expel in a nondirected manner in the vicinity of invading organisms. Combined, these trap and destroy multiple genera of microbes including bacteria, fungi, viruses, and protozoans, limiting infection especially where phagocytosis is not possible. At first, NET formation was thought to be a terminal event for neutrophils; however, it is now apparent that some neutrophils survive this process, becoming anuclear, and may drive ongoing tissue damage. NETs are now known to be directly cytotoxic to lung epithelium and endothelium, and their excessive production is seen in pneumonia and acute lung injury as well as several chronic diseases, including COPD, asthma, and cystic fibrosis. NETs also appear to play a role in both tumor defense and dissemination, depending on the local microenvironment and the specific tumor subtype. It is becoming increasingly apparent that NET formation can exert a positive or negative influence on multiple respiratory pathologies and that simply globally reducing or increasing NET formation is unlikely to be a therapeutic success. Rather, as our understanding grows, it is likely that targeted NET up- or downregulation along with destruction or protection of already formed NETs may become an additional point of intervention for respiratory physicians.
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Nova |
2019 |
Lokwani R, Wark PAB, Baines KJ, Fricker M, Barker D, Simpson JL, 'Blood neutrophils in copd but not asthma exhibit a primed phenotype with downregulated cd62l expression', International Journal of COPD, 14 2517-2525 (2019) [C1]
Purpose: To characterize neutrophils in obstructive airway disease by measuring their surface adhesion molecules and oxidative burst along with characterizing them into different ... [more]
Purpose: To characterize neutrophils in obstructive airway disease by measuring their surface adhesion molecules and oxidative burst along with characterizing them into different subsets as per their adhesion molecule expression. Patients and methods: Peripheral blood from adults with COPD (n=17), asthma (n=20), and healthy participants (n=19) was examined for expression of CD16, CD62L, CD11b, CD11c, and CD54, and analyzed by flow cytometry. For oxidative burst and CD62L shedding analysis, CD16 and CD62L stained leukocytes were loaded with Dihydrorhodamine-123 (DHR-123) and stimulated with N-Formylmethionine-leucyl-phenylalanine (fMLF). Neutrophil subsets were characterized based on CD16 and CD62L expression. Marker surface expression was recorded on CD16+ neutrophils as median fluorescence intensity (MFI). Results: Neutrophil surface expression of CD62L was significantly reduced in COPD (median (IQR) MFI: 1156 (904, 1365)) compared with asthma (1865 (1157, 2408)) and healthy controls (2079 (1054, 2960)); p=0.028. COPD neutrophils also demonstrated a significant reduction in CD62L expression with and without fMLF stimulation. Asthma participants had a significantly increased proportion and number of CD62Lbright/CD16dim neutrophils (median: 5.4% and 0.14 × 109/L, respectively), in comparison with healthy (3.54% and 0.12 × 109/L, respectively); p<0.017. Conclusion: Reduced CD62L expression suggests blood neutrophils have undergone priming in COPD but not in asthma, which may be the result of systemic inflammation. The increased shedding of CD62L receptor by COPD blood neutrophils suggests a high sensitivity for activation.
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Nova |
2019 |
McLoughlin R, Berthon BS, Rogers GB, Baines KJ, Leong LEX, Gibson PG, et al., 'Soluble fibre supplementation with and without a probiotic in adults with asthma: A 7-day randomised, double blind, three way cross-over trial', EBioMedicine, 46 473-485 (2019) [C1]
Background: Soluble fibre modulates airway inflammation in animal models. The aim of this study was to investigate the effects of soluble fibre supplementation, with and without a... [more]
Background: Soluble fibre modulates airway inflammation in animal models. The aim of this study was to investigate the effects of soluble fibre supplementation, with and without a probiotic, on plasma short chain fatty acids (SCFA), airway inflammation, asthma control and gut microbiome in adults with asthma. Methods: A randomised, double-blinded, placebo controlled 3-way cross-over trial in 17 subjects with stable asthma at the Hunter Medical Research Institute, Newcastle, Australia. Subjects received 3 × 7 day oral interventions in random order; soluble fibre (inulin 12 g/day), soluble fibre + probiotic (inulin 12 g/day + multi-strain probiotic >25 billion CFU) and placebo. Plasma SCFA, sputum cell counts and inflammatory gene expression, asthma control gut microbiota, adverse events including gastrointestinal symptoms were measured. Findings: There was no difference in change in total plasma SCFA levels (µmol/L) in the placebo versus soluble fibre (¿median [95% CI] 16·3 [-16·9, 49·5], p = 0·335) or soluble fibre+probiotic (18·7 [-14·5, 51·9], p = 0·325) group. Following the soluble fibre intervention there was an improvement in the asthma control questionnaire (ACQ6) (¿median (IQR) -0·35 (-0·5, -0·13), p = 0·006), sputum %eosinophils decreased (-1.0 (-2·5, 0), p = 0·006) and sputum histone deacetylase 9 (HDAC9) gene expression decreased (-0.49 (-0.83, -0.27) 2-¿Ct, p =.008). Individual bacterial operational taxonomic units changed following both inulin and inulin+probiotic arms. Interpretation: Soluble fibre supplementation for 7 days in adults with asthma did not change SCFA levels. Within group analysis showed improvements in airway inflammation, asthma control and gut microbiome composition following inulin supplementation and these changes warrant further investigation, in order to evaluate the potential of soluble fibre as a non-pharmacological addition to asthma management. Fund: John Hunter Hospital Charitable Trust.
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Nova |
2018 |
Chen AC-H, Tran HB, Xi Y, Yerkovich ST, Baines KJ, Pizzutto SJ, et al., 'Multiple inflammasomes may regulate the interleukin-1-driven inflammation in protracted bacterial bronchitis.', ERJ open research, 4 1-11 (2018) [C1]
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Nova |
2018 |
Periyalil HA, Wood LG, Wright TA, Karihaloo C, Starkey MR, Miu AS, et al., 'Obese asthmatics are characterized by altered adipose tissue macrophage activation', CLINICAL AND EXPERIMENTAL ALLERGY, 48 641-649 (2018) [C1]
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Nova |
2018 |
Baines KJ, Wright TK, Gibson PG, Powell H, Hansbro PM, Simpson JL, 'Azithromycin treatment modifies airway and blood gene expression networks in neutrophilic COPD.', ERJ open research, 4 (2018) [C1]
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Nova |
2018 |
Porsbjerg C, Sverrild A, Baines KJ, Searles A, Maltby S, Foster PS, et al., 'Advancing the management of obstructive airways diseases through translational research', CLINICAL AND EXPERIMENTAL ALLERGY, 48 493-501 (2018) [C1]
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Nova |
2018 |
Chen ACH, Pena OM, Nel HJ, Yerkovich ST, Chang AB, Baines KJ, et al., 'Airway cells from protracted bacterial bronchitis and bronchiectasis share similar gene expression profiles', Pediatric Pulmonology, 53 575-582 (2018) [C1]
Aim: Protracted bacterial bronchitis (PBB) is a common cause of prolonged cough in young children, and may be a precursor of bronchiectasis. Bacteria are often present in the lowe... [more]
Aim: Protracted bacterial bronchitis (PBB) is a common cause of prolonged cough in young children, and may be a precursor of bronchiectasis. Bacteria are often present in the lower airways in both PBB and bronchiectasis and may cause persistent infections. However, there is a paucity of information available on the pathogenesis of PBB and the factors associated with persistent bacterial infection and progression to bronchiectasis. This study hypothesised that lung immune cells in recurrent PBB and bronchiectasis differentially express genes related to immune cell dysfunction compared to lung immune cells from control subjects. Method: Cells isolated from bronchoalveolar lavage (adult-control and PBB BAL cells) were stimulated with nontypeable Haemophilus influenzae (NTHi), and expression of genes involved in various inflammatory pathways was assessed. Result: NTHi induced production of large amounts of IL-1ß, IL-6, and IL-8 in adult-control BAL cells, however BAL cells from PBB airways appeared refractory to NTHi stimulation. BAL cells from PBB and bronchiectasis showed differential expression of several genes relative to control cells, including CCL20, MARCO, CCL24, IL-10, PPAR-¿, CD200R, TREM2, RelB. Expression of genes involved in resolution of inflammation and anti-inflammation response, such as CD200R and IL-10, was associated with the number of pathogenic bacteria found in the airways. Conclusion: In summary, we have shown that the expression of genes related to macrophage function and resolution of inflammation are similar in PBB and bronchiectasis. Lung immune cell dysfunction in PBB and bronchiectasis may contribute to poor bacterial clearance and prolonged resolution of inflammation.
