/manager/Index ${session.getAttribute("locale")} 5 Occupational exposures, smoking and airway inflammation in refractory asthma /manager/Repository/uon:19489 Wed 11 Apr 2018 16:22:13 AEST ]]> The effect of azithromycin in adults with stable neutrophilic COPD: a double blind randomised, placebo controlled trial /manager/Repository/uon:16827 Wed 11 Apr 2018 16:01:09 AEST ]]> Systemic inflammation in older adults with asthma-COPD overlap syndrome /manager/Repository/uon:20946 Wed 11 Apr 2018 15:38:18 AEST ]]> Periostin levels and eosinophilic inflammation in poorly-controlled asthma /manager/Repository/uon:24852 Wed 11 Apr 2018 15:27:07 AEST ]]> Galectin-3: its role in asthma and potential as an anti-inflammatory target /manager/Repository/uon:17053 Wed 11 Apr 2018 15:00:47 AEST ]]> Airway β-defensin-1 protein Is elevated in COPD and severe asthma /manager/Repository/uon:22673 Wed 11 Apr 2018 14:30:23 AEST ]]> Treatment burden, clinical outcomes, and comorbidities in COPD: an examination of the utility of medication regimen complexity index in COPD /manager/Repository/uon:30658 Wed 11 Apr 2018 14:14:35 AEST ]]> Peripheral blood eosinophils: a surrogate marker for airway eosinophilia in stable COPD /manager/Repository/uon:29745 9/L vs 0.15×109/L; P<0.0001). Blood eosinophils correlated with both the percentage (ρ=0.535; P<0.0001) and number of sputum eosinophils (ρ=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 ≥0.3×10/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.]]> Wed 11 Apr 2018 12:22:14 AEST ]]> Anti-inflammatory deficiencies in neutrophilic asthma: reduced galectin-3 and IL-1RA/IL-1β /manager/Repository/uon:27569 Wed 11 Apr 2018 11:56:33 AEST ]]> Haemophilus influenzae infection drives IL-17-mediated neutrophilic allergic airways disease /manager/Repository/uon:14153 Wed 11 Apr 2018 10:56:29 AEST ]]> Influence of age, past smoking, and disease severity on TLR2, neutrophilic inflammation, and MMP-9 levels in COPD /manager/Repository/uon:13988 Wed 11 Apr 2018 10:50:22 AEST ]]> Sputum colour can identify patients with neutrophilic inflammation in asthma /manager/Repository/uon:30796 60 years), whereas neutrophilic bronchitis (NB) was defined as high total cell count (=5.1×10 6 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 spu tum processing and differential cell count, which may facilitate asthma management.]]> Wed 11 Apr 2018 09:27:38 AEST ]]> Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy /manager/Repository/uon:17847  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.]]> Wed 04 Sep 2019 10:59:19 AEST ]]> The expression of IL-6, TNF-α and MCP-1 in respiratory viral infection in acute exacerbations of chronic obstructive pulmonary disease /manager/Repository/uon:34645 0.05). Additionally, VP patients were less likely to have received influenza vaccination. VP patients had a systemic inflammation response involving IL-6, TNF-µ, and MCP-1 which may be due to virus-induced activation of macrophages. There are important opportunities for further investigating AECOPD mechanisms and for the development of better strategies in the management and prevention of virus-related AECOPD.]]> Wed 04 Sep 2019 10:06:43 AEST ]]> Efficacy of azithromycin in severe asthma from the AMAZES randomised trial /manager/Repository/uon:37078 Tue 29 Sep 2020 11:48:51 AEST ]]> Older peoples' perception of tests used in the assessment and management of COPD and asthma /manager/Repository/uon:19319 55 years) with obstructive airway disease and healthy controls (N=56) underwent inhaler technique assessment, skin allergy testing, venepuncture, fractional exhaled nitric oxide (FENO) and gas diffusion measurement, exercise testing, sputum induction, and questionnaire assessment. They then completed an assessment burden questionnaire across five domains: difficulty, discomfort, pain, symptoms and test duration. Results: Test perception was generally favourable. Induced sputum had the greatest test burden perceived as being more difficult (mean 0.83, P=0.001), associated with more discomfort (mean 1.3, P<0.001), more painful (0.46, P=0.019), longer test duration (0.84, P<0.001) and worsening symptoms (0.55, P=0.001) than the questionnaires. FENO had a more favourable assessment but was assessed to be difficult to perform. Inhaler technique received the most favourable assessment. Conclusions: Older adults hold favourable perceptions to a range of tests that they might encounter in the course of their care for airway disease. The newer tests of sputum induction and FENO have some observed difficulties, in particular sputum induction. The results of this study can inform current practice by including details of the test and its associated adverse effects when conducting the test, as well as providing clear explanations of the utility of tests and how the results might aid in patient care.]]