Publications by authors named "Brian G Oliver"

164 Publications

Airway smooth muscle cells from severe asthma patients with fixed airflow obstruction are responsive to steroid and bronchodilator treatment .

ERJ Open Res 2021 Apr 31;7(2). Epub 2021 May 31.

Airway Physiology and Imaging Group, Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia.

https://bit.ly/3muvNsW.
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http://dx.doi.org/10.1183/23120541.00117-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165371PMC
April 2021

Particulate Matter, an Intrauterine Toxin Affecting Foetal Development and Beyond.

Antioxidants (Basel) 2021 May 6;10(5). Epub 2021 May 6.

Renal Research Laboratory, Kolling Institute of Medical Research, Sydney, NSW 2065, Australia.

Air pollution is the 9th cause of the overall disease burden globally. The solid component in the polluted air, particulate matters (PMs) with a diameter of 2.5 μm or smaller (PM) possess a significant health risk to several organ systems. PM has also been shown to cross the blood-placental barrier and circulate in foetal blood. Therefore, it is considered an intrauterine environmental toxin. Exposure to PM during the perinatal period, when the foetus is particularly susceptible to developmental defects, has been shown to reduce birth weight and cause preterm birth, with an increase in adult disease susceptibility in the offspring. However, few studies have thoroughly studied the health outcome of foetuses due to intrauterine exposure and the underlying mechanisms. This perspective summarises currently available evidence, which suggests that intrauterine exposure to PM promotes oxidative stress and inflammation in a similar manner as occurs in response to direct PM exposure. Oxidative stress and inflammation are likely to be the common mechanisms underlying the dysfunction of multiple systems, offering potential targets for preventative strategies in pregnant mothers for an optimal foetal outcome.
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http://dx.doi.org/10.3390/antiox10050732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148178PMC
May 2021

Total IgE Variability Is Associated with Future Asthma Exacerbations: A 1-Year Prospective Cohort Study.

J Allergy Clin Immunol Pract 2021 May 12. Epub 2021 May 12.

Airway Physiology and Imaging Group and Woolcock Emphysema Centre, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia; Discipline of Medical Sciences, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Background: Few prospective studies have investigated the relationship between IgE variability and risk for asthma exacerbations (AEs).

Objective: To explore the relationship between IgE variability and AEs.

Methods: Recruited patients with stable asthma underwent two serum total IgE tests within a month (at screening [baseline IgE] and at 1 month) to obtain the coefficient of variation (CV) of base 10 log-transformed IgE. Patients with IgE CV were divided into IgE CV-high and IgE CV-low cohorts based on the CV median and were observed within 12 months, during which the association between IgE variability and AEs was explored using a negative binomial regression model.

Results: The IgE CV levels obtained from 340 patients classified patients into two groups (n = 170 for the IgE CV-high and IgE CV-low groups, respectively) based on the serum total IgE CV median of 2.12% (quartiles 1 and 3: 0.98% and 3.91%, respectively). The IgE CV-high patients exhibited worse asthma control and lung function and more marked airway inflammation, and received more intensive medication use compared with IgE CV-low patients. The IgE CV-high patients exhibited increased rates of moderate-to-severe (adjusted rate ratio = 2.88; 95% confidence interval, 1.65-5.03; P < .001) and severe (adjusted rate ratio = 2.16; 95% confidence interval, 1.08-4.32; P = .029) AEs during the follow-up year compared with IgE CV-low patients. Furthermore, sputum IL-6 partially mediated the associations between IgE CV with moderate-to-severe and severe AEs.

Conclusions: Variability in total serum IgE levels is an easily obtained and practical measure for predicting AEs. Future studies are needed to investigate whether IgE variability can be used to guide precision medicine in asthma.
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http://dx.doi.org/10.1016/j.jaip.2021.04.065DOI Listing
May 2021

Current-Smoking alters Gene Expression and DNA Methylation in the Nasal Epithelium of Asthmatics.

Am J Respir Cell Mol Biol 2021 May 14. Epub 2021 May 14.

University of Technology Sydney, 1994, Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, Sydney, New South Wales, Australia.

Current-smoking contributes to worsened asthma prognosis, more severe symptoms and limits the beneficial effects of corticosteroids. As the nasal epithelium can reflect smoking-induced changes in the lower airways, it is a relevant source to investigate changes in gene expression and DNA methylation. This study explores gene expression and DNA methylation changes in current and ex-smokers with asthma. Matched gene expression and epigenome-wide DNA methylation samples collected from nasal brushings of 55 patients enrolled in a clinical trial investigation of current and ex-smoker asthma patients were analysed. Differential gene expression and DNA methylation analyses were conducted comparing current- vs ex-smokers. Expression quantitative trait methylation (eQTM) analysis was completed to explore smoking relevant genes by CpG sites that differ between current and ex-smokers. To investigate the relevance of the smoking-associated DNA methylation changes for the lower airways, significant CpG sites were explored in bronchial biopsies from patients who had stopped smoking. 809 genes and 18,814 CpG sites were differentially associated with current-smoking in the nose. The cis-eQTM analysis uncovered 171 CpG sites whose methylation status associated with smoking-related gene expression, including AHRR, ALDH3A1, CYP1A1 and CYP1B1. Methylation status of CpG sites altered by current-smoking reversed with one-year smoking cessation. We confirm current-smoking alters epigenetic patterns and affects gene expression in the nasal epithelium of asthma patients, which is partially reversible in bronhcial biopsies after smoking cessation. We demonstrate the ability to discern molecular changes in the nasal epithelium, presenting this as a tool in future investigations into disease-relevant effects of tobacco smoke.
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http://dx.doi.org/10.1165/rcmb.2020-0553OCDOI Listing
May 2021

Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques.

PLoS Pathog 2021 May 7;17(5):e1009575. Epub 2021 May 7.

Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.
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http://dx.doi.org/10.1371/journal.ppat.1009575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133453PMC
May 2021

Small Airway Dysfunction in Asthma Is Associated with Perceived Respiratory Symptoms, Non-Type 2 Airway Inflammation, and Poor Responses to Therapy.

Respiration 2021 Apr 23:1-13. Epub 2021 Apr 23.

School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Background: Emerging evidence has indicated that small airway dysfunction (SAD) contributes to the clinical expression of asthma.

Objectives: The aim of the study was to explore the relationships of SAD assessed by forced expiratory flow between 25 and 75% (FEF25-75%), with clinical and inflammatory profile and treatment responsiveness in asthma.

Method: In study I, dyspnea intensity (Borg scale), chest tightness, wheezing and cough (visual analog scales, VASs), and pre- and post-methacholine challenge testing (MCT) were analyzed in asthma patients with SAD and non-SAD. In study II, asthma subjects with SAD and non-SAD underwent sputum induction, and inflammatory mediators in sputum were detected. Asthma patients with SAD and non-SAD receiving fixed treatments were prospectively followed up for 4 weeks in study III. Spirometry, Asthma Control Questionnaire (ACQ), and Asthma Control Test (ACT) were carried out to define treatment responsiveness.

Results: SAD subjects had more elevated ΔVAS for dyspnea (p = 0.027) and chest tightness (p = 0.032) after MCT. Asthma patients with SAD had significantly elevated interferon (IFN)-γ in sputum (p < 0.05), and Spearman partial correlation found FEF25-75% significantly related to IFN-γ and interleukin-8 (both having p < 0.05). Furthermore, multivariable regression analysis indicated SAD was significantly associated with worse treatment responses (decrease in ACQ ≥0.5 and increase in ACT ≥3) (p = 0.022 and p = 0.032).

Conclusions: This study indicates that SAD in asthma predisposes patients to greater dyspnea intensity and chest tightness during bronchoconstriction. SAD patients with asthma are characterized by non-type 2 inflammation that may account for poor responsiveness to therapy.
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http://dx.doi.org/10.1159/000515328DOI Listing
April 2021

Treatable Traits in Elderly Asthmatics from the Australasian Severe Asthma Network: A Prospective Cohort Study.

J Allergy Clin Immunol Pract 2021 Apr 5. Epub 2021 Apr 5.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.

Background: Data on treatable traits (TTs) in different populations are limited.

Objective: To assess TTs in elderly patients with asthma and compare them to younger patients, to evaluate the association of TTs with future exacerbations, and to develop an exacerbation prediction model.

Methods: We consecutively recruited 521 participants at West China Hospital, Sichuan University based on the Australasian Severe Asthma Network, classified as elderly (n = 62) and nonelderly (n = 459). Participants underwent a multidimensional assessment to characterize the TTs and were then followed up for 12 months. TTs and their relationship with future exacerbations were described. Based on the TTs and asthma control levels, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort.

Results: A total of 38 TTs were assessed. Elderly patients with asthma had more chronic metabolic diseases, fixed airflow limitation, emphysema, and neutrophilic inflammation, whereas nonelderly patients with asthma exhibited more allergic characteristics and psychiatric diseases. Nine traits were associated with increased future exacerbations, of which exacerbation prone, upper respiratory infection-induced asthma attack, cardiovascular disease, diabetes, and depression were the strongest. A model including exacerbation prone, psychiatric disease, cardiovascular disease, upper respiratory infection-induced asthma attack, noneosinophilic inflammation, cachexia, food allergy, and asthma control was developed to predict exacerbation risk and showed good performance.

Conclusions: TTs can be systematically assessed in elderly patients with asthma, some of which are associated with future exacerbations, proving their clinical utility of evaluating them. A model based on TTs can be used to predict exacerbation risk in people with asthma.
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http://dx.doi.org/10.1016/j.jaip.2021.03.042DOI Listing
April 2021

Maternal High Fat Diet Consumption Exaggerates Metabolic Disorders in Mice With Cigarette-Smoking Induced Intrauterine Undernutrition.

Front Nutr 2021 16;8:638576. Epub 2021 Mar 16.

Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.