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Nova |
2017 |
McLoughlin RF, Berthon BS, Jensen ME, Baines KJ, Wood LG, 'Short-chain fatty acids, prebiotics, synbiotics, and systemic inflammation: A systematic review and meta-analysis', American Journal of Clinical Nutrition, 106 930-945 (2017) [C1]
Background: Prebiotic soluble fibers are fermented by beneficial bacteria in the colon to produce short-chain fatty acids (SCFAs), which are proposed to have systemic anti-inflamm... [more]
Background: Prebiotic soluble fibers are fermented by beneficial bacteria in the colon to produce short-chain fatty acids (SCFAs), which are proposed to have systemic anti-inflammatory effects. Objective: This review examines the effect of SCFAs, prebiotics, and pre- and probiotic combinations (synbiotics) on systemic inflammation. Design: Relevant English language studies from 1947 to May 2017 were identified with the use of online databases. Studies were considered eligible if they examined the effects of SCFAs, prebiotics, or synbiotics; were delivered orally, intravenously, or per rectum; were on biomarkers of systemic inflammation in humans; and performed meta-analysis where possible. Results: Sixty-eight studies were included. Fourteen of 29 prebiotic studies and 13 of 26 synbiotic studies reported a significant decrease in =1 marker of systemic inflammation. Eight studies compared prebiotic and synbiotic supplementation, 2 of which reported a decrease in inflammation with synbiotics only, with 1 reporting a greater anti-inflammatory effect with synbiotics than with prebiotics alone. Meta-analyses indicated that prebiotics reduce C-reactive protein (CRP) [standardized mean difference (SMD): -0.60; 95% CI: -0.98, -0.23], and synbiotics reduce CRP (SMD: -0.40; 95% CI: -0.73, -0.06) and tumor necrosis factor-a (SMD -0.90; 95% CI: -1.50, -0.30). Conclusions: There is significant heterogeneity of outcomes in studies examining the effect of prebiotics and synbiotics on systemic inflammation. Approximately 50% of included studies reported a decrease in =1 inflammatory biomarker. The inconsistency in reported outcomes may be due to heterogeneity in study design, supplement formulation, dosage, duration, and subject population. Nonetheless, meta-analyses provide evidence to support the systemic anti-inflammatory effects of prebiotic and synbiotic supplementation.
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Nova |
2017 |
Halnes I, Baines KJ, Berthon BS, MacDonald-Wicks LK, Gibson PG, Wood LG, 'Soluble fibre meal challenge reduces airway inflammation and expression of GPR43 and GPR41 in asthma', Nutrients, 9 1-11 (2017) [C1]
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Nova |
2017 |
Williams EJ, Baines KJ, Berthon BS, Wood LG, 'Effects of an Encapsulated Fruit and Vegetable Juice Concentrate on Obesity-Induced Systemic Inflammation: A Randomised Controlled Trial', NUTRIENTS, 9 (2017) [C1]
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Nova |
2017 |
Pabreja K, Gibson P, Lochrin AJ, Wood L, Baines KJ, Simpson JL, 'Sputum colour can identify patients with neutrophilic inflammation in asthma', BMJ Open Respiratory Research, 4 (2017) [C1]
Introduction Sputum colour is associated with neutrophilic inflammation in chronic bronchitis and chronic obstructive pulmonary disease (COPD). Neutrophilia and sputum expectorati... [more]
Introduction Sputum colour is associated with neutrophilic inflammation in chronic bronchitis and chronic obstructive pulmonary disease (COPD). Neutrophilia and sputum expectoration is notable in asthma, but whether sputum colour is associated with and predicts the presence of neutrophilic inflammation in asthma is unknown. The objective of the study is to assess the ability of sputum colour in distinguishing asthma inflammatory phenotypes. Methods Induced sputum samples collected from 271 adults with stable asthma were retrospectively assessed. Sputum colour was determined using the BronkoTest sputum colour chart and correlated to differential cell counts and CXCL-8 concentration. Neutrophilic inflammation was defined as an age-corrected sputum neutrophil proportion (=61.6% for age 20¿40 years; =63.2% for age 40¿60 and =67.2% for age >60 years), whereas neutrophilic bronchitis (NB) was defined as high total cell count (=5.1×106 cells/mL) plus an increased age-corrected neutrophil proportion. The optimal cut-off for sputum colour to predict neutrophilic inflammation and NB was determined using receiver operator characteristic curve analysis. Results A sputum colour score of =3 represented and predicted neutrophilic inflammation with modest accuracy (area under the curve (AUC)=0.64; p<0.001, specificity=78.4%, sensitivity=49.2%). Participants with a sputum colour score of =3 had significantly (p<0.05) higher CXCL-8, total cells and neutrophil number and proportion. Sputum colour score was also positively correlated with these factors. Sputum colour score =3 predicted NB with reasonably good accuracy (AUC=0.79, p<0.001, specificity=79.3%, sensitivity=70.7%). Conclusions Visual gradation of sputum colour in asthma relates to high total cell count and neutrophilic inflammation. Assessment of sputum colour can identify adults with asthma who are likely to have NB without the need for sputum processing and differential cell count, which may facilitate asthma management.
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Nova |
2017 |
Baines KJ, Fu JJ, McDonald VM, Gibson PG, 'Airway gene expression of IL-1 pathway mediators predicts exacerbation risk in obstructive airway disease', International Journal of COPD, 12 541-550 (2017) [C1]
Background: Exacerbations of asthma and COPD are a major cause of morbidity and mortality and are responsible for significant health care costs. This study further investigates in... [more]
Background: Exacerbations of asthma and COPD are a major cause of morbidity and mortality and are responsible for significant health care costs. This study further investigates interleukin (IL)-1 pathway activation and its relationship with exacerbations of asthma and COPD. Methods: In this prospective cohort study, 95 participants with stable asthma (n=35) or COPD (n=60) were recruited and exacerbations recorded over the following 12 months. Gene expressions of IL-1 pathway biomarkers, including the IL-1 receptors (IL1R1, IL1R2, and IL1RN), and signaling molecules (IRAK2, IRAK3, and PELI1), were measured in sputum using real-time quantitative polymerase chain reaction. Mediators were compared between the frequent (2 exacerbations in the 12 months) and infrequent exacerbators, and the predictive relationships investigated using receiver operating characteristic curves and area under the curve (AUC) values. Results: Of the 95 participants, 89 completed the exacerbation follow-up, where 30 participants (n=22 COPD, n=8 asthma) had two or more exacerbations. At the baseline visit, expressions of IRAK2, IRAK3, PELI1, and IL1R1 were elevated in participants with frequent exacerbations of both asthma and COPD combined and separately. In the combined population, sputum gene expression of IRAK3 (AUC=75.4%; P,0.001) was the best predictor of future frequent exacerbations, followed by IL1R1 (AUC=72.8%; P,0.001), PELI1 (AUC=71.2%; P,0.001), and IRAK2 (AUC=68.6; P=0.004). High IL-1 pathway gene expression was associated with frequent prior year exacerbations and correlated with the number and severity of exacerbations. Conclusion: The upregulation of IL-1 pathway mediators is associated with frequent exacerbations of obstructive airway disease. Further studies should investigate these mediators as both potential diagnostic biomarkers predicting at-risk patients and novel treatment targets.