> Tue 26 Jun 2018 11:28:14 AEST ]]> Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients /manager/Repository/uon:34928 Tue 04 Jun 2019 14:03:19 AEST ]]> Inflammatory phenotypes in patients with severe asthma are associated with distinct airway microbiology /manager/Repository/uon:34787 Tue 03 Sep 2019 18:00:04 AEST ]]> Azithromycin treatment modifies airway and blood gene expression networks in neutrophilic COPD /manager/Repository/uon:36424 61% or >162x10⁴ cells per mL sputum neutrophils) were randomised to receive either azithromycin or placebo for 12 weeks. Sputum and blood were obtained before and after 12 weeks of treatment. Gene expression was defined using microarrays. Networks were analysed using the Search Tool for the Retrieval of Interacting Gene database. In sputum, 403 genes were differentially expressed following azithromycin treatment (171 downregulated and 232 upregulated), and three following placebo treatment (one downregulated and two upregulated) compared to baseline (adjusted p<0.05 by paired t-test, fold-change >1.5). In blood, 138 genes were differentially expressed with azithromycin (121 downregulated and 17 upregulated), and zero with placebo compared to baseline (adjusted p<0.05 by paired t-test, fold-change >1.3). Network analysis revealed one key network in both sputum (14 genes) and blood (46 genes), involving interferon-stimulated genes, human leukocyte antigens and genes regulating T-cell responses. Long-term, low-dose azithromycin is associated with downregulation of genes regulating antigen presentation, interferon and T-cell responses, and numerous inflammatory pathways in the airways and blood of neutrophilic COPD patients.]]> Thu 30 Apr 2020 12:50:04 AEST ]]> Dysregulation of sputum columnar epithelial cells and products in distinct asthma phenotypes /manager/Repository/uon:37118 Thu 20 Aug 2020 17:48:44 AEST ]]> Oncostatin M (OSM) is increased in asthma with incompletely reversible airflow obstruction /manager/Repository/uon:7293 Sat 24 Mar 2018 08:42:13 AEDT ]]> Immune responses of airway neutrophils are impaired in asthma /manager/Repository/uon:7208 Sat 24 Mar 2018 08:39:57 AEDT ]]> Assessment and reproducibility of non-eosinophilic asthma using induced sputum /manager/Repository/uon:7452 Sat 24 Mar 2018 08:38:47 AEDT ]]> Biology of neutrophils /manager/Repository/uon:8668 Sat 24 Mar 2018 08:38:44 AEDT ]]> Neutrophilic asthma has different radiographic features to COPD and smokers /manager/Repository/uon:7665 Sat 24 Mar 2018 08:36:00 AEDT ]]> Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis /manager/Repository/uon:8036 Sat 24 Mar 2018 08:35:05 AEDT ]]> Airway eosinophilia is associated with wheeze but is uncommon in children with persistent cough and frequent chest colds /manager/Repository/uon:1274 2.5%) was 45% in the wheeze group, which was significantly higher than the control group (9.35%, p = 0.04). Eosinophilic bronchitis was present in two children with cough (20%) and two with chest colds (15%, p > 0.05 versus control). In these groups, eosinophilic bronchitis was not associated with airway hyperresponsiveness (AHR) to hypertonic saline (p > 0.05). Children with cough and chest colds reported greater exposure to environmental tobacco smoke. In conclusion, this community-based survey of children with chronic respiratory symptoms has shown that wheeze is a good discriminator for the presence of eosinophilic bronchitis, and that persistent cough and recurrent chest colds without wheeze should not be considered a variant of asthma. Eosinophilic bronchitis did occur in a significant minority of these "variant asthma" syndromes.]]