Maternal smoking causes fetal underdevelopment and results in births which are small for gestation age due to intrauterine undernutrition, leading to various metabolic disorders in adulthood. Furthermore, postnatal high fat diet (HFD) consumption is also a potent obesogenic factor, which can interact with maternal smoking. In this study, we aimed to determine whether maternal HFD consumption during pregnancy can reverse the adverse impact of maternal smoking and change the response to postnatal HFD consumption. Female mice were exposed to cigarette smoke (SE, 2 cigarettes/day) or sham exposed for 5 weeks before mating, with half of the SE dams fed HFD (43% fat, SE+HFD). The same treatment continued throughout gestation and lactation. Male offspring from each maternal group were fed the same HFD or chow after weaning and sacrificed at 13 weeks. Maternal SE alone increased body weight and fat mass in HFD-fed offspring, while SE+HFD offspring showed the highest energy intake and glucose metabolic disorder in adulthood. In addition, postnatal HFD increased the body weight and aggravated the metabolic disorder caused by maternal SE and SE+HFD. Maternal HFD consumption could not ameliorate the adverse effect of maternal SE but exaggerate metabolic disorders in adult offspring. Smoking cessation and a healthy diet are needed during pregnancy to optimize the health outcome in the offspring.
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http://dx.doi.org/10.3389/fnut.2021.638576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007928PMC
March 2021

Applications and practice of advanced drug delivery systems for targeting Toll-like receptors in pulmonary diseases.

Nanomedicine (Lond) 2021 04 18;16(10):783-786. Epub 2021 Mar 18.

University of Alberta, Faculty of Pharmacy & Pharmaceutical Sciences, Edmonton, AB T6G 2N8, Canada.

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http://dx.doi.org/10.2217/nnm-2021-0056DOI Listing
April 2021

Drug delivery advances in mitigating inflammation via matrix metalloproteinases in respiratory diseases.

Nanomedicine (Lond) 2021 03 18;16(6):437-439. Epub 2021 Feb 18.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia.

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http://dx.doi.org/10.2217/nnm-2021-0016DOI Listing
March 2021

A chinese herbal formula ameliorates COPD by inhibiting the inflammatory response via downregulation of p65, JNK, and p38.

Phytomedicine 2021 Mar 20;83:153475. Epub 2021 Jan 20.

Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.

Background: Bufei Yishen formula (BYF), a traditional Chinese medicine (TCM), is an effective therapeutic strategy for patients with chronic obstructive pulmonary disease (COPD).

Purpose: To evaluate the efficacy of BYF and investigate its therapeutic mechanisms.

Methods: A total of 134 patients completed the study: 68 patients treated by BYF combined with conventional Western medicine in the trial group; and 66 patients treated using conventional Western medicine in the control group. The efficacy of BYF was evaluated by a subgroup analysis of data obtained from a four-center, open-label, randomized controlled trial of comprehensive TCM interventions. A rat model of COPD was treated with the key active molecules (KAM) of BYF for 8 weeks. An in vitro model of COPD was also treated with KAM.

Results: Patients treated with BYF had reduced frequency of acute exacerbation of COPD (p < 0.001) and duration (p = 0.028), dyspnea scale (p = 0.007), 6-min walking distance (p = 0.048). There were no differences observed in forced vital capacity in one second (FVC), forced expiratory volume in one second (FEV1), and FEV1 percentage of the predicted value (FEV1%). The five KAM of BYF (KAM-BYF) improved lung function, including tidal volume, minute ventilation, peak expiratory flow, FVC, FEV0.1, and FEV0.3, and pathological changes in COPD rats. Treatment with KAM-BYF markedly decreased the levels of interleukin 6 (IL6), tumor necrosis factor-α (TNF-α), matrix metalloproteinase 9 (MMP9), and MMP12 in serum and bronchial alveolar lavage fluid. In airway epithelial cells, KAM-BYF decreased the levels of TNF-α-induced IL8 and IL6. Finally, we discovered that the anti-inflammatory effects of KAM-BYF in COPD rats and BEAS-2Bs were mediated through inhibition of nuclear factor-kappaB (NF-κB) p65, c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase signaling.

Conclusions: BYF exerts beneficial effects in patients with COPD via inhibition of inflammation.
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http://dx.doi.org/10.1016/j.phymed.2021.153475DOI Listing
March 2021

BET proteins are associated with the induction of small airway fibrosis in COPD.

Thorax 2021 Jan 27. Epub 2021 Jan 27.

Respiratory Cell and Molecular Biology, Woolcock Institute of Medical Research, Glebe, New South Wales, Australia.

Rationale: In COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed.

Objectives: Determine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1).

Methods: Primary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of and . Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at and promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed.

Measurements And Main Results: COPD ASM show significantly higher and expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at and promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at and .

Conclusions: BET protein binding to acetylated histones is important in TGF-β1 induced expression of and and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215092DOI Listing
January 2021

Differential inflammatory and toxic effects in-vitro of wood smoke and traffic-related particulate matter from Sydney, Australia.