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Nova |
2017 |
Berthon BS, Gibson PG, Wood LG, MacDonald-Wicks LK, Baines KJ, 'A sputum gene expression signature predicts oral corticosteroid response in asthma', EUROPEAN RESPIRATORY JOURNAL, 49 (2017) [C1]
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Nova |
2017 |
Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al., 'Role for NLRP3 inflammasome-mediated, IL-1ß-dependent responses in severe, steroid-resistant asthma', American Journal of Respiratory and Critical Care Medicine, 196 283-297 (2017) [C1]
Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identifica... [more]
Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1ß responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1ß in severe, steroid-resistant asthma. Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1ß responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1ß responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1ß antibody. Roles for IL-1ß-induced neutrophilic inflammation were examined using IL-1ß and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1ß responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1ß expression. Treatment with anti-IL-1ß, Ac- YVAD-cho, and MCC950 suppressed IL-1ß responses and the important steroid-resistant features of disease in mice, whereas IL-1ß administration recapitulated these features. Neutrophil depletion suppressed IL-1ß-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
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Nova |
2017 |
Chen ACH, Xi Y, Carroll M, Petsky HL, Gardiner SJ, Pizzutto SJ, et al., 'Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1ß', ERJ Open Research, 3 (2017) [C1]
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Nova |
2017 |
Hsu AC-Y, Dua K, Starkey MR, Haw T-J, Nair PM, Nichol K, et al., 'MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD', JCI INSIGHT, 2 (2017) [C1]
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Nova |
2016 |
Li Q, Baines KJ, Gibson PG, Wood LG, 'Changes in expression of genes regulating airway inflammation following a high-fat mixed meal in asthmatics', Nutrients, 8 (2016) [C1]
Consumption of a high fat meal can increase neutrophilic airway inflammation in asthma subjects. This study investigates the molecular mechanisms driving airway neutrophilia follo... [more]
Consumption of a high fat meal can increase neutrophilic airway inflammation in asthma subjects. This study investigates the molecular mechanisms driving airway neutrophilia following a high fat meal in asthmatics. Subjects with asthma (n = 11) and healthy controls (n = 8) consumed a high-fat/energy meal, containing total energy (TE) of 3846 kJ and 48 g of total fat (20.5 g saturated). Sputum was induced at 0 and 4 h, and gene expression was examined by microarray and quantitative real-time PCR (qPCR). Following the high fat dietary challenge, 168 entities were significantly differentially expressed greater than >1.5 fold in subjects with asthma, whereas, in healthy controls, only 14 entities were differentially expressed. Of the 168 genes that were changed in asthma, several biological processes were overrepresented, with 25 genes involved in "immune system processes". qPCR confirmed that S100P, S100A16, MAL and MUC1 were significantly increased in the asthma group post-meal. We also observed a strong correlation and a moderate correlation between the change in NLRP12 and S100A16 gene expression at 4 h compared to baseline, and the change in total and saturated non-esterified plasma fatty acid levels at 2 h compared to baseline. In summary, our data identifies differences in inflammatory gene expression that may contribute to increased airway neutrophilia following a high fat meal in subjects with asthma and may provide useful therapeutic targets for immunomodulation. This may be particularly relevant to obese asthmatics, who are habitually consuming diets with a high fat content.
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Nova |
2016 |
Wang G, Baines KJ, Fu JJ, Wood LG, Simpson JL, McDonald VM, et al., 'Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma', European Respiratory Journal, 47 1123-1133 (2016) [C1]
Mast cells are a resident inflammatory cell of the airways, involved in both the innate and adaptive immune response. The relationship between mast cells and inflammatory phenotyp... [more]
Mast cells are a resident inflammatory cell of the airways, involved in both the innate and adaptive immune response. The relationship between mast cells and inflammatory phenotypes and treatment response of asthma is not clear. Clinical characteristics of subjects with stable asthma (n=55), inflammatory cell counts and gene expression microarrays in induced sputum were analysed. Sputum mast cell subtypes were determined by molecular phenotyping based on expression of mast cell biomarkers (tryptase (TPSAB1), chymase (CMA1) and carboxypeptidase A3 (CPA3)). Effects of mast cell subtypes on steroid response were observed in a prospective cohort study (n=50). MCT (n=18) and MCT/CPA3 (mRNA expression of TPSAB1 and CPA3; n=29) subtypes were identified, as well as a group without mast cell gene expression (n=8). The MCT/CPA3 subtype had elevated exhaled nitric oxide fraction, sputum eosinophils, bronchial sensitivity and reactivity, and poorer asthma control. This was accompanied by upregulation of 13 genes. Multivariable logistic regression identified CPA3 (OR 1.21, p=0.004) rather than TPSAB1 (OR 0.92, p=0.502) as a determinant of eosinophilic asthma. The MCT/CPA3 subtype had a better clinical response and reduced signature gene expression with corticosteroid treatment. Sputum mast cell subtypes of asthma can be defined by a molecular phenotyping approach. The MCT/CPA3 subtype demonstrated increased bronchial sensitivity and reactivity, and signature gene expression, which was associated with airway eosinophilia and greater corticosteroid responsiveness.
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Nova |
2016 |
Tang FSM, Van Ly D, Spann K, Reading PC, Burgess JK, Hartl D, et al., 'Differential neutrophil activation in viral infections: Enhanced TLR-7/8-mediated CXCL8 release in asthma', Respirology, 21 172-179 (2016) [C1]
© 2015 The Authors. Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology.Background and objective Respiratory viral infections ... [more]
© 2015 The Authors. Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology.Background and objective Respiratory viral infections are a major cause of asthma exacerbations. Neutrophils accumulate in the airways and the mechanisms that link neutrophilic inflammation, viral infections and exacerbations are unclear. This study aims to investigate anti-viral responses in neutrophils from patients with and without asthma and to investigate if neutrophils can be directly activated by respiratory viruses. Methods Neutrophils from peripheral blood from asthmatic and non-asthmatic individuals were isolated and stimulated with lipopolysaccharide (LPS) (1 µg/mL), f-met-leu-phe (fMLP) (100 nM), imiquimod (3 µg/mL), R848 (1.5 µg/mL), poly I:C (10 µg/mL), RV16 (multiplicity of infection (MOI)1), respiratory syncytial virus (RSV) (MOI1) or influenza virus (MOI1). Cell-free supernatants were collected after 1 h of neutrophil elastase (NE) and matrix metalloproteinase (MMP)-9 release, or after 24 h for CXCL8 release. Results LPS, fMLP, imiquimod and R848 stimulated the release of CXCL8, NE and MMP-9 whereas poly I:C selectively induced CXCL8 release only. R848-induced CXCL8 release was enhanced in neutrophils from asthmatics compared with non-asthmatic cells (P < 0.01). RSV triggered the release of CXCL8 and NE from neutrophils, whereas RV16 or influenza had no effect. Conclusion Neutrophils release CXCL8, NE and MMP-9 in response to viral surrogates with R848-induced CXCL8 release being specifically enhanced in asthmatic neutrophils. Toll-like receptor (TLR7/8) dysregulation may play a role in neutrophilic inflammation in viral-induced exacerbations. We aimed to investigate and compare neutrophil responses to bacterial compounds and viral mimetics as well as compare responses between people with and without asthma. We also investigated neutrophil responses to live respiratory viruses. Here we provide a novel comprehensive comparison showing differential and specific activation in innate immune cells. See Editorial, page 10
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Nova |
2016 |
Simpson JL, Baines KJ, Horvat JC, Essilfie AT, Brown AC, Tooze M, et al., 'COPD is characterized by increased detection of Haemophilus influenzae, Streptococcus pneumoniae and a deficiency of Bacillus species', Respirology, 21 697-704 (2016) [C1]
Background and objective Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and inflammation. Airway bacterial colonization is increas... [more]
Background and objective Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and inflammation. Airway bacterial colonization is increased in COPD; however, the role of potentially pathogenic and non-pathogenic bacteria in the pathogenesis of disease is unclear. This study characterized the presence of bacteria in a well-characterized cohort of adults with COPD and healthy controls. Methods Adults with COPD (n = 70) and healthy controls (n = 51) underwent clinical assessment and sputum induction. Sputum was dispersed, and total and differential cell counts were performed. Bacteria were cultured, identified and enumerated. Supernatants were assessed for neutrophil elastase (NE) and IL-1ß. Common respiratory pathogens were also determined using real-time PCR. Results Participants with COPD had a typical neutrophilic inflammatory profile. The total load of bacteria was increased in COPD and was associated with poorer respiratory health status, as measured by the St George's Respiratory Questionnaire (Spearman's r = 0.336, P = 0.013). Significantly lower levels of culturable Bacillus species were identified compared with healthy controls. PCR analyses revealed increased rates of detection of potentially pathogenic bacteria with Haemophilus influenzae detection associated with higher sputum levels of NE and IL-1ß, while Streptococcus pneumoniae was more common in male ex-smokers with emphysema and a deficit in diffusion capacity. Conclusion Non-pathogenic and pathogenic bacteria were altered in the sputum of patients with COPD. These observations highlight the potential to identify treatment and management strategies that both target specific bacterial pathogens and restore the microbial balance, which may lead to reductions in inflammation and subsequent improvements in lung health.
