Biochemistry and Pharmacology - Research Publications
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ItemCross-talk between IL-6 trans-signaling and AIM2 inflammasome/IL-1β axes bridge innate immunity and epithelial apoptosis to promote emphysema(NATL ACAD SCIENCES, 2022-09-06)Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema. In the lungs of emphysematous patients, as well as spontaneous gp130F/F and cigarette smoke (CS)-induced mouse models of emphysema, the expression (messenger RNA and protein) and activation of ASC, Caspase-1, and the inflammasome-associated PRR and DNA sensor AIM2 were up-regulated. AIM2 up-regulation in emphysema coincided with the biased production of the mature downstream inflammasome effector cytokine IL-1β but not IL-18. These observations were supported by the genetic blockade of ASC, AIM2, and the IL-1 receptor and therapy with AIM2 antagonistic suppressor oligonucleotides, which ameliorated emphysema in gp130F/F mice by preventing elevated alveolar cell apoptosis. The functional requirement for AIM2 in driving apoptosis in the lung epithelium was independent of its expression in hematopoietic-derived immune cells and the recruitment of infiltrating immune cells in the lung. Genetic and inhibitor-based blockade of AIM2 also protected CS-exposed mice from pulmonary alveolar cell apoptosis. Intriguingly, IL-6 trans-signaling via the soluble IL-6 receptor, facilitated by elevated levels of IL-6, acted upstream of the AIM2 inflammasome to augment AIM2 expression in emphysema. Collectively, we reveal cross-talk between the AIM2 inflammasome/IL-1β and IL-6 trans-signaling axes for potential exploitation as a therapeutic strategy for emphysema.
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ItemTreatable traits in the NOVELTY study(WILEY, 2022-11)BACKGROUND AND OBJECTIVE: Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent and complex diseases that require personalized management. Although a strategy based on treatable traits (TTs) has been proposed, the prevalence and relationship of TTs to the diagnostic label and disease severity established by the attending physician in a real-world setting are unknown. We assessed how the presence/absence of specific TTs relate to the diagnosis and severity of 'asthma', 'COPD' or 'asthma + COPD'. METHODS: The authors selected 30 frequently occurring TTs from the NOVELTY study cohort (NOVEL observational longiTudinal studY; NCT02760329), a large (n = 11,226), global study that systematically collects data in a real-world setting, both in primary care clinics and specialized centres, for patients with 'asthma' (n = 5932, 52.8%), 'COPD' (n = 3898, 34.7%) or both ('asthma + COPD'; n = 1396, 12.4%). RESULTS: The results indicate that (1) the prevalence of the 30 TTs evaluated varied widely, with a mean ± SD of 4.6 ± 2.6, 5.4 ± 2.6 and 6.4 ± 2.8 TTs/patient in those with 'asthma', 'COPD' and 'asthma + COPD', respectively (p < 0.0001); (2) there were no large global geographical variations, but the prevalence of TTs was different in primary versus specialized clinics; (3) several TTs were specific to the diagnosis and severity of disease, but many were not; and (4) both the presence and absence of TTs formed a pattern that is recognized by clinicians to establish a diagnosis and grade its severity. CONCLUSION: These results provide the largest and most granular characterization of TTs in patients with airway diseases in a real-world setting to date.
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ItemProteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD(PUBLIC LIBRARY SCIENCE, 2022-12-08)OBJECTIVE: Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology. METHODS: Serum samples were collected from 241 COPD subjects in the multicenter French Cohort of Bronchial obstruction and Asthma to measure the expression of 1305 proteins using SOMAscan proteomic platform. Clustering of the proteomics was applied to identify disease subtypes and their functional annotation and association with key clinical parameters were examined. Cluster findings were revalidated during a follow-up visit, and compared to those obtained in a group of 47 COPD patients included in the Melbourne Longitudinal COPD Cohort. RESULTS: Unsupervised clustering identified two clusters within COPD subjects at inclusion. Cluster 1 showed elevated levels of factors contributing to tissue injury, whereas Cluster 2 had higher expression of proteins associated with enhanced immunity and host defense, cell fate, remodeling and repair and altered metabolism/mitochondrial functions. Patients in Cluster 2 had a lower incidence of exacerbations, unscheduled medical visits and prevalence of emphysema and diabetes. These protein expression patterns were conserved during a follow-up second visit, and substanciated, by a large part, in a limited series of COPD patients. Further analyses identified a signature of 15 proteins that accurately differentiated the two COPD clusters at the 2 visits. CONCLUSIONS: This study provides insights into COPD heterogeneity and suggests that overexpression of factors involved in lung immunity/host defense, cell fate/repair/ remodelling and mitochondrial/metabolic activities contribute to better clinical outcomes. Hence, high throughput proteomic assay offers a powerful tool for identifying COPD endotypes and facilitating targeted therapies.