Chemosphere 2021 Jun 12;272:129616. Epub 2021 Jan 12.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia; Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia. Electronic address:

Background: It is well known that PM generated by traffic or burning wood is pro-inflammatory and induces various adverse health outcomes in humans. In Sydney, New South Wales, Australia, the main anthropogenic contributors to particulate matter (PM) air pollution are wood combustion heaters, on-road vehicles, and coal-fired power stations. However, the relative toxicity of these local sources has not to date been investigated.

Method: PM was collected on filters from the same sampling site in Liverpool, one suburb of Sydney. According to the positive matrix factorisation and collection season, filters were representative of either day with high traffic-related air pollution (TRAP), wood smoke, or both TRAP and woodsmoke (mixed air pollution). The elemental composition of the PM was assessed by accelerator-based ion beam analysis techniques (i.e. PIXE & PIGE) and size by Dynamic Light Scattering. Toxicity and inflammation were assessed in-vitro in human bronchial epithelial cells by measuring interleukin-6 (IL-6), interleukin-8 (IL-8) release, and MTT.

Results: Mixed air pollution (TRAP/wood smoke) PM had more nanometer (nm) sized PM than the other two groups. Using an in-vitro model of the lungs, the mixed air pollution PM was the most toxic, whereas the PM from woodsmoke induced greater IL-6 release than TRAP PM. There was no difference in the induction of IL-8 between the three sources of PM.

Conclusion: Marked differences occur in the cellular response to PM from different sources, with differences in both toxicity and inflammation.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129616DOI Listing
June 2021

Heterogeneity of Paucigranulocytic Asthma: A Prospective Cohort Study with Hierarchical Cluster Analysis.

J Allergy Clin Immunol Pract 2021 Jun 20;9(6):2344-2355. Epub 2021 Jan 20.

Priority Research Center for Healthy Lungs, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia; Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.

Background: Asthma, a heterogeneous disease, can be divided into 4 inflammatory phenotypes using induced sputum cell counts-eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma, and paucigranulocytic asthma (PGA). Although research has focused on EA and NA, there is little known about PGA.

Objective: To study the heterogeneity of PGA and identify possible PGA clusters to guide clinical treatment.

Methods: Patients with PGA were grouped by hierarchical cluster analysis and enrolled into a prospective cohort study to validate the clusters, relative to future risk of asthma exacerbations in a real-world setting. Clusters were validated by tree analysis in a separate population. Finally, we explored PGA stability.

Results: Cluster analysis of 145 patients with PGA identified 3 clusters: cluster 1 (n = 110, 75.9%) was "mild PGA," cluster 2 (n = 20, 13.8%) was "PGA with psychological dysfunction and rhinoconjunctivitis and other allergic diseases," and cluster 3 (n = 15, 10.3%) was "smoking-associated PGA." Cluster 3 had significantly increased risk of severe exacerbation (relative risk [RR] = 6.43, P = .01), emergency visit (RR = 8.61, P = .03), and hospitalization (RR = 12.94, P < .01). Results of the cluster analysis were successfully validated in an independent PGA population classified using decision tree analysis. Although PGA can transform into or develop from other phenotypes, 70% were stable over time.

Conclusions: Among 3 identified PGA clusters, cluster 3 had a higher risk of severe exacerbation. PGA heterogeneity indicates the requirement of novel targeted interventions.
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http://dx.doi.org/10.1016/j.jaip.2021.01.004DOI Listing
June 2021

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities.

Life Sci 2021 Feb 2;267:118973. Epub 2021 Jan 2.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI), University of Newcastle, New Lambton Heights, Newcastle, NSW 2305, Australia; School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh 173229, India. Electronic address:

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.
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http://dx.doi.org/10.1016/j.lfs.2020.118973DOI Listing
February 2021

COPD-derived fibroblasts secrete higher levels of senescence-associated secretory phenotype proteins.

Thorax 2020 Dec 3. Epub 2020 Dec 3.

Pathology and Medical Biology, University Medical Centre Groningen, Groningen, The Netherlands

COPD-derived fibroblasts have increased cellular senescence. Senescent cell accumulation can induce tissue dysfunction by their senescence-associated secretory phenotype (SASP). We aimed to determine the SASP of senescent fibroblasts and COPD-derived lung fibroblasts, including severe, early-onset (SEO)-COPD. SASP protein secretion was measured after paraquat-induced senescence in lung fibroblasts using Olink Proteomics and compared between (SEO-)COPD-derived and control-derived fibroblasts. We identified 124 SASP proteins of senescent lung fibroblasts, of which 42 were secreted at higher levels by COPD-derived fibroblasts and 35 by SEO-COPD-derived fibroblasts compared with controls. Interestingly, the (SEO-)COPD-associated SASP included proteins involved in chronic inflammation, which may contribute to (SEO-)COPD pathogenesis.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070616PMC
December 2020

Clinical and Inflammatory Features of Exacerbation-Prone Asthma: A Cross-Sectional Study Using Multidimensional Assessment.