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Nova |
2016 |
Sverrild A, Bergqvist A, Baines KJ, Porsbjerg C, Andersson CK, Thomsen SF, et al., 'Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation', Clinical and Experimental Allergy, 46 288-297 (2016) [C1]
Background: Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown ho... [more]
Background: Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. Methods: Airway hyperresponsiveness to inhaled mannitol was measured in 23 non-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. Results: The proportion of submucosal MCTC was higher in asthmatic individuals with AHR to mannitol compared with asthmatic individuals without AHR (median: 40.3% vs. 18.7%, P=0.03). Increased submucosal MCTC numbers were associated with increased levels of mRNA for thymic stromal lymphopoietin (TSLP) and CPA3 in asthmatics. Reactivity to mannitol correlated significantly with eosinophils in submucosa (r(s): 0.56, P=0.01). Conclusion: Airway hyperresponsiveness to inhaled mannitol is associated with an altered submucosal mast cell profile in asthmatic individuals. This mast cell profile is associated with increased levels of TSLP and CPA3. The degree of AHR to mannitol is correlated with the degree of eosinophilic inflammation in the airway submucosa.
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Nova |
2016 |
Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, et al., 'TNF-a and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease', Journal of Immunology, 196 3547-3558 (2016) [C1]
Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation... [more]
Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation, we established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation after allergen sensitization and challenge. RSV infection of OVA-sensitized/challenged BALB/c mice resulted in significantly increased airway hyperresponsiveness (AHR) and macrophage and neutrophil lung infiltration. Exacerbation was accompanied by increased levels of inflammatory cytokines (including TNF-a, MCP-1, and keratinocyte-derived protein chemokine [KC]) compared with uninfected OVA-treated mice or OVA-treated mice exposed to UV-inactivated RSV. Dexamethasone treatment completely inhibited all features of allergic disease, including AHR and eosinophil infiltration, in uninfected OVAsensitized/challenged mice. Conversely, dexamethasone treatment following RSV-induced exacerbation only partially suppressed AHR and failed to dampen macrophage and neutrophil infiltration or inflammatory cytokine production (TNF-a, MCP-1, and KC). This mimics clinical observations in patients with exacerbations, which is associated with increased neutrophils and often poorly responds to corticosteroid therapy. Interestingly, we also observed increased TNF-a levels in sputum samples from patients with neutrophilic asthma. Although RSV-induced exacerbation was resistant to steroid treatment, inhibition of TNF-a and MCP-1 function or depletion of macrophages suppressed features of disease, including AHR and macrophage and neutrophil infiltration. Our findings highlight critical roles for macrophages and inflammatory cytokines (including TNF-a and MCP-1) in viral-induced exacerbation of asthma and suggest examination of these pathways as novel therapeutic approaches for disease management.
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Nova |
2016 |
Wright TK, Gibson PG, Simpson JL, McDonald VM, Wood LG, Baines KJ, 'Neutrophil extracellular traps are associated with inflammation in chronic airway disease', Respirology, 21 467-475 (2016) [C1]
Background and objective Neutrophil extracellular traps (NETs) are web-like structures comprising DNA and antimicrobial proteins, expelled from neutrophils during NETosis. Persist... [more]
Background and objective Neutrophil extracellular traps (NETs) are web-like structures comprising DNA and antimicrobial proteins, expelled from neutrophils during NETosis. Persistence of NETs can be pro-inflammatory, yet their role in respiratory disease remains unclear. This study aimed to investigate the presence of NETs in sputum from patients with asthma and COPD, and the relationship of NETs with inflammatory phenotype and disease severity. Methods Induced sputum was collected from healthy controls, asthma and COPD patients. Extracellular DNA (eDNA) was quantified by PicoGreen. LL-37, a-defensins1-3, NE, IL-1ß and CXCL8 were quantified by ELISA. PAD4 and NLRP3 gene expression was performed using qPCR. NETs were imaged in sputum smears using immunofluorescence microscopy. Results Sputum eDNA and NET neutrophil antimicrobial proteins were significantly elevated in asthma and COPD compared with healthy controls. Levels of eDNA and NET components were significantly higher in neutrophilic versus non-neutrophilic asthma and COPD. NETs were clearly visualized in sputum smears. PAD4 mRNA was upregulated in neutrophilic COPD. The level of eDNA was higher in severe asthma. High eDNA levels were associated with heightened innate immune responses, including elevated CXCL8 and IL-1ß, and NLRP3 gene expression in both COPD and asthma. Antimicrobial proteins and eDNA were positively correlated with airway neutrophils, and negatively correlated with lung function and symptoms. Conclusion NETs are present in the airways of subjects with asthma and COPD. Accumulation of excessive NETs was associated with activation of innate immune responses contributing to disease pathogenesis in chronic airway disease.
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Nova |
2016 |
Tang FSM, Hansbro PM, Burgess JK, Ammit AJ, Baines KJ, Oliver BG, 'A novel immunomodulatory function of neutrophils on rhinovirus-Activated monocytes in vitro', Thorax, 71 1039-1049 (2016) [C1]
Background Rhinovirus (RV) infections are the major precipitant of asthma exacerbations. While neutrophilic lung inflammation occurs during such infections, its role remains uncle... [more]
Background Rhinovirus (RV) infections are the major precipitant of asthma exacerbations. While neutrophilic lung inflammation occurs during such infections, its role remains unclear. Neutrophilic inflammation is associated with increased asthma severity and steroid refractory disease. Neutrophils are vital for controlling infections but also have immunomodulatory functions. Previously, we found that neutrophils respond to viral mimetics but not replication competent RV. We aimed to investigate if neutrophils are activated and/or modulate immune responses of monocytes during RV16 infection. Methods Primary human monocytes and autologous neutrophils were cocultured with or without RV16, in direct contact or separated by transwells. RV16-stimulated monocytes were also exposed to lysed neutrophils, neutrophil membrane components or soluble neutrophil intracellular components. Interleukin 6 (IL-6) and C-X-C motif (CXC)L8 mRNA and proteins were measured by quantitative PCR and ELISA at 24â ¿..hours. Results RV16 induced IL-6 and CXCL8 in monocytes, but not neutrophils. RV16-induced IL-6 and CXCL8 from monocytes was reduced in the presence of live neutrophils. Transwell separation abolished the inhibitory effects. Lysed neutrophils inhibited RV16-induced IL-6 and CXCL8 from monocytes. Neutrophil intracellular components alone effectively inhibited RV16-induced monocyte-derived IL-6 and CXCL8. Neutrophil intracellular components reduced RV16-induced IL-6 and CXCL8 mRNA in monocytes. Conclusions Cell contact between monocytes and neutrophils is required, and preformed neutrophil mediator(s) are likely to be involved in the suppression of cytokine mRNA and protein production. This study demonstrates a novel regulatory function of neutrophils on RV-Activated monocytes in vitro, challenging the paradigm that neutrophils are predominantly proinflammatory.
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Nova |
2016 |
Backer V, Baines KJ, Powell H, Porsbjerg C, Gibson PG, 'Increased asthma and adipose tissue inflammatory gene expression with obesity and Inuit migration to a western country', Respiratory Medicine, 111 8-15 (2016) [C1]
Background An overlap between obesity and asthma exists, and inflammatory cells in adipose tissue could drive the development of asthma. Comparison of adipose tissue gene expressi... [more]
Background An overlap between obesity and asthma exists, and inflammatory cells in adipose tissue could drive the development of asthma. Comparison of adipose tissue gene expression among Inuit living in Greenland to those in Denmark provides an opportunity to assess how changes in adipose tissue inflammation can be modified by migration and diet. Objective To examine mast cell and inflammatory markers in adipose tissue and the association with asthma. Methods Two Inuit populations were recruited, one living in Greenland and another in Denmark. All underwent adipose subcutaneous biopsy, followed by clinical assessment of asthma, and measurement of AHR. Adipose tissue biopsies were homogenised, RNA extracted, and PCR was performed to determine the relative gene expression of mast cell (tryptase, chymase, CPA3) and inflammatory markers (IL-6, IL-1ß, and CD163). Results Of the 1059 Greenlandic Inuit participants, 556 were living in Greenland and 6.4% had asthma. Asthma was increased in Denmark (9%) compared to Greenland (3.6%, p < 0.0001) and associated with increased adipose tissue IL-6 gene expression and increased BMI. There was no association between asthma and adipose tissue mast cell gene expression. Pro-inflammatory gene expression (IL-6, IL-1ß) was higher in those living in Denmark, and with increasing BMI and dietary changes. The anti-inflammatory (M2) macrophage marker, CD163, was higher in Greenland-dwelling Inuit (p < 0.01). Conclusions No association was found between gene expression of mast cell markers in adipose tissue and asthma. Among Greenlandic Inuit, adipose tissue inflammation is also increased in those who migrate to Denmark, possibly as a result of dietary changes.
