https://ogma.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48718 Wed 29 Mar 2023 16:01:20 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53093 Wed 28 Feb 2024 16:21:51 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45003 n = 19), including 7 with NEA and healthy controls (n = 10) underwent a clinical assessment, venepuncture and sputum induction. MDMs were co-cultured with apoptotic granulocytes isolated from healthy donors with or without exogenous recombinant galectin-3 (50 μg/mL) and efferocytosis was assessed by flow cytometry. Galectin-3 expression and localisation in MDMs was visualised by immunofluorescence staining and fluorescence microscopy. Galectin-3, interleukin (IL)-6 and CXCL8 secretion were measured in cell culture supernatants by ELISA and cytometric bead array. Results: Baseline efferocytosis (mean (±standard deviation)) was lower in participants with asthma (33.2 (±17.7)%) compared with healthy controls (45.3 (±15.9)%; p = 0.081). Efferocytosis did not differ between the participants with eosinophilic asthma (EA) (31.4 (±19.2)%) and NEA (28.7 (±21.5)%; p = 0.748). Addition of galectin-3 significantly improved efferocytosis in asthma, particularly in NEA (37.8 (±18.1)%) compared with baseline (30.4 (±19.7)%; p = 0.012). Efferocytosis was not associated with any of the clinical outcomes but was negatively correlated with sputum macrophage numbers (Spearman r = − 0.671; p = 0.017). Galectin-3 was diffusely distributed in most MDMs but formed punctate structures in 5% of MDMs. MDM galectin-3 secretion was lower in asthma (9.99 (2.67, 15.48) ng/mL) compared with the healthy controls (20.72 (11.28, 27.89) ng/mL; p = 0.044) while IL-6 and CXCL8 levels were similar. Conclusions: Galectin-3 modulates macrophage function in asthma, indicating a potential role for galectin-3 to reverse impaired efferocytosis in NEA.]]> Wed 26 Oct 2022 09:42:24 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:24139 Wed 24 Nov 2021 15:51:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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.]]> Wed 17 Nov 2021 16:31:05 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:24377 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.]]> Wed 17 Nov 2021 16:29:16 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47060 Wed 13 Mar 2024 08:04:20 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:16827 Wed 11 Apr 2018 16:01:09 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22587 0.75, n=7), and healthy controls (HC) (n=9) were stimulated with bacterial (LPS (1 g/mL), fMLF (100 nM)), and viral (imiquimod (3 g/mL), R848 (1.5 g/mL), and poly I:C (10 g/mL)) surrogates or live rhinovirus (RV) 16 (MOI1). Cell-free supernatant was collected after 1 h for neutrophil elastase (NE) and matrix metalloproteinase- (MMP-) 9 measurements or after 24 h for CXCL8 release. Results: Constitutive NE was enhanced in AGood neutrophils compared to HC. fMLF stimulated neutrophils from ASubopt but not AGood produced 50% of HC levels. fMLF induced MMP-9 was impaired in ASubopt and AGood compared to HC. fMLF stimulated CXCL8 but not MMP-9 was positively correlated with FEV1 and FEV1/FVC. ASubopt and AGood responded similarly to other stimuli. Conclusions: Circulating neutrophils are different in asthma; however, this is likely to be related to airflow limitation rather than asthma control.]]> Wed 11 Apr 2018 14:23:49 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20527 Wed 11 Apr 2018 13:11:00 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:25075 Wed 11 Apr 2018 12:27:25 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27569 Wed 11 Apr 2018 11:56:33 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14144 Wed 11 Apr 2018 11:35:52 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14773 Wed 11 Apr 2018 11:04:31 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:13988 Wed 11 Apr 2018 10:50:22 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /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 CD62L^bright/CD16^dim 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]]> Wed 10 Nov 2021 15:05:07 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54659 Wed 10 Apr 2024 09:45:50 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /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 09 Mar 2022 16:04:19 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:32913 Wed 09 Mar 2022 16:01:55 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:24323 T (n=18) and MC_T/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 MC_T/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 MC_T/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 MC_T/CPA3 subtype demonstrated increased bronchial sensitivity and reactivity, and signature gene expression, which was associated with airway eosinophilia and greater corticosteroid responsiveness.]]> Wed 09 Mar 2022 15:59:02 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:24433 Wed 09 Feb 2022 15:59:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45666 Wed 02 Nov 2022 15:59:10 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:26567 TM 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.]]> Wed 02 Mar 2022 14:27:20 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44806 Wed 01 May 2024 12:05:04 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49760 Tue 30 May 2023 18:39:10 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43636 Tue 27 Sep 2022 09:39:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39820 Tue 26 Jul 2022 11:33:21 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49105 Tue 14 Nov 2023 14:40:06 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34928 Tue 04 Jun 2019 14:03:19 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36051 Thu 28 Oct 2021 13:04:53 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:31397 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]]> Thu 28 Oct 2021 13:03:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:32992 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, ho wever 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.]]> Thu 28 Oct 2021 13:03:20 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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.]]> Thu 28 Oct 2021 13:02:17 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:25846 Thu 28 Oct 2021 12:37:11 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45375 Thu 27 Oct 2022 16:54:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45086 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 (Δmedian [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^-ΔCt, 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.]]> Thu 27 Oct 2022 14:06:45 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45337 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.]]