Respiration 2020;99(12):1109-1121. Epub 2020 Dec 3.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.

Background: Reducing asthma exacerbations is a major target of current clinical guidelines, but identifying features of exacerbation-prone asthma (EPA) using multidimensional assessment (MDA) is lacking.

Objective: To systemically explore the clinical and inflammatory features of adults with EPA in a Chinese population.

Methods: We designed a cross-sectional study using the Severe Asthma Web-based Database from the Australasian Severe Asthma Network (ASAN). Eligible Chinese adults with asthma (n = 546) were assessed using MDA. We stratified patients based on exacerbation frequency: none, few (1 or 2), and exacerbation prone (≥3). Univariate and multivariable negative binomial regression analyses were performed to investigate features associated with the frequency of exacerbations.

Results: Of 546 participants, 61.9% had no exacerbations (n = 338), 29.6% had few exacerbations (n = 162), and 8.4% were exacerbation prone (n = 46) within the preceding year. EPA patients were characterized by elevated blood and sputum eosinophils but less atopy, with more controller therapies but worse asthma control and quality of life (all p < 0.05). In multivariable models, blood and sputum eosinophils (adjusted rate ratio = 2.23, 95% confidence interval = [1.26, 3.84] and 1.67 [1.27, 2.21], respectively), FEV1 (0.90 [0.84, 0.96]), bronchodilator responsiveness (1.16 [1.05, 1.27]), COPD (2.22 [1.41, 3.51]), bronchiectasis (2.87 [1.69, 4.89]), anxiety (2.56 [1.10, 5.95]), and depression (1.94 [1.20, 3.13]) were found. Further, upper respiratory tract infection (1.83 [1.32, 2.54]) and food allergy (1.67 [1.23, 2.25]) were at high risk of asthma symptom triggers.

Conclusion: EPA is a clinically recognizable phenotype associated with several recognizable traits that could be addressed by targeted treatment.
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http://dx.doi.org/10.1159/000510793DOI Listing
December 2020

Brain health is independently impaired by E-vaping and high-fat diet.

Brain Behav Immun 2021 02 20;92:57-66. Epub 2020 Nov 20.

School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia; Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, NSW 2037, Australia. Electronic address:

Tobacco smoking and high-fat diet (HFD) independently impair short-term memory. E-cigarettes produce e-vapour containing flavourings and nicotine. Here, we investigated whether e-vapour inhalation interacts with HFD to affect short-term memory and neural integrity. Balb/c mice (7 weeks, male) were fed a HFD (43% fat, 20 kJ/g) for 16 weeks. In the last 6 weeks, half of the mice were exposed to tobacco-flavoured e-vapour from nicotine-containing (18 mg/L) or nicotine-free (0 mg/L) e-fluids twice daily. Short-term memory function was measured in week 15. HFD alone did not impair memory function, but increased brain phosphorylated (p)-Tau and astrogliosis marker, while neuron and microglia levels were decreased. E-vapour exposure significantly impaired short-term memory function independent of diet and nicotine. Nicotine free e-vapour induced greater changes compared to the nicotine e-vapour and included, increased systemic cytokines, increased brain p-Tau and decreased postsynaptic density protein (PSD)-95 levels in chow-fed mice, and decreased astrogliosis marker, increased microglia and increased glycogen synthase kinase levels in HFD-fed mice. Increased hippocampal apoptosis was also differentially observed in chow and HFD mice. In conclusion, E-vapour exposure impaired short-term memory independent of diet and nicotine, and was correlated to increased systemic inflammation, reduced PSD-95 level and increased astrogliosis in chow-fed mice, but decreased gliosis and increased microglia in HFD-fed mice, indicating the inflammatory nature of e-vapour leading to short term memory impairment.
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http://dx.doi.org/10.1016/j.bbi.2020.11.028DOI Listing
February 2021

Sex-specific effects of in utero and adult tobacco smoke exposure.

Am J Physiol Lung Cell Mol Physiol 2021 01 21;320(1):L63-L72. Epub 2020 Oct 21.

School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Tobacco smoke has harmful effects on a multiorgan level. Exposure to smoke, whether in utero or environmental, significantly increases susceptibility. This susceptibility has been identified to be divergent between males and females. However, there remains a distinct lack of thorough research into the relationship between sex and exposure to tobacco. Females tend to generate a more significant response than males during adulthood exposure. The intrauterine environment is meticulously controlled, and exposure to tobacco presents a significant factor that contributes to poor health outcomes and susceptibility later in life. Analysis of these effects in relation to the sex of the offspring is yet to be holistically reviewed and summarized. In this review, we will delineate the time-dependent relationship between tobacco smoke exposure and sex-specific disease susceptibility. We further outline possible biological mechanisms that may contribute to the identified pattern.
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http://dx.doi.org/10.1152/ajplung.00273.2020DOI Listing
January 2021

Multidimensional Assessment of Asthma Identifies Clinically Relevant Phenotype Overlap: A Cross-Sectional Study.