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Nova |
2016 |
Simpson JL, Daly J, Baines KJ, Yang IA, Upham JW, Reynolds PN, et al., 'Airway dysbiosis: Haemophilus influenza and Tropheryma in poorly controlled asthma', European Respiratory Journal, 47 792-800 (2016) [C1]
Asthma is a chronic inflammatory disorder of the airways where bacteria may act as protagonists of chronic inflammation. Little is known about the relation of airway inflammation ... [more]
Asthma is a chronic inflammatory disorder of the airways where bacteria may act as protagonists of chronic inflammation. Little is known about the relation of airway inflammation to the presence of specific bacterial taxa. We sought to describe the sputum microbiome in adults with poorly controlled asthma. DNA was extracted from induced sputum and microbial communities were profiled using 16S rRNA pyrosequencing. Bacterial species were characterised, and the relationship between microbial populations, asthma inflammatory subtypes and other covariates was explored. Real-time PCR was used to identify Tropheryma whipplei and Haemophilus influenzae in sputum. Adults with neutrophilic asthma had reduced bacterial diversity and species richness. Tropheryma was identified and confirmed with real-time PCR in 12 (40%) participants. Haemophilus occurred most often in a group of younger atopic males with an increased proportion of neutrophils. PCR confirmed the presence of H. influenzae in 35 (76%) participants with poorly controlled asthma. There are phenotype-specific alterations to the airway microbiome in asthma. Reduced bacterial diversity combined with a high prevalence of H. influenzae was observed in neutrophilic asthma, whereas eosinophilic asthma had abundant T. whipplei.
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Nova |
2016 |
Hodge S, Upham JW, Pizzutto S, Petsky HL, Yerkovich S, Baines KJ, et al., 'Is alveolar macrophage phagocytic dysfunction in children with protracted bacterial bronchitis a forerunner to bronchiectasis?', Chest, 149 508-515 (2016) [C1]
Background: Children with recurrent protracted bacterial bronchitis (PBB) and bronchiectasis share common features, and PBB is likely a forerunner to bronchiectasis. Both diseases... [more]
Background: Children with recurrent protracted bacterial bronchitis (PBB) and bronchiectasis share common features, and PBB is likely a forerunner to bronchiectasis. Both diseases are associated with neutrophilic inflammation and frequent isolation of potentially pathogenic microorganisms, including nontypeable Haemophilus influenzae (NTHi), from the lower airway. Defective alveolar macrophage phagocytosis of apoptotic bronchial epithelial cells (efferocytosis), as found in other chronic lung diseases, may also contribute to tissue damage and neutrophil persistence. Thus, in children with bronchiectasis or PBB and in control subjects, we quantified the phagocytosis of airway apoptotic cells and NTHi by alveolar macrophages and related the phagocytic capacity to clinical and airway inflammation. Methods: Children with bronchiectasis (n = 55) or PBB (n = 13) and control subjects (n = 13) were recruited. Alveolar macrophage phagocytosis, efferocytosis, and expression of phagocytic scavenger receptors were assessed by flow cytometry. Bronchoalveolar lavage fluid interleukin (IL) 1ß was measured by enzyme-linked immunosorbent assay. Results: For children with PBB or bronchiectasis, macrophage phagocytic capacity was significantly lower than for control subjects (P=.003 and P<.001 for efferocytosis and P=.041 and P = .004 for phagocytosis of NTHi; PBB and bronchiectasis, respectively); median phagocytosis of NTHi for the groups was as follows: bronchiectasis, 13.7% (interquartile range [IQR], 11%-16%); PBB, 16% (IQR, 11%-16%); control subjects, 19.0% (IQR, 13%-21%); and median efferocytosis for the groups was as follows: bronchiectasis, 14.1% (IQR, 10%-16%); PBB, 16.2% (IQR, 14%-17%); control subjects, 18.1% (IQR, 16%-21%). Mannose receptor expression was significantly reduced in the bronchiectasis group (P = .019), and IL-1ß increased in both bronchiectasis and PBB groups vs control subjects. Conclusions: A reduced alveolar macrophage phagocytic host response to apoptotic cells or NTHi may contribute to neutrophilic inflammation and NTHi colonization in both PBB and bronchiectasis. Whether this mechanism also contributes to the progression of PBB to bronchiectasis remains unknown.
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Nova |
2016 |
Negewo NA, McDonald VM, Baines KJ, Wark PAB, Simpson JL, Jones PW, Gibson PG, 'Peripheral blood eosinophils: A surrogate marker for airway eosinophilia in stable COPD', International Journal of COPD, 11 1495-1504 (2016) [C1]
Introduction: Sputum eosinophilia occurs in approximately one-third of stable chronic obstructive pulmonary disease (COPD) patients and can predict exacerbation risk and response ... [more]
Introduction: Sputum eosinophilia occurs in approximately one-third of stable chronic obstructive pulmonary disease (COPD) patients and can predict exacerbation risk and response to corticosteroid treatments. Sputum induction, however, requires expertise, may not always be successful, and does not provide point-of-care results. Easily applicable diagnostic markers that can predict sputum eosinophilia in stable COPD patients have the potential to progress COPD management. This study investigated the correlation and predictive relationship between peripheral blood and sputum eosinophils. It also examined the repeatability of blood eosinophil counts. Methods: Stable COPD patients (n=141) were classified as eosinophilic or noneosinophilic based on their sputum cell counts (=3%), and a cross-sectional analysis was conducted comparing their demographics, clinical characteristics, and blood cell counts. Receiver operating characteristic curve analysis was used to assess the predictive ability of blood eosinophils for sputum eosinophilia. Intraclass correlation coefficient was used to examine the repeatability of blood eosinophil counts. Results: Blood eosinophil counts were significantly higher in patients with sputum eosinophilia (n=45) compared to those without (0.3×109/L vs 0.15×109/L; P<0.0001). Blood eosinophils correlated with both the percentage (¿=0.535; P<0.0001) and number of sputum eosinophils (¿=0.473; P<0.0001). Absolute blood eosinophil count was predictive of sputum eosinophilia (area under the curve =0.76, 95% confidence interval [CI] =0.67¿0.84; P<0.0001). At a threshold of =0.3×109/L (specificity =76%, sensitivity =60%, and positive likelihood ratio =2.5), peripheral blood eosinophil counts enabled identification of the presence or absence of sputum eosinophilia in 71% of the cases. A threshold of =0.4×109/L had similar classifying ability but better specificity (91.7%) and higher positive likelihood ratio (3.7). In contrast, =0.2×109/L offered a better sensitivity (91.1%) for ruling out sputum eosinophilia. There was a good agreement between two measurements of blood eosinophil count over a median of 28 days (intraclass correlation coefficient =0.8; 95% CI =0.66¿0.88; P<0.0001). Conclusion: Peripheral blood eosinophil counts can help identify the presence or absence of sputum eosinophilia in stable COPD patients with a reasonable degree of accuracy.