> Sat 24 Mar 2018 08:32:31 AEDT ]]> Induced sputum 8-isoprostane concentrations in inflammatory airway diseases /manager/Repository/uon:1603 Sat 24 Mar 2018 08:30:39 AEDT ]]> Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma /manager/Repository/uon:1628 99%) was inactivated (and bound to tissue inhibitor of metalloproteinase-1). In neutrophilic asthma, more subjects had NE activity (39%) compared with both healthy control subjects (0%), subjects with eosinophilic asthma (6%), or subjects with paucigranulocytic asthma (0%, p < 0.05). There were strong and consistent positive correlations between interleukin-8, neutrophils, and proteolytic enzymes. MMP-9 was inversely correlated with NE (r = –0.93). Conclusions: Proteolytic enzyme activity in asthma is dependent on the underlying inflammatory phenotype and is differentially regulated with MMP-9 activity a feature of eosinophilic inflammation, and active NE in neutrophilic inflammation.]]> Sat 24 Mar 2018 08:30:34 AEDT ]]> Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples /manager/Repository/uon:14184 1% predicted of 76%, and 69% were taking inhaled corticosteroids. Thirteen healthy controls without asthma were also assessed. Inflammatory cell counts were performed, and RNA was extracted from selected sputum. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by using GeneSpring GX11. Results: Unsupervised hierarchical clustering of gene expression profiles in asthma revealed 3 distinct groups. The first transcriptional phenotype (n = 21) had lower FEV1% predicted and higher asthma control questionnaire scores, exhaled nitric oxide, and sputum eosinophils. The second transcriptional phenotype (n = 14) had lower FEV1% predicted and forced vital capacity % predicted and higher sputum neutrophils compared with a third transcriptional phenotype (n = 24) that had higher sputum macrophages and resembled healthy controls. Differentially expressed genes between transcriptional asthma phenotypes were related to inflammatory and immune responses. Genes in the IL-1 and TNF-α/nuclear factor-κB pathways were overexpressed and correlated with clinical parameters and neutrophilic airway inflammation. Conclusion: Gene expression profiling provides a novel means to investigate the molecular mechanisms and classifications of asthma phenotypes. There are 3 distinct transcriptional phenotypes of asthma that relate to both clinical and inflammatory parameters.]]> Sat 24 Mar 2018 08:21:53 AEDT ]]> Inflammatory phenotypes in stable and acute childhood asthma /manager/Repository/uon:12346 Sat 24 Mar 2018 08:18:33 AEDT ]]> Identification of novel diagnostic biomarkers for asthma and chronic obstructive pulmonary disease /manager/Repository/uon:12974 Sat 24 Mar 2018 08:16:09 AEDT ]]> Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia /manager/Repository/uon:10440 106 cfu/mL) was cultured from the sputum of 17 (15%) subjects with stable asthma and was associated with higher total cell counts, proportion and number of neutrophils, sputum IL-8 and 8-isoprostane concentrations. The role of bacteria in potentiating neutrophilic asthma warrants further investigation. Therapies such as antibiotic and antioxidant treatment may be most effective in this sub-group of patients.]]> Sat 24 Mar 2018 08:13:16 AEDT ]]> Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes /manager/Repository/uon:20832 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.]]> Sat 24 Mar 2018 08:05:55 AEDT ]]> Mechanisms of cough /manager/Repository/uon:21447 Sat 24 Mar 2018 08:05:44 AEDT ]]> Relationship between airway neutrophilia and ageing in asthmatics and non-asthmatics /manager/Repository/uon:18993 95th percentile of non-asthmatic counts for any given age group) were significantly more likely to be asthmatic (odds ratio = 2.5; 95% CI: 1.3, 5.0), with the greatest effect observed in the older age group. Other factors that independently associated with increased sputum neutrophil levels included atopy in non-asthmatic adults, male gender and current use of ICS in asthmatic adults. Age-specific reference values for neutrophil percentage were under 20 years-76%, 20–40 years-62%, 40–60 years-63% and over 60 years-67%. Conclusions: Airway neutrophilia is related to age in adults, with a neutrophilic asthma phenotype present in older adults. The use of appropriate age-specific reference values is recommended for future studies aimed at elucidating the role of neutrophils in asthma.]]