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ItemHeparin Inhibits SARS-CoV-2 Replication in Human Nasal Epithelial Cells(MDPI, 2022-12)SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Vaccination, supported by social and public health measures, has proven efficacious for reducing disease severity and virus spread. However, the emergence of highly transmissible viral variants that escape prior immunity highlights the need for additional mitigation approaches. Heparin binds the SARS-CoV-2 spike protein and can inhibit virus entry and replication in susceptible human cell lines and bronchial epithelial cells. Primary infection predominantly occurs via the nasal epithelium, but the nasal cell biology of SARS-CoV-2 is not well studied. We hypothesized that prophylactic intranasal administration of heparin may provide strain-agnostic protection for household contacts or those in high-risk settings against SARS-CoV-2 infection. Therefore, we investigated the ability of heparin to inhibit SARS-CoV-2 infection and replication in differentiated human nasal epithelial cells and showed that prolonged exposure to heparin inhibits virus infection. Furthermore, we establish a method for PCR detection of SARS-CoV-2 viral genomes in heparin-treated samples that can be adapted for the detection of viruses in clinical studies.
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ItemVaccine strain affects seroconversion after influenza vaccination in COPD patients and healthy older people(NATURE PORTFOLIO, 2022-01-24)Though clinical guidelines recommend influenza vaccination for chronic obstructive pulmonary disease (COPD) patients and other high-risk populations, it is unclear whether current vaccination strategies induce optimal antibody responses. This study aimed to identify key variables associated with strain-specific antibody responses in COPD patients and healthy older people. 76 COPD and 72 healthy participants were recruited from two Australian centres and inoculated with influenza vaccine. Serum strain-specific antibody titres were measured pre- and post-inoculation. Seroconversion rate was the primary endpoint. Antibody responses varied between vaccine strains. The highest rates of seroconversion were seen with novel strains (36-55%), with lesser responses to strains included in the vaccine in more than one consecutive year (27-33%). Vaccine responses were similar in COPD patients and healthy participants. Vaccine strain, hypertension and latitude were independent predictors of seroconversion. Our findings reassure that influenza vaccination is equally immunogenic in COPD patients and healthy older people; however, there is room for improvement. There may be a need to personalise the yearly influenza vaccine, including consideration of pre-existing antibody titres, in order to target gaps in individual antibody repertoires and improve protection.
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ItemHeterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort(EUROPEAN RESPIRATORY SOC JOURNALS LTD, 2021-09-01)BACKGROUND: Studies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice. We investigated heterogeneity and overlap by diagnosis and severity in this cohort. METHODS: Patients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, and stratified by diagnosis and severity. Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity. Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis. RESULTS: Of 11 243 patients, 5940 (52.8%) had physician-assigned asthma, 1396 (12.4%) had asthma+COPD and 3907 (34.8%) had COPD; almost half were from primary care. Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD, with 23%, 62% and 64% of patients, respectively, having a ratio of post-bronchodilator forced expiratory volume in 1 s to forced vital capacity below the lower limit of normal. Symptoms and exacerbations increased with greater physician-assessed severity and were higher in asthma+COPD. However, 24.3% with mild asthma and 20.4% with mild COPD had experienced ≥1 exacerbation in the past 12 months. Medication records suggested both under-treatment and over-treatment relative to severity. Blood eosinophil counts varied little across diagnosis and severity groups, but blood neutrophil counts increased with severity across all diagnoses. CONCLUSION: This analysis demonstrates marked heterogeneity within, and overlap between, physician-assigned diagnosis and severity groups in patients with asthma and/or COPD. Current diagnostic and severity classifications in clinical practice poorly differentiate between clinical phenotypes that may have specific risks and treatment implications.
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ItemChronic lung diseases: prospects for regeneration and repair(EUROPEAN RESPIRATORY SOC JOURNALS LTD, 2021-03-31)COPD and idiopathic pulmonary fibrosis (IPF) together represent a considerable unmet medical need, and advances in their treatment lag well behind those of other chronic conditions. Both diseases involve maladaptive repair mechanisms leading to progressive and irreversible damage. However, our understanding of the complex underlying disease mechanisms is incomplete; with current diagnostic approaches, COPD and IPF are often discovered at an advanced stage and existing definitions of COPD and IPF can be misleading. To halt or reverse disease progression and achieve lung regeneration, there is a need for earlier identification and treatment of these diseases. A precision medicine approach to treatment is also important, involving the recognition of disease subtypes, or endotypes, according to underlying disease mechanisms, rather than the current "one-size-fits-all" approach. This review is based on discussions at a meeting involving 38 leading global experts in chronic lung disease mechanisms, and describes advances in the understanding of the pathology and molecular mechanisms of COPD and IPF to identify potential targets for reversing disease degeneration and promoting tissue repair and lung regeneration. We also discuss limitations of existing disease measures, technical advances in understanding disease pathology, and novel methods for targeted drug delivery.