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Nova |
2016 |
Williams EJ, Baines KJ, Smart JM, Gibson PG, Wood LG, 'Rosuvastatin, lycopene and omega-3 fatty acids: A potential treatment for systemic inflammation in COPD; a pilot study', Journal of Nutrition and Intermediary Metabolism, 5 86-95 (2016) [C1]
Background/Aims Chronic Obstructive Pulmonary Disease (COPD) is characterized by airway inflammation, in which contributes to loss of lung function. Systemic inflammation is also ... [more]
Background/Aims Chronic Obstructive Pulmonary Disease (COPD) is characterized by airway inflammation, in which contributes to loss of lung function. Systemic inflammation is also a feature of COPD contributing to many associated co-morbidities. Statins, omega-3 fatty acids (docosahexanoic acid, DHA and eicosapentanoic acid, EPA) and lycopene have been shown to decrease systemic inflammation; however their combined effects have not been investigated. This study aims to identify changes in systemic and airway inflammation induced by statins alone or in combination with DHA, EPA and lycopene in COPD. Methods COPD patients (n¿=¿11) received rosuvastatin (20¿mg/day) for 4 weeks, then a combination of rosuvastatin (20¿mg/day), DHA and EPA (1.5¿g/day) and lycopene (45¿mg/day) for 8 weeks. Blood and sputum were collected and lung function measured by spirometry at baseline, week 4 and 12. Plasma fatty acids were measured using gas chromatography, while plasma carotenoids were analysed using high-performance liquid chromatography. Plasma CRP and IL-6 concentrations were measured using ELISA; and peripheral blood gene expression was measured using the nCounter¿ GX Human Inflammation Kit 2. Results Following the interventions, clinical characteristics and plasma IL-6 and CRP were unchanged. Sputum neutrophil proportion and absolute count was increased and macrophage proportion decreased by rosuvastatin (P¿=¿0.020 and P¿=¿0.015; respectively). Rosuvastatin increased LTB4R and decreased CXCL10 and AGER gene expression in white blood cells. The addition of lycopene and omega-3 fatty acids decreased LTB4R and increased CXCL10 to basal levels, whilst combined use of interventions increased ALOX15 blood gene expression. Conclusion This study shows that rosuvastatin, omega-3 fatty acids and lycopene have some anti-inflammatory effects systemically, but rosuvastatin may increase airway neutrophils, which would be undesirable in COPD patients, warranting further investigation.
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Nova |
2016 |
Porsbjerg C, Baines K, Gibson P, Bergqvist A, Erjefält JS, Sverrild A, Backer V, 'IL-33 is related to innate immune activation and sensitization to HDM in mild steroid-free asthma', Clinical and Experimental Allergy, 46 564-574 (2016) [C1]
Summary: Background: IL-33 represents a potential link between the airway epithelium and induction of a Th2-type inflammatory response in asthma. However, the association with mar... [more]
Summary: Background: IL-33 represents a potential link between the airway epithelium and induction of a Th2-type inflammatory response in asthma. However, the association with markers of eosinophilic airway inflammation has not previously been reported in patients with steroid-free asthma. Aim: To describe the relationship between airway IL-33 and markers of eosinophilic airway inflammation, as well potential triggers of IL-33, in mild, steroid-free asthma. Methods: IL-33 mRNA expression and IL-33 immunoreactivity were measured in bronchial biopsies from patients with asthma untreated with inhaled steroids and healthy individuals. Furthermore, fractional exhaled nitric oxide (FeNO) and eosinophils in sputum and BAL were measured, as well as airway hyperresponsiveness to mannitol and methacholine. Epithelial integrity was assessed by computerized image analysis on haematoxylin-stained sections, and TLR mRNA expression by PCR. Results: A total of 23 patients with asthma and 10 healthy individuals were examined (age: 24 years (20-40); females: 53%). The level of IL-33 mRNA expression was significantly higher in patients with asthma compared to healthy individuals (Median (IQR) 1.12 (0.78) vs. 0.86, P = 0.04). There was a positive correlation between IL-33 mRNA expression and the level of FeNO (r = 0.56, P = 0.01), whereas there was no association with airway or blood eosinophils. IL-33 expression was unrelated to loss of epithelial integrity, but correlated with an increased expression of TLR2 and TLR4 (TLR2: = 0.47, P = 0.04; TLR4: 0.68, P < 0.001), as well allergy to house dust mites (HDMs). Conclusion: In mild untreated asthma, the expression of IL-33 mRNA in bronchial mucosa is related to innate immune activation and allergic sensitization to HDM, rather than epithelial damage, and correlates with FeNO. These findings suggest that in mild allergic asthma, IL-33 may represent a link between innate immune activation and FeNO production.
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Nova |
2015 |
Tang FSM, Foxley GJ, Gibson PG, Burgess JK, Baines KJ, Oliver BG, 'Altered Innate Immune Responses in Neutrophils from Patients with Well- and Suboptimally Controlled Asthma', Mediators of Inflammation, 2015 1-11 (2015) [C1]
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Nova |
2015 |
Scott HA, Latham JR, Callister R, Pretto JJ, Baines K, Saltos N, et al., 'Acute exercise is associated with reduced exhaled nitric oxide in physically inactive adults with asthma', Annals of Allergy, Asthma and Immunology, 114 470-479 (2015) [C1]
Background Although exercise has multiple health benefits, relatively little attention has been paid to its potential therapeutic effects in those with asthma. Objective To examin... [more]
Background Although exercise has multiple health benefits, relatively little attention has been paid to its potential therapeutic effects in those with asthma. Objective To examine the effects of acute exercise on inflammation in physically inactive and active adults with asthma. Methods Fourteen adults with asthma (n = 6 physically inactive, n = 8 physically active) completed (1) 30 minutes of moderate-intensity exercise on a treadmill and (2) 30 minutes of rest in random order, with 4 weeks between sessions. Exhaled nitric oxide (eNO) was measured before and after the intervention (0, 0.5, 1, 2, 4, and 24 hours). Blood inflammatory mediators were measured before and after the intervention (0, 2, and 24 hours). Results Physically inactive participants had a significant decrease in eNO 4 hours after exercise (-4.8 ppb, -6.4 to -0.5 ppb, P =.028), which was not observed in physically active participants (P =.362). Interluekin-1 receptor antagonist increased in the physically inactive group 2 hours after exercise, with this increase strongly correlated with the decrease in eNO at 4 hours (R = -0.685, P =.007) and 24 hours (R = -0.659, P =.014) after exercise. Interleukin-6 was increased significantly 2 hours after exercise in physically inactive participants. Blood neutrophils and nuclear factor erythroid 2-like 2 gene expression were increased 2 hours after exercise in the overall cohort. Conclusion This study demonstrates that acute moderate-intensity exercise is associated with decreased eNO in physically inactive adults with asthma and suggests that interluekin-1 receptor antagonist could have a role in mediating this effect. The attenuated response in physically active participants might be due to the sustained anti-inflammatory effects of exercise training. Future studies should investigate the impact of exercise intensity and exercise training on airway inflammation in those with asthma.
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Nova |
2015 |
Baines KJ, Backer V, Gibson PG, Powell H, Porsbjerg CM, 'Investigating the effects of arctic dietary intake on lung health', European Journal of Clinical Nutrition, 69 1262-1266 (2015) [C1]
Background/Objective:Preservation of lung health requires understanding the modifiable risk factors of airflow limitation. This study investigates the association between diet and... [more]
Background/Objective:Preservation of lung health requires understanding the modifiable risk factors of airflow limitation. This study investigates the association between diet and lung function in a population of Greenland Inuit residing in the Arctic (Greenland) or Western Europe (Denmark).Subjects/Methods:Two unselected Inuit populations were recruited, one living in Greenland (Urban (Nuuk) n=358; Rural (Uummannaq) n=207) and the other in Denmark (n=539). Lung function was measured using spirometry and diet by a food frequency questionnaire. Factors associated with airflow limitation were assessed using multiple linear regression models.Results:The dietary composition differed significantly in the two regions, with higher whale, seal and wild meat intake and lower fruit and vegetable intake in the Arctic regions compared with Denmark. Consumption of vegetables (P=0.004) and whale and/or seal (P<0.0001) was significantly and positively associated with FEV 1, as well as with FVC (vegetables: P=0.001, whale and/or seal: P=0.002). Regular fruit intake was included in the statistical models; however, it did not reach statistical significance (FEV 1: P=0.053; FVC: P=0.055).Conclusions:High dietary intake of vegetables as well as intake of arctic marine mammals had independent positive associations with lung function in this cohort of Greenlandic Inuit. These findings suggest an additive role of dietary intake of antioxidants and unsaturated fatty acids in lung health, which warrants prospective evaluation.