J Allergy Clin Immunol Pract 2021 01 11;9(1):349-362.e18. Epub 2020 Aug 11.

Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, Sichuan, China. Electronic address:

Background: Asthma is a heterogeneous disease with multiple phenotypes; however, the relevance of phenotype overlap remains largely unexplored.

Objective: To examine the relationship between phenotype overlap and clinical and inflammatory profiles of asthma.

Methods: In this cross-sectional study, adult participants with stable asthma (n = 522) underwent multidimensional assessments. The 10 most common phenotypes of asthma were defined and then classified into those commonly associated with Type (T) 2 or non-T2 inflammation. Furthermore, phenotype overlap scores (POS), representing the cumulative concomitant phenotypes, were used to analyze its association with clinical and inflammatory asthmatic profiles.

Results: Among the 522 participants, 73.4% (n = 383) had phenotype overlap, and mixed T2 and non-T2 inflammation coexisted in 47.5% (n = 248). T2 POS was positively associated with eosinophils, IgE, and fractional exhaled nitric oxide (FeNO), and negatively with Asthma Quality of Life Questionnaire (AQLQ), sputum neutrophils, IL-17A, IL-8, and TNF-α. Non-T2 POS was positively associated with Asthma Control Questionnaire, neutrophils and sputum IL-8, and negatively with AQLQ, forced expiratory volume in 1 s, blood eosinophils, IgE, and FeNO (all P < .05). Patients with phenotypes that are associated with mixed T2 and non-T2 inflammation had elevated T2 inflammation biomarkers but worse asthma control. Both T2 (adjusted β = -0.191, P = .035) and non-T2 (adjusted β = 0.310, P < .001) POS were significantly associated with severe exacerbations.

Conclusions: Phenotype overlap is extremely common in asthmatic patients and significantly associated with clinical and inflammatory profiles. Patients with phenotypes associated with mixed T2 and non-T2 inflammation might be unresponsive to medications owing to increased non-T2 inflammation. Multidimensional asthma assessment identifies clinically relevant phenotype overlap.
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http://dx.doi.org/10.1016/j.jaip.2020.07.048DOI Listing
January 2021

Offspring sex affects the susceptibility to maternal smoking-induced lung inflammation and the effect of maternal antioxidant supplementation in mice.

J Inflamm (Lond) 2020 5;17:24. Epub 2020 Aug 5.

Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2007 Australia.

Background: Cigarette smoke exposure (SE) during pregnancy is the largest modifiable risk factor for the development of lung disorders in offspring. We have previously shown that maternal L-Carnitine treatment can reduce the adverse impacts of maternal SE on renal and brain disorders in offspring. Here, we investigated the effect of maternal L-Carnitine supplementation on lung inflammatory pathways, autophagy, and mitophagy markers in the offspring in response to maternal SE.

Methods: Female BALB/c mice (8 weeks) were exposed to cigarette smoke for 6 weeks prior to mating, during gestation and lactation. Some of the SE dams were given L-Carnitine supplementation (1.5 mM in drinking water, SE + LC) during gestation and lactation. Lungs from the offspring were studied at birth and adulthood (13 weeks).

Results: At birth, in male offspring, there were increased levels of inflammatory markers (phosphorylated(p)-ERK1,2, p-P38 MAPK, p- NF-κB), and inflammasome marker (NLRP3), as well as mitophagy fission marker Drp-1 and autophagosome marker (LC3A/B-II) in the lung. Maternal L-Carnitine supplementation significantly reduced NLRP3 level. In contrast, maternal SE only increased IL1-β in female offspring, which was reversed by maternal L-Carnitine supplementation. At 13 weeks, there was an increase in LC3A/B-II and p- NF-κB in the male SE offspring with reduced p-JNK1,2, which were partially normalised by maternal L-Carnitine treatment. Female offspring were not affected by maternal SE at this age.

Conclusion: Maternal SE had adverse impacts on the male offspring's lung, which were partially alleviated by maternal L-Carnitine supplementation. Females seem to be less affected by the adverse effects of maternal SE.
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http://dx.doi.org/10.1186/s12950-020-00253-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409429PMC
August 2020

Replacing smoking with vaping during pregnancy: Impacts on metabolic health in mice.

Reprod Toxicol 2020 Aug 1;96:293-299. Epub 2020 Aug 1.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.