> Sat 24 Mar 2018 08:05:37 AEDT ]]> Elevated expression of the NLRP3 inflammasome in neutrophilic asthma /manager/Repository/uon:17510 Sat 24 Mar 2018 08:04:13 AEDT ]]> Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice /manager/Repository/uon:20102 Sat 24 Mar 2018 08:00:09 AEDT ]]> Combined haemophilus influenzae respiratory infection and allergic airways disease drives chronic infection and features of neutrophilic asthma /manager/Repository/uon:21800 Haemophilus influenzae is one of the most commonly isolated bacteria. The relationship between chronic airway colonisation and the development of steroid-resistant neutrophilic asthma is unclear. Objectives: To investigate the relationship between H influenzae respiratory infection and neutrophilic asthma using mouse models of infection and ovalbumin (OVA)-induced allergic airways disease. Methods: BALB/c mice were intratracheally infected with H influenzae (day 10), intraperitoneally sensitised (day 0) and intranasally challenged (day 12–15) with OVA. Treatment groups were administered dexamethasone intranasally during OVA challenge. Infection, allergic airways disease, steroid sensitivity and immune responses were assessed (days 11, 16 and 21). Results: The combination of H influenzae infection and allergic airways disease resulted in chronic lung infection that was detected on days 11, 16 and 21 (21, 26 and 31 days after infection). Neutrophilic allergic airways disease and T helper 17 cell development were induced, which did not require active infection. Importantly, all features of neutrophilic allergic airways disease were steroid resistant. Toll-like receptor 4 expression and activation of phagocytes was reduced, but most significantly the influx and/or development of phagocytosing neutrophils and macrophages into the airways was inhibited. Conclusions: The combination of infection and allergic airways disease promotes bacterial persistence, leading to the development of a phenotype similar to steroid-resistant neutrophilic asthma and which may result from dysfunction in innate immune cells. This indicates that targeting bacterial infection in steroid-resistant asthma may have therapeutic benefit.]]> Sat 24 Mar 2018 07:59:21 AEDT ]]> Systemic upregulation of neutrophil α-defensins and serine proteases in neutrophilic asthma /manager/Repository/uon:17886 Sat 24 Mar 2018 07:56:18 AEDT ]]> Multidimensional assessment of older people with asthma and COPD: clinical management and health status /manager/Repository/uon:17917 55 years) (n = 100) with an OAD underwent a multidimensional assessment (MDA) involving questionnaires, clinical assessments, physiological measurements and biomarkers. Results: the assessment identified a mean (SD) of 11.3 (2.5) clinical management issues and 3.1 (1.8) comorbid conditions per participant. Common problems were: airways hyper-responsiveness (80%); airway inflammation (74%); activity limitation (74%) and systemic inflammation (60.5%). The number and type of issues were similar irrespective of a diagnosis of asthma or COPD (P = 0.2). The degree of health status impairment correlated significantly with the number of clinical management issues detected (r = 0.59; P < 0.0001). Conclusions: older people with OAD experience multiple clinical issues that adversely impact their health status. The number and type are similar irrespective of diagnosis. This MDA identifies significant clinical issues that may not be addressed in a diagnosis centred approach suggesting that a multidisciplinary approach is necessary when assessing and managing older people with OAD.]]> Sat 24 Mar 2018 07:56:15 AEDT ]]> Longitudinal changes in clinical outcomes in older patients with asthma, COPD and asthma-COPD overlap syndrome /manager/Repository/uon:19123 55 years) with OADs who underwent a multidimensional assessment at baseline and 4 years which involved spirometry, 6-min walk distance (6MWD), assessments of health status (Saint George's Respiratory Questionnaire, SGRQ), comorbidity, and serum and sputum biomarkers. All-cause mortality and respiratory hospitalisation during the follow-up period were recorded. Clinical outcomes were compared between basal and final visits, and changes in clinical outcomes were compared among asthma, COPD and asthma-COPD overlap groups. Associations