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Nova |
2015 |
Fu J-J, McDonald VM, Baines KJ, Gibson PG, 'Airway IL-1 beta and Systemic Inflammation as Predictors of Future Exacerbation Risk in Asthma and COPD', CHEST, 148 618-629 (2015) [C1]
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Nova |
2015 |
Hodge G, Upham JW, Chang AB, Baines KJ, Yerkovich ST, Pizzutto SJ, Hodge S, 'Increased Peripheral Blood Pro-Inflammatory/Cytotoxic Lymphocytes in Children with Bronchiectasis', PLOS ONE, 10 (2015) [C1]
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Nova |
2015 |
Bowden NA, Beveridge NJ, Ashton KA, Baines KJ, Scott RJ, 'Understanding xeroderma pigmentosum complementation groups using gene expression profiling after UV-light exposure', International Journal of Molecular Sciences, 16 15985-15996 (2015) [C1]
Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live bey... [more]
Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease.
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Nova |
2015 |
Gao P, Gibson PG, Baines KJ, Yang IA, Upham JW, Reynolds PN, et al., 'Anti-inflammatory deficiencies in neutrophilic asthma: Reduced galectin-3 and IL-1RA/IL-1ß', Respiratory Research, 16 1-10 (2015) [C1]
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Nova |
2015 |
Baines KJ, Wright TK, Simpson JL, McDonald VM, Wood LG, Parsons KS, et al., 'Airway beta-Defensin-1 Protein Is Elevated in COPD and Severe Asthma', MEDIATORS OF INFLAMMATION, 2015 (2015) [C1]
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Nova |
2014 |
Simpson JL, Powell H, Baines KJ, Milne D, Coxson HO, Hansbro PM, Gibson PG, 'The Effect of Azithromycin in Adults with Stable Neutrophilic COPD: A Double Blind Randomised, Placebo Controlled Trial', PLOS ONE, 9 (2014) [C1]
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Nova |
2014 |
Baines KJ, Upham JW, Yerkovich ST, Chang AB, Marchant JM, Carroll M, et al., 'Mediators of neutrophil function in children with protracted bacterial bronchitis', Chest, 146 1013-1020 (2014) [C1]
BACKGROUND: Protracted bacterial bronchitis (PBB) is a common and treatable cause of chronic wet cough in children in which the mechanisms are not understood. Th is study investig... [more]
BACKGROUND: Protracted bacterial bronchitis (PBB) is a common and treatable cause of chronic wet cough in children in which the mechanisms are not understood. Th is study investigates the IL-1 pathway and a neutrophil gene expression signature in PBB.
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Nova |
2014 |
Gunawardhana LP, Gibson PG, Simpson JL, Benton MC, Lea RA, Baines KJ, 'Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma.', Epigenetics, 9 1302-1316 (2014) [C1]
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Nova |
2014 |
Baines KJ, Backer V, Gibson PG, Powel H, Porsbjerg CM, 'Impaired lung function is associated with systemic inflammation and macrophage activation.', The European Respiratory Journal, 45 557-559 (2014) [C1]
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Nova |
2014 |
Simpson JL, Baines KJ, Ryan N, Gibson PG, 'Neutrophilic asthma is characterised by increased rhinosinusitis with sleep disturbance and GERD', Asian Pacific Journal of Allergy and Immunology, 32 66-74 (2014) [C1]
Background: Asthma is a heterogeneous inflammatory disease and eosinophilic, noneosinophilic and neutrophilic forms are recognised. While clinically similar to eosinophilic asthma... [more]
Background: Asthma is a heterogeneous inflammatory disease and eosinophilic, noneosinophilic and neutrophilic forms are recognised. While clinically similar to eosinophilic asthma, patients with non-eosinophilic asthma have different responses to treatment and little is known about the triggers of symptoms and inflammation. Objective: This study sought to characterise asthma control, exacerbation frequency and potential triggers of non-eosinophilic and specifically neutrophilic asthma such as infection, gastroesophageal reflux disease, and rhinosinusitis. Methods: Adults with asthma (n=65; doctor's diagnosis plus demonstrated response to bronchodilator and/or airways hyperresponsiveness to hypertonic saline) were recruited from the Respiratory and Sleep Medicine Ambulatory Care Service at John Hunter Hospital, NSW, Australia. Questionnaires were administered to assess gastroesophageal reflux disease, rhinosinusitis and asthma control. A sputum induction was performed and sputum was processed for assessment of inflammatory cells, infection, and lipid laden macrophages (Oil Red O). Results: Participants with neutrophilic asthma (n=11, 23%) had a higher frequency of primary care doctor visits for asthma exacerbations and a high prevalence (>70%) of chest infections in the previous 12 months. There was also an increased prevalence of rhinosinusitis (64%) and increased symptoms of gastroesophageal reflux disease compared to those with eosinophilic asthma. Conclusions: The clinical pattern of neutrophilic asthma is different from paucigranulocytic and eosinophilic asthma with evidence of abnormal upper airways responses. Specific and targeted treatment of these airway problems may assist in the control and management of neutrophilic asthma.
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Nova |
2014 |
Simpson JL, Phipps S, Baines KJ, Oreo KM, Gunawardhana L, Gibson PG, 'Elevated expression of the NLRP3 inflammasome in neutrophilic asthma', European Respiratory Journal, 43 1067-1076 (2014) [C1]
Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1ß is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation... [more]
Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1ß is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1ß requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1ß endotype associated with the nucleotide-binding domain, leucine-rich repeat-containing family protein (NLRP)3/apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)/caspase-1 inflammasome is characteristic of patients with the neutrophilic subtype of asthma. Participants with asthma (n=85) and healthy controls (n=27) underwent clinical assessment, spirometry and sputum induction. Sputum was processed for differential cell count, gene expression and protein mediators. NLRP3 and caspase-1 expression was also determined by immunocytochemistry. Sputum macrophages were isolated (n=8) and gene expression of NLRP3 and IL-1ß determined. There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1ß in participants with neutrophilic asthma. Protein levels of IL-1ß were significantly higher in those with neutrophilic asthma and correlated with sputum IL-8 levels. Sputum macrophages, as well as sputum neutrophils in neutrophilic asthma, expressed NLRP3 and caspase-1 protein. NLRP3 inflammasome is upregulated in neutrophilic asthma and may regulate the inflammation process observed in this asthma phenotype through production of IL-1ß. Copyright © ERS 2014.
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Nova |
2014 |
Murphy VE, Mattes J, Powell H, Baines KJ, Gibson PG, 'Respiratory viral infections in pregnant women with asthma are associated with wheezing in the first 12 months of life', Pediatric Allergy and Immunology, 25 151-158 (2014) [C1]
Background: There are few studies investigating the relationship between respiratory viral infection in pregnancy and asthma in the offspring, and none among mothers with asthma. ... [more]
Background: There are few studies investigating the relationship between respiratory viral infection in pregnancy and asthma in the offspring, and none among mothers with asthma. Infants of mothers with asthma are more likely to wheeze and have a higher risk of developing asthma than infants of non-asthmatic mothers. Methods: A prospective cohort study of viral infection in pregnancy was conducted between 2007 and 2009, and a subgroup of infants of mothers with asthma was followed up at 6 and 12 months of age. During common colds, nasal and throat swabs were collected from mothers and respiratory viruses detected by polymerase chain reaction. Respiratory health of infants was assessed by parent-completed questionnaire. Results: Twelve-month-old infants whose mothers had confirmed viral infections in pregnancy (n = 26) reported more frequent wheeze (40% had 4-12 wheeze attacks compared with 0%), sleep disturbed by wheeze (1 night per week or more in 60% vs. 11%), beta agonist treatment for wheeze (27% vs. 0%), prolonged colds (2 wk or longer 31% vs. 0%), more eczema (40% vs. 6.3%), and parent-perceived asthma (32% vs. 0%), compared with infants whose mothers had common colds without laboratory-confirmed viral infection (n = 16). Conclusions: This study demonstrates a relationship between maternal respiratory viral infection in pregnancy and wheezing illness in infants of mothers with asthma. Viral infections are the most common cause of asthma exacerbations in pregnancy, and infants of asthmatic mothers are at increased risk of asthma themselves. Further research is needed to elucidate the mechanisms involved. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Nova |
2014 |
Oreo KM, Gibson PG, Simpson JL, Wood LG, Mcdonald VM, Baines KJ, 'Sputum ADAM8 expression is increased in severe asthma and COPD', Clinical and Experimental Allergy, 44 342-352 (2014) [C1]
Background: Severe asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which the mechanisms are not fully understood. A disintegrin... [more]
Background: Severe asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which the mechanisms are not fully understood. A disintegrin and metalloproteinase domain 8 (ADAM8) is an enzyme expressed on most leucocytes and may be important for facilitating leucocyte migration in respiratory disease. Objective: To investigate ADAM8 mRNA and protein expression in asthma and COPD and its relationship between asthma severity and inflammatory phenotypes. Methods: Induced sputum was collected from 113 subjects with asthma (severe n = 31, uncontrolled n = 39 and controlled n = 35), 20 subjects with COPD and 21 healthy controls. Sputum ADAM8 mRNA expression was measured by qPCR, and soluble ADAM8 (sADAM8) protein was measured in the sputum supernatant by validated ELISA. Results: ADAM8 mRNA correlated with ADAM8 protein levels (r = 0.27, P < 0.01). ADAM8 mRNA (P = 0.004) and sADAM8 protein (P = 0.014) levels were significantly higher in both asthma and COPD compared with healthy controls. ADAM8 mRNA (P = 0.035) and sADAM8 protein (P = 0.002) levels were significantly higher in severe asthma compared with controlled asthma. Total inflammatory cell count (P < 0.01) and neutrophils (P < 0.01) were also elevated in severe asthmatic sputum. Although ADAM8 mRNA was significantly higher in eosinophilic and neutrophilic asthma (P < 0.001), sADAM8 did not differ between asthma inflammatory phenotypes. ADAM8 expression positively correlated with sputum total cell count and sputum neutrophils. Conclusions and Clinical Relevance: ADAM8 expression is increased in both severe asthma and COPD and associated with sputum total cell count and neutrophils. ADAM8 may facilitate neutrophil migration to the airways in severe asthma and COPD. © 2013 John Wiley & Sons Ltd.