> Thu 27 Oct 2022 10:46:43 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29360 Thu 27 Jan 2022 15:58:57 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46113 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.]]> Thu 18 Apr 2024 11:56:00 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /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.]]> Thu 17 Feb 2022 09:29:13 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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.]]> Thu 13 Jan 2022 10:29:04 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48843 ±2) including genes associated with innate immunity response, neutrophil degranulation and IL-10 signalling. NA presented enrichment to pathways previously linked to neutrophilic inflammation; dendritic cell maturation, Th1, TREM1, inflammasome, Th17 and p38 MAPK, as well as novel links to neuroinflammation, NFAT and PKCθ signalling. EA presented similar transcriptomic profiles to PGA and HC. Despite the higher proportion of bacterial colonization in NA, no changes were observed in the transcriptomic profiles of severe asthma culture positive compared with severe asthma culture negative. Conclusions & Clinical Relevance: NA features a distinct transcriptomic profile with seven pathways enriched in NA compared to EA, PGA and HC. All those with severe asthma had significant enrichment for SUMOylation, basal cell carcinoma signalling and Wnt/β-catenin pathways compared to HC, despite high-dose inhaled corticosteroids. These findings contribute to the understanding of mechanistic pathways in endobronchial biopsies associated with NA and identify potential novel treatment targets for severe asthma.]]> Thu 13 Apr 2023 09:45:44 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49306 Thu 11 May 2023 14:32:33 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30756 Thu 03 Feb 2022 12:22:32 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:7293 Sat 24 Mar 2018 08:42:13 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:7715 10% change in sputum neutrophils using Illumina Humanref-8 expression microarrays. There were 104 genes differentially expressed following the dietary change. Upregulated genes were involved in the innate immune response and included the innate immune receptors TLR2, IL1R2, CD93, the signaling molecules IRAK2, IRAK3, and neutrophil proteases MMP25 and CPD. Downregulated genes included those involved in endogenous antioxidant defenses (GSTA1, GSTA2) and protease inhibition (SLPI, SERPINB3). Altered expression of five genes (TLR2, IRAK2, IL1R2, C20orf114, and SERPINB3) was confirmed using real-time polymerase chain reaction (PCR). These observations suggest that depletion of dietary antioxidants in asthma may result in upregulation of genes involved in the innate immune response. A diet low in antioxidants may be contributing to the development of neutrophilic asthma through activation of the innate immune response.]]> Sat 24 Mar 2018 08:41:39 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:7208 Sat 24 Mar 2018 08:39:57 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:8668 Sat 24 Mar 2018 08:38:44 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:11518 Sat 24 Mar 2018 08:10:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:16941 10CRP. Sex, BMI, and %FEV₁ were significant predictors of log₁₀IL-6. Conclusions: Systemic inflammation is increased in patients with asthma with neutrophilic airway inflammation and associated with worse clinical outcomes. Systemic inflammation may contribute to the pathophysiology of neutrophilic asthma.]]> Sat 24 Mar 2018 08:05:31 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17510 Sat 24 Mar 2018 08:04:13 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20102 Sat 24 Mar 2018 08:00:09 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19962 Sat 24 Mar 2018 07:58:34 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17886 Sat 24 Mar 2018 07:56:18 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20295 Sat 24 Mar 2018 07:55:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:18790 Sat 24 Mar 2018 07:51:07 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:28998 Sat 24 Mar 2018 07:29:24 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:24758 Sat 24 Mar 2018 07:14:04 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:23391 Sat 24 Mar 2018 07:13:56 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48193 Sat 11 Mar 2023 12:30:04 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47276 Mon 27 Mar 2023 13:58:24 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39780 Mon 25 Jul 2022 11:26:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:32658 Mon 23 Sep 2019 11:23:10 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46104 adj = 9.6, 95% CI: 1.8–50.1) and the presence of Haemophilus influenzae in the BAL (OR_adj = 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 (OR_adj = 14.8, 95% CI: 2.2–100.8) at baseline and bronchomalacia (OR_adj = 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.]]> Mon 21 Nov 2022 09:17:31 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50981 Mon 14 Aug 2023 15:39:12 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44178 Mon 10 Oct 2022 10:20:29 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33965 Fri 25 Jan 2019 14:42:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34249 Fri 22 Feb 2019 16:55:30 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49427 Fri 12 May 2023 15:16:07 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46163 Fri 11 Nov 2022 19:34:08 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46094 1 and FVC. Trends towards similar clinical associations with elevated MCs were observed in a paucigranulocytic subpopulation (n = 15) lacking airway eosinophilia or neutrophilia. Receiver operator characteristic (ROC) analysis showed peripheral blood eosinophil (PBE) count predicted elevated sputum eosinophils and basophils, but not MCs. Conclusions and Clinical Relevance: Sputum MCs are elevated in asthma, and their measurement may be useful as they relate to key clinical features of asthma (spirometry, asthma control, AHR). PBE count did not predict airway MC status, suggesting direct measurement of airway MCs by sensitive methods such as flow cytometry should be further developed.]]> Fri 11 Nov 2022 11:01:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22673 Fri 11 Jun 2021 13:31:32 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38377 Fri 10 Sep 2021 12:38:35 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30780 Fri 03 Dec 2021 10:34:35 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37118 Fri 03 Dec 2021 10:32:20 AEDT ]]>