between clinical parameters, biomarkers and prognosis were examined. Results: After a median follow-up of 4.2 years, outcome data were available for 75 (75.8%) patients. There were 16 (16.2%) deaths. The BODE index predicted all-cause mortality in older people with OADs. While spirometry, 6MWD and SGRQ deteriorated significantly over the 4 years, there was significant heterogeneity in the longitudinal changes in these clinical outcomes. Participants with COPD had a significant decline in FEV1 (p = 0.003), SGRQ (p = 0.030) and 6MWD [decline of 75.5 (93.4) m, p = 0.024]. The change in 6MWD was lower in the asthma-COPD overlap group. Airflow reversibility was associated with a reduced decline in 6MWD. Conclusion: COPD patients had a poor prognosis compared with asthma and asthma-COPD overlap patients. The BODE index is a useful prognostic indicator in older adults with OADs. Both airway disease diagnosis and BODE index warrant specific attention in clinical practice.]]> Sat 24 Mar 2018 07:55:56 AEDT ]]> Mediators of neutrophil function in children with protracted bacterial bronchitis /manager/Repository/uon:20295 Sat 24 Mar 2018 07:55:14 AEDT ]]> Neutrophilic asthma is characterised by increased rhinosinusitis with sleep disturbance and GERD /manager/Repository/uon:21276 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.]]> Sat 24 Mar 2018 07:54:40 AEDT ]]> Altered sputum granzyme B and granzyme B/proteinase inhibitor-9 in patients with non-eosinophilic asthma /manager/Repository/uon:21345 n = 10), and patients with NEA (n = 22) or eosinophilic asthma (EA) (n = 15) using flow cytometry. Results: Granzyme B expression and the ratio of granzyme B to PI-9 positive cells were highest in those with NEA for both CD3+ and CD4+ T cells. The expression of granzyme B was not statistically different between patients with NEA and EA; however, the ratio of granzyme B to PI-9 positive cells for CD3+ T cells was significantly higher in those with NEA compared with EA. Conclusions: Induced sputum provides a non-invasive tool for investigating T cell cytotoxic mediators in the various asthma subtypes. Granzyme B expression is increased in NEA and the contribution of granzyme B to chronic inflammation requires further study.]]> Sat 24 Mar 2018 07:51:24 AEDT ]]> Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma. /manager/Repository/uon:18790 Sat 24 Mar 2018 07:51:07 AEDT ]]> Innate immunity in asthma /manager/Repository/uon:5103 Sat 24 Mar 2018 07:48:49 AEDT ]]> The role of exhaled nitric oxide and exhaled breath condensates in evaluating airway inflammation in asthma /manager/Repository/uon:5383 Sat 24 Mar 2018 07:43:54 AEDT ]]> Absence of airway inflammation in a large proportion of adolescents with asthma /manager/Repository/uon:26123 Sat 24 Mar 2018 07:41:07 AEDT ]]> Reduced antiviral interferon production in poorly controlled asthma is associated with neutrophilic inflammation and high-dose inhaled corticosteroids /manager/Repository/uon:26090 Sat 24 Mar 2018 07:39:55 AEDT ]]> Is alveolar macrophage phagocytic dysfunction in children with protracted bacterial bronchitis a forerunner to bronchiectasis? /manager/Repository/uon:29360 Sat 24 Mar 2018 07:34:17 AEDT ]]> Oxidized vitamin E and glutathione as markers of clinical status in asthma /manager/Repository/uon:4850 Sat 24 Mar 2018 07:18:52 AEDT ]]> Clarithromycin targets neutrophilic airway inflammation in refractory asthma /manager/Repository/uon:4857 Sat 24 Mar 2018 07:18:49 AEDT ]]> Neutrophil extracellular traps are associated with inflammation in chronic airway disease /manager/Repository/uon:24433 Sat 24 Mar 2018 07:17:20 AEDT ]]> Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma /manager/Repository/uon:22009 Chlamydia and Haemophilus lung infection-induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment. Results: Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor a and interleukin 17 responses that induce SSIAAD. Conclusions: Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD.]]> Sat 24 Mar 2018 07:15:55 AEDT ]]> Airway dysbiosis: Haemophilus influenza and Tropheryma in poorly controlled asthma /manager/Repository/uon:24324 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.]]> Sat 24 Mar 2018 07:14:41 AEDT ]]> Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma /manager/Repository/uon:24323 T (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.]]