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Nova |
2014 |
Gunawardhana LP, Gibson PG, Simpson JL, Powell H, Baines KJ, 'Activity and expression of histone acetylases and deacetylases in inflammatory phenotypes of asthma', Clinical & Experimental Allergy, 44 47-57 (2014) [C1]
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Nova |
2014 |
Baines KJ, Simpson JL, Wood LG, Scott RJ, Fibbens NL, Powell H, et al., 'Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes', Journal of Allergy and Clinical Immunology, 133 997-1007 (2014) [C1]
Background Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective This study aimed to identify and validate a sputu... [more]
Background Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. Methods An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. Results From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1ß (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P <.0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. Conclusions A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma. © 2013 American Academy of Allergy, Asthma & Immunology.
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Nova |
2014 |
Gunawardhana LP, Baines KJ, Mattes J, Murphy VE, Simpson JL, Gibson PG, 'Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy', Pediatric Pulmonology, 49 852-862 (2014) [C1]
Background Asthma is a complex disease that involves both genetic factors and environmental exposures. Aberrant epigenetic modifications, such as DNA methylation, may be important... [more]
Background Asthma is a complex disease that involves both genetic factors and environmental exposures. Aberrant epigenetic modifications, such as DNA methylation, may be important in asthma development. Fetal exposure to maternal asthma during critical periods of in utero development may lead to epigenetic alterations that predispose infants to a greater risk of developing asthma themselves. We investigated alterations in the DNA methylation profile of peripheral blood from infants exposed to maternal asthma during pregnancy. Methods Peripheral blood was collected from 12-month-old infants born to women with (n = 25) and without (n = 15) doctor diagnosed asthma during pregnancy. Genomic DNA was extracted, bisulfite converted, and hybridized to Infinium Methylation 27 arrays (Illumina), containing over27,000 CpGs from 14,495 genes. CpG loci in only autosomal genes were classified as differentially methylated at the 99% level (P < 0.01, |DiffScore| > 22 and delta beta >0.06). Results There were 70 CpG loci, corresponding to 67 genes that were significantly differentially methylated. Twelve CpG loci (11 genes) showed greater than 10% comparative difference in DNA methylation, including hyper-methylated loci of FAM181A, MRI1, PIWIL1, CHFR, DEFA1, MRPL28, AURKA, and hypo-methylated loci of NALP1L5, MAP8KIP3, ACAT2, and PM20D1 in maternal asthma. Methylation of MAPK8IP3 was significantly negatively correlated with maternal blood eosinophils (r = -0.38; P = 0.022), maternal eNO (r = -0.44; P = 0.005), and maternal serum total IgE (r = -0.39, P = 0.015). Methylation of AURKA negatively correlated with maternal hemoglobin (r = -0.43; P = 0.008), infants height (r = -0.51; P < 0.001) and weight (r = -0.36; P = 0.021). Methylation of PM20D1 was lower in infants born to mothers with asthma on inhaled corticosteroid treatment. Methylation of PM20D1 was lower and MRI1 was higher in infants born to atopic mothers without asthma. Conclusions In an Australian study population, exposure to maternal asthma during pregnancy is associated with differential methylation profiles of infants' peripheral blood DNA, which may act as risk factors for future asthma development. © 2013 Wiley Periodicals, Inc.
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2014 |
Baines KJ, Pavord ID, Gibson PG, 'The role of biomarkers in the management of airways disease.', Int J Tuberc Lung Dis, 18 1264-1268 (2014) [C1]
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Nova |
2013 |
Kaiko GE, Loh Z, Spann K, Lynch JP, Lalwani A, Zheng Z, et al., 'Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 131 1331-U132 (2013) [C1]
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Nova |
2013 |
Simpson JL, McDonald VM, Baines KJ, Oreo KM, Wang F, Hansbro PM, Gibson PG, 'Influence of Age, Past Smoking, and Disease Severity on TLR2, Neutrophilic Inflammation, and MMP-9 Levels in COPD', MEDIATORS OF INFLAMMATION, 2013 (2013) [C1]
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Nova |
2013 |
Baines KJ, Hsu AC-Y, Tooze M, Gunawardhana LP, Gibson PG, Wark PAB, 'Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD', RESPIRATORY RESEARCH, 14 (2013) [C1]
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Nova |
2013 |
Fu J-J, Baines KJ, Wood LG, Gibson PG, 'Systemic Inflammation Is Associated with Differential Gene Expression and Airway Neutrophilia in Asthma', OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY, 17 187-199 (2013) [C1]
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Nova |
2012 |
Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG, 'The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma', Chest, 142 86-93 (2012) [C1]
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Nova |
2011 |
Baines KJ, Simpson JL, Gibson PG, 'Innate immune responses are increased in chronic obstructive pulmonary disease', PLoS ONE, 36 (2011) [C1]
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Nova |
2011 |
Baines KJ, Simpson JL, Wood LG, Scott R, Gibson PG, 'Systemic upregulation of neutrophil a-defensins and serine proteases in neutrophilic asthma', Thorax, 66 942-947 (2011) [C1]
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Nova |
2011 |
Baines KJ, Simpson JL, Wood LG, Scott R, Gibson PG, 'Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples', Journal of Allergy and Clinical Immunology, 127 153.e9-160.e9 (2011) [C1]
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Nova |
2011 |
Wang F, He XY, Baines KJ, Gunawardhana LP, Simpson JL, Li F, Gibson PG, 'Different inflammatory phenotypes in adults and children with acute asthma', European Respiratory Journal, 38 567-574 (2011) [C1]
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Nova |
2010 |
Li J, Wang W, Baines KJ, Bowden NA, Hansbro PM, Gibson PG, et al., 'IL-27/IFN-y induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages', Journal of Immunology, 185 4401-4409 (2010) [C1]
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Nova |
2010 |
Baines KJ, Simpson JL, Bowden NA, Scott R, Gibson PG, 'Differential gene expression and cytokine production from neutrophils in asthma phenotypes', European Respiratory Journal, 35 522-531 (2010) [C1]
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Nova |
2009 |
Baines KJ, Wood LG, Gibson PG, 'The nutrigenomics of asthma: Molecular mechanisms of airway neutrophilia following dietary antioxidant withdrawal', OMICS: A Journal of Integrative Biology, 13 355-365 (2009) [C1]
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Nova |
2009 |
Baines KJ, Simpson JL, Scott R, Gibson PG, 'Immune responses of airway neutrophils are impaired in asthma', Experimental Lung Research, 35 554-569 (2009) [C1]
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Nova |
2009 |
Simpson JL, Baines KJ, Boyle MJ, Scott R, Gibson PG, 'Oncostatin M (OSM) is increased in asthma with incompletely reversible airflow obstruction', Experimental Lung Research, 35 781-794 (2009) [C1]
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Nova |