Smoking is a significant risk factor for the development of metabolic diseases. Due to social pressures to quit smoking, many pregnant women are vaping as an alternative nicotine source. However, the metabolic consequences of replacing tobacco cigarettes with e-cigarettes during pregnancy are unknown. Therefore, in the mothers and their offspring, we investigated the metabolic and hepatic impacts of replacing cigarette smoke with e-vapour during pregnancy. Female BALB/c mice were either air-exposed or cigarette smoke-exposed (SE) from six weeks before pregnancy until lactation. At mating, a subset of the SE mice were instead exposed to e-vapour. Markers of glucose and lipid metabolism were measured in the livers and plasma, from the mothers and their male offspring (13 weeks). In the SE mothers, plasma insulin levels were reduced, leading to downstream increases in hepatic gluconeogenesis and plasma non-esterified fatty acids (NEFA). In the e-vapour replacement mothers, these changes were not as significant. In the SE offspring, there was impaired glucose tolerance, and increased plasma NEFA and liver triglyceride concentrations. E-vapour replacement restored lipid homeostasis but did not improve glucose tolerance. Therefore, in a murine model, low dose e-cigarette replacement during pregnancy is less toxic than cigarette smoke.
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http://dx.doi.org/10.1016/j.reprotox.2020.07.012DOI Listing
August 2020

Is there an association between the level of ambient air pollution and COVID-19?

Am J Physiol Lung Cell Mol Physiol 2020 09 22;319(3):L416-L421. Epub 2020 Jul 22.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.

Epidemiological studies suggest that environmental factors (e.g., air pollution) can influence the spread and infectivity of coronavirus disease 2019 (COVID-19); however, very few papers have investigated or discussed the mechanism behind the phenomenon. Given the fact that pollution will increase as social distancing rules are relaxed, we summarized the current understanding of how air pollution may affect COVID-19 transmission and discussed several possible mechanisms. Air pollution exposure can dysregulate the human immune response and make people more susceptible to infections, and affect infectivity. For example, in response to exposure to air pollution, angiotensin-converting enzyme 2 will increase, which is the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This may increase the efficiency of viral infection. It is also possible that air pollution can facilitate SARS-CoV-2 spread by increasing the transmission, and potentially, SARS-CoV-2 can also survive longer when attached to a pollutant.
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http://dx.doi.org/10.1152/ajplung.00244.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839633PMC
September 2020

E-cigarettes damage the liver and alter nutrient metabolism in pregnant mice and their offspring.

Ann N Y Acad Sci 2020 09 17;1475(1):64-77. Epub 2020 Jun 17.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia.

Approximately 15% of pregnant women vape electronic cigarettes (e-cigarettes), exposing the fetus to a range of toxic compounds, including nicotine and by-products of e-cigarette liquid (e-liquid) pyrolysis. Owing to the recent emergence of these products, research mainly focuses on immediate users, and not on in utero exposure. Therefore, this study aimed to understand the impact of intrauterine e-cigarette vapor (e-vapor) exposure, with and without nicotine, on liver metabolic markers in the male offspring. E-vapor was generated using an e-cigarette filled with tobacco-flavored e-liquid (18 or 0 mg/mL nicotine). Female Balb/c mice were exposed to e-vapor for 6 weeks before mating, through gestation and lactation, without direct exposure to the offspring. Livers and plasma from dams and male offspring (13 weeks old) were examined. Exposure to nicotine-free e-vapor promoted metabolic changes and liver damage in both the dams and their offspring. Furthermore, exposure to nicotine-containing e-vapor did not cause liver damage but induced hepatic steatosis in the adult offspring. Therefore, maternal vaping is detrimental to both the dams and their offspring, with nicotine providing a potential protective effect.
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http://dx.doi.org/10.1111/nyas.14411DOI Listing
September 2020

Sexually dimorphic production of interleukin-6 in respiratory disease.

Physiol Rep 2020 06;8(11):e14459

School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia.

Diverging susceptibility and severity in respiratory diseases is prevalent between males and females. Sex hormones have inconclusively been attributed as the cause of these differences, however, strong evidence exists promoting genetic factors leading to sexual dimorphism. As such, we investigate differential proinflammatory cytokine (interleukin (IL)-6 and CXCL8) release from TNF-α stimulated primary human lung fibroblasts in vitro. We present, for the first time, in vitro evidence supporting clinical findings of differential production of IL-6 between males and females across various respiratory diseases. IL-6 was found to be produced approximately two times more from fibroblasts derived from females compared to males. As such we demonstrate sexual dimorphism in cytokine production of IL-6 outside the context of biological factors in the human body. As such, our data highlight that differences exist between males and females in the absence of sex hormones. We, for the first time, demonstrate inherent in vitro differences exist between males and females in pulmonary fibroblasts.
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http://dx.doi.org/10.14814/phy2.14459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260763PMC
June 2020

Link between increased cellular senescence and extracellular matrix changes in COPD.

Am J Physiol Lung Cell Mol Physiol 2020 07 27;319(1):L48-L60. Epub 2020 May 27.

Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Chronic obstructive pulmonary disease (COPD) is associated with features of accelerated aging, including cellular senescence, DNA damage, oxidative stress, and extracellular matrix (ECM) changes. We propose that these features are particularly apparent in patients with severe, early-onset (SEO)-COPD. Whether fibroblasts from COPD patients display features of accelerated aging and whether this is also present in relatively young SEO-COPD patients is unknown. Therefore, we aimed to determine markers of aging in (SEO)-COPD-derived lung fibroblasts and investigate the impact on ECM. Aging hallmarks and ECM markers were analyzed in lung fibroblasts from SEO-COPD and older COPD patients and compared with fibroblasts from matched non-COPD groups ( = 9-11 per group), both at normal culture conditions and upon Paraquat-induced senescence. COPD-related differences in senescence and ECM expression were validated in lung tissue. Higher levels of cellular senescence, including senescence-associated β-galactosidase (SA-β-gal)-positive cells (19% for COPD vs. 13% for control) and p16 expression, DNA damage (γ-H2A.X-positive nuclei), and oxidative stress () were detected in COPD compared with control-derived fibroblasts. Most effects were also different in SEO-COPD, with SA-β-gal-positive cells only being significant in SEO-COPD vs. matched controls. Lower decorin expression in COPD-derived fibroblasts correlated with higher p16 expression, and this association was confirmed in lung tissue. Paraquat treatment induced cellular senescence along with clear changes in ECM expression, including decorin. Fibroblasts from COPD patients, including SEO-COPD, display higher levels of cellular senescence, DNA damage, and oxidative stress. The association between cellular senescence and ECM expression changes may suggest a link between accelerated aging and ECM dysregulation in COPD.
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http://dx.doi.org/10.1152/ajplung.00028.2020DOI Listing
July 2020

Exposure to Air Pollution Exacerbates Inflammation in Rats with Preexisting COPD.

Mediators Inflamm 2020 8;2020:4260204. Epub 2020 May 8.

Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, China.

Particulate matter with an aerodynamic diameter equal or less than 2.5 micrometers (PM2.5) is associated with the development of chronic obstructive pulmonary disease (COPD). The mechanisms by which PM2.5 accelerates disease progression in COPD are poorly understood. In this study, we aimed to investigate the effect of PM2.5 on lung injury in rats with hallmark features of COPD. Cardinal features of human COPD were induced in a rat model by repeated cigarette smoke inhalation and bacterial infection for 8 weeks. Then, from week 9 to week 16, some of these rats with COPD were subjected to real-time concentrated atmospheric PM2.5. Lung function, pathology, inflammatory cytokines, oxidative stress, and mucus and collagen production were measured. As expected, the COPD rats had developed emphysema, inflammation, and deterioration in lung function. PM2.5 exposure resulted in greater lung function decline and histopathological changes, as reflected by increased Mucin (MUC) 5ac, MUC5b, Collagen I, Collagen III, and the profibrotic cytokine -smooth muscle-actin (SMA), transforming growth factor- (TGF-) 1 in lung tissues. PM2.5 also aggravated inflammation, increasing neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF) and cytokines including Interleukin- (IL-) 1, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-4. The likely mechanism is through oxidative stress as antioxidants levels were decreased, whereas oxidants were increased, indicating a detrimental shift in the oxidant-antioxidant balance. Altogether, these results suggest that PM2.5 exposure could promote the development of COPD by impairing lung function and exacerbating pulmonary injury, and the potential mechanisms are related to inflammatory response and oxidative stress.
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http://dx.doi.org/10.1155/2020/4260204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231193PMC
May 2020

Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin.

Endocr Metab Immune Disord Drug Targets 2020 ;20(10):1590-1596

Department of Pharmaceutical Technology, School of Pharmacy, International Medical University (IMU), Bukit Jalil, Kuala Lumpur, 57000, Malaysia

The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
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http://dx.doi.org/10.2174/1871530320666200503053846DOI Listing
January 2020

Gene expression profiling of bronchial brushes is associated with the level of emphysema measured by computed tomography-based parametric response mapping.

Am J Physiol Lung Cell Mol Physiol 2020 06 22;318(6):L1222-L1228. Epub 2020 Apr 22.

Respiratory Bioinformatics and Molecular Biology, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patients with chronic obstructive pulmonary disease (COPD). It is capable of differentiating emphysema-related air trapping with nonemphysematous air trapping (small airway disease), which helps to identify the extent and localization of the disease. Most studies evaluating the gene expression in smokers and COPD patients related this to spirometric measurements, but none have investigated the relationship with CT-based measurements of lung structure. The current study aimed to examine gene expression profiles of brushed bronchial epithelial cells in association with the PRM-defined CT-based measurements of emphysema (PRM) and small airway disease (PRM). Using the Top Institute Pharma (TIP) study cohort (COPD = 12 and asymptomatic smokers = 32), we identified a gene expression signature of bronchial brushings, which was associated with PRM in the lungs. One hundred thirty-three genes were identified to be associated with PRM. Among the most significantly associated genes, is a potent chemokine involved with CD8 T cell activation during inflammation in COPD, indicating that it may play an essential role in the development of emphysema. The PRM signature was then replicated in two independent data sets. Pathway analysis showed that the PRM signature is associated with proinflammatory and notch signaling pathways. Together these findings indicate that airway epithelium may play a role in the development of emphysema and/or may act as a biomarker for the presence of emphysema. In contrast, its role in relation to functional small airways disease is less clear.
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http://dx.doi.org/10.1152/ajplung.00051.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938773PMC
June 2020