> Sat 24 Mar 2018 07:14:40 AEDT ]]> TNF-α and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease /manager/Repository/uon:24758 Sat 24 Mar 2018 07:14:04 AEDT ]]> The role of lower airway dysbiosis in asthma: dysbiosis and asthma /manager/Repository/uon:32243 Mon 23 Sep 2019 11:29:32 AEST ]]> COPD is characterized by increased detection of Haemophilus influenzae, Streptococcus pneumoniae and a deficiency of Bacillus species /manager/Repository/uon:21992 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-1β, 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.]]> Mon 15 Aug 2016 09:18:51 AEST ]]> Multiple inflammasomes may regulate the interleukin-1-driven inflammation in protracted bacterial bronchitis /manager/Repository/uon:32993 Haemophilus influenzae (NTHi). The mechanisms responsible for IL-1-driven inflammation in PBB are poorly understood. We hypothesised that the inflammation in PBB involves the NLRP3 and/or AIM2 inflammasome/IL-1ß axis. Lung macrophages obtained from bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMCs), blood monocytes and monocyte-derived macrophages from patients with PBB and age-matched healthy controls were cultured in control medium or exposed to live NTHi. In healthy adult PBMCs, CD14⁺ monocytes contributed to 95% of total IL-1ß-producing cells upon NTHi stimulation. Stimulation of PBB PBMCs with NTHi significantly increased IL-1ß expression (p<0.001), but decreased NLRC4 expression (p<0.01). NTHi induced IL-1ß secretion in PBMCs from both healthy controls and patients with recurrent PBB. This was inhibited by Z-YVAD-FMK (a caspase-1 selective inhibitor) and by MCC950 (a NLRP3 selective inhibitor). In PBB BAL macrophages inflammasome complexes were visualised as fluorescence specks of NLRP3 or AIM2 colocalised with cleaved caspase-1 and cleaved IL-1ß. NTHi stimulation induced formation of specks of cleaved IL-1ß, NLRP3 and AIM2 in PBMCs, blood monocytes and monocyte-derived macrophages. We conclude that both the NLRP3 and AIM2 inflammasomes probably drive the IL-1ß-dominated inflammation in PBB.]]> Mon 08 Jul 2019 11:29:52 AEST ]]> A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma /manager/Repository/uon:36051 Fri 31 Jan 2020 16:36:12 AEDT ]]> Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial /manager/Repository/uon:33089 Fri 24 Aug 2018 16:46:54 AEST ]]> Mechanisms and treatments for severe, steroid-resistant allergic airway disease and asthma /manager/Repository/uon:33083 Fri 24 Aug 2018 15:43:56 AEST ]]> Role for NLRP3 inflammasome-mediated, IL-1ß-dependent responses in severe, steroid-resistant asthma /manager/Repository/uon:33076 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.]]> Fri 24 Aug 2018 14:40:56 AEST ]]> Blood neutrophils in COPD but not asthma exhibit a primed phenotype with downregulated CD62L expression /manager/Repository/uon:36433 + 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 x 109/L, respectively), in comparison with healthy (3.54% and 0.12 x 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]]> Fri 01 May 2020 15:05:04 AEST ]]> Hypersegmented airway neutrophils and its association with reduced lung function in adults with obstructive airway disease: an exploratory study /manager/Repository/uon:36434 4 lobes), normal (2-4 lobes) and banded (1 lobe) neutrophils and enumerated. Results: Neutrophils from each subset were identified in all participants. Numbers of hypersegmented neutrophils were elevated in participants with airway disease compared with healthy controls (p<0.001). Both the number and the proportion of hypersegmented neutrophils were highest in COPD participants (median (Q1-Q3) of 1073.6 (258.8-2742) x 10 2/mL and 24.5 (14.0-46.5)%, respectively). An increased proportion of hypersegmented neutrophils in airway disease participants was significantly associated with lower forced expiratory volume in 1 s/forced vital capacity per cent (Spearman's r=-0.322, p=0.004). Conclusion: Neutrophil heterogeneity is common in BL and is associated with more severe airflow obstruction in adults with airway disease. Further work is required to elucidate the functional consequences of hypersegmented neutrophils in the pathogenesis of disease.]]> Fri 01 May 2020 15:05:04 AEST ]]>