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ItemNo Preview AvailableCD11b immunophenotyping identifies inflammatory profiles in the mouse and human lungs(NATURE PUBLISHING GROUP, 2016-03)The development of easily accessible tools for human immunophenotyping to classify patients into discrete disease endotypes is advancing personalized therapy. However, no systematic approach has been developed for the study of inflammatory lung diseases with often complex and highly heterogeneous disease etiologies. We have devised an internally standardized flow cytometry approach that can identify parallel inflammatory alveolar macrophage phenotypes in both the mouse and human lungs. In mice, lung innate immune cell alterations during endotoxin challenge, influenza virus infection, and in two genetic models of chronic obstructive lung disease could be segregated based on the presence or absence of CD11b alveolar macrophage upregulation and lung eosinophilia. Additionally, heightened alveolar macrophage CD11b expression was a novel feature of acute lung exacerbations in the SHIP-1(-/-) model of chronic obstructive lung disease, and anti-CD11b antibody administration selectively blocked inflammatory CD11b(pos) but not homeostatic CD11b(neg) alveolar macrophages in vivo. The identification of analogous profiles in respiratory disease patients highlights this approach as a translational avenue for lung disease endotyping and suggests that heterogeneous innate immune cell phenotypes are an underappreciated component of the human lung disease microenvironment.
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ItemNo Preview AvailableOseltamivir treatment of mice before or after mild influenza infection reduced cellular and cytokine inflammation in the lung(WILEY, 2011-09)BACKGROUND: Lung inflammation is a critical determinant of influenza infection outcomes but is seldom evaluated in animal studies of oseltamivir (OS), which have focused on viral titre and survival. OBJECTIVES: To study the effects of pre- and post-infection dosing with OS on viral replication and inflammation in a mouse model of non-lethal influenza infection. METHODS: BALB/c mice were infected with a laboratory-adapted H3N1 strain of influenza. In pre-dosing studies, OS was gavaged twice daily (1 and 10 mg/kg/day) from 4 hours prior to infection and continuing for 5 days (d) post-infection (p.i). In the second post-infection dosing study, dosing at 10 mg/kg/day began at 24-48 hours p.i. Mice were dissected at d3, d5 and d7 p.i. (pre-dosing study) and d5 p.i. (post-dosing study). Lung viral titres were determined by plaque assay. Bronchoalveolar lavage fluid (BALF) was collected and used for the quantitation of inflammatory cells and mediators. RESULTS: Pre-infection dosing of OS reduced total cells, neutrophils and macrophages in BALF. With pre- or post-infection dosing, the pro-inflammatory mediators TNF-α, IL-1β, IL-6 and granulocyte-macrophage colony-stimulating factor, the neutrophil chemokines keratinocyte-derived chemokine and MIP-1α and the macrophage chemokine MCP-1 were reduced in BALF. Pre-dosing with 1 mg/kg OS did not reduce viral titres, while 10 mg/kg slightly reduced viral titres at d3 and d5 p.i. CONCLUSIONS: Oseltamivir reduced the inflammatory response to influenza when given pre- or post-infection. This anti-inflammatory effect may contribute to the clinical benefit of OS.
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ItemNo Preview AvailableIdentifying viral infections in vaccinated Chronic Obstructive Pulmonary Disease (COPD) patients using clinical features and inflammatory markers(WILEY, 2010-01)BACKGROUND: Known inflammatory markers have limited sensitivity and specificity to differentiate viral respiratory tract infections from other causes of acute exacerbation of COPD (AECOPD). To overcome this, we developed a multi-factorial prediction model combining viral symptoms with inflammatory markers. METHODS: Interleukin-6 (IL-6), serum amyloid A (SAA) and viral symptoms were measured in stable COPD and at AECOPD onset and compared with the viral detection rates on multiplex PCR. The predictive accuracy of each measure was assessed using logistic regression and receiver operating characteristics curve (ROC) analysis. RESULTS: There was a total of 33 viruses detected at the onset of 148 AECOPD, the majority 26 (79%) were picornavirus. Viral symptoms with the highest predictive values were rhinorrhoea [Odds ratio (OR) 4.52; 95% CI 1.99-10.29; P < 0.001] and sore throat (OR 2.64; 95% CI 1.14-6.08; P = 0.022), combined the AUC ROC curve was 0.67. At AECOPD onset patients experienced a 1.6-fold increase in IL-6 (P = 0.008) and 4.5-fold increase in SAA (P < 0.001). The addition of IL-6 to the above model significantly improved diagnostic accuracy compared with symptoms alone (AUC ROC 0.80 (P = 0.012). CONCLUSION: The addition of inflammatory markers increases the specificity of a clinical case definition for viral infection, particularly picornavirus infection.