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  • 1
    Online Resource
    Online Resource
    Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma
    European Respiratory Society (ERS) ; 2020
    In:  European Respiratory Journal Vol. 55, No. 4 ( 2020-04), p. 1901340-
    Details
    In: European Respiratory Journal, European Respiratory Society (ERS), Vol. 55, No. 4 ( 2020-04), p. 1901340-
    Abstract: Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma. We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild–moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV 1 ). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV 1 /forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 ( DMT1 ) and transferrin receptor 1 ( TFR1 ) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1 + macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo , including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses. Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
    Type of Medium: Online Resource
    ISSN: 0903-1936 , 1399-3003
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1183/13993003.01340-2019
    DOI: 10.1183/13993003.01340-2019.Supp1
    DOI: 10.1183/13993003.01340-2019.Shareable1
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2020
    detail.hit.zdb_id: 2834928-3
    detail.hit.zdb_id: 1499101-9
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  • 2
    Online Resource
    Online Resource
    Cellular mechanisms underlying steroid-resistant asthma
    European Respiratory Society (ERS) ; 2019
    In:  European Respiratory Review Vol. 28, No. 153 ( 2019-09-30), p. 190096-
    Details
    In: European Respiratory Review, European Respiratory Society (ERS), Vol. 28, No. 153 ( 2019-09-30), p. 190096-
    Abstract: Severe steroid-resistant asthma is clinically important, as patients with this form of the disease do not respond to mainstay corticosteroid therapies. The heterogeneity of this form of asthma and poor understanding of the pathological mechanisms involved hinder the identification of therapeutic targets and the development of more effective therapies. A major limiting factor in the understanding of severe steroid-resistant asthma is the existence of multiple endotypes represented by different immunological and inflammatory phenotypes, particularly in adults. Several clinical and experimental studies have revealed associations between specific respiratory infections and steroid-resistant asthma in adults. Here, we discuss recent findings from other authors as well as our own studies that have developed novel experimental models for interrogating the association between respiratory infections and severe steroid-resistant asthma. These models have enabled the identification of new therapies using macrolides, as well as several novel disease mechanisms, including the microRNA-21/phosphoinositide 3-kinase/histone deacetylase 2 axis and NLRP3 inflammasomes, and highlight the potential of these mechanisms as therapeutic targets.
    Type of Medium: Online Resource
    ISSN: 0905-9180 , 1600-0617
    URL: Article
    DOI: 10.1183/16000617.0096-2019
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2019
    detail.hit.zdb_id: 2202947-3
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  • 3
    Online Resource
    Online Resource
    Asthma-COPD overlap: current understanding and the utility of experimental models
    European Respiratory Society (ERS) ; 2021
    In:  European Respiratory Review Vol. 30, No. 159 ( 2021-03-31), p. 190185-
    Details
    In: European Respiratory Review, European Respiratory Society (ERS), Vol. 30, No. 159 ( 2021-03-31), p. 190185-
    Abstract: Pathological features of both asthma and COPD coexist in some patients and this is termed asthma-COPD overlap (ACO). ACO is heterogeneous and patients exhibit various combinations of asthma and COPD features, making it difficult to characterise the underlying pathogenic mechanisms. There are no controlled studies that define effective therapies for ACO, which arises from the lack of international consensus on the definition and diagnostic criteria for ACO, as well as scant in vitro and in vivo data. There remain unmet needs for experimental models of ACO that accurately recapitulate the hallmark features of ACO in patients. The development and interrogation of such models will identify underlying disease-causing mechanisms, as well as enabling the identification of novel therapeutic targets and providing a platform for assessing new ACO therapies. Here, we review the current understanding of the clinical features of ACO and highlight the approaches that are best suited for developing representative experimental models of ACO.
    Type of Medium: Online Resource
    ISSN: 0905-9180 , 1600-0617
    URL: Article
    DOI: 10.1183/16000617.0185-2019
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2021
    detail.hit.zdb_id: 2202947-3
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  • 4
    Online Resource
    Online Resource
    IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis
    European Respiratory Society (ERS) ; 2019
    In:  European Respiratory Journal Vol. 54, No. 1 ( 2019-07), p. 1800174-
    Details
    In: European Respiratory Journal, European Respiratory Society (ERS), Vol. 54, No. 1 ( 2019-07), p. 1800174-
    Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis. Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients. However, its roles in the pathogenesis of COPD is poorly understood. Here, we investigated the role of IL-22 in human COPD and in cigarette smoke (CS)-induced experimental COPD. IL-22 and IL-22 receptor mRNA expression and protein levels were increased in COPD patients compared to healthy smoking or non-smoking controls. IL-22 and IL-22 receptor levels were increased in the lungs of mice with experimental COPD compared to controls and the cellular source of IL-22 included CD4 + T-helper cells, γδ T-cells, natural killer T-cells and group 3 innate lymphoid cells. CS-induced pulmonary neutrophils were reduced in IL-22-deficient ( Il22 −/− ) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22 −/− mice. Il22 −/− mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance. These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD.
    Type of Medium: Online Resource
    ISSN: 0903-1936 , 1399-3003
    URL: Article
    URL: Article
    DOI: 10.1183/13993003.00174-2018
    DOI: 10.1183/13993003.00174-2018.Supp1
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2019
    detail.hit.zdb_id: 2834928-3
    detail.hit.zdb_id: 1499101-9
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  • 5
    Online Resource
    Online Resource
    Understanding the pathogenesis of occupational coal and silica dust-associated lung disease
    European Respiratory Society (ERS) ; 2022
    In:  European Respiratory Review Vol. 31, No. 165 ( 2022-09-30), p. 210250-
    Details
    In: European Respiratory Review, European Respiratory Society (ERS), Vol. 31, No. 165 ( 2022-09-30), p. 210250-
    Abstract: Workers in the mining and construction industries are at increased risk of respiratory and other diseases as a result of being exposed to harmful levels of airborne particulate matter (PM) for extended periods of time. While clear links have been established between PM exposure and the development of occupational lung disease, the mechanisms are still poorly understood. A greater understanding of how exposures to different levels and types of PM encountered in mining and construction workplaces affect pathophysiological processes in the airways and lungs and result in different forms of occupational lung disease is urgently required. Such information is needed to inform safe exposure limits and monitoring guidelines for different types of PM and development of biomarkers for earlier disease diagnosis. Suspended particles with a 50% cut-off aerodynamic diameter of 10 µm and 2.5 µm are considered biologically active owing to their ability to bypass the upper respiratory tract's defences and penetrate deep into the lung parenchyma, where they induce potentially irreversible damage, impair lung function and reduce the quality of life. Here we review the current understanding of occupational respiratory diseases, including coal worker pneumoconiosis and silicosis, and how PM exposure may affect pathophysiological responses in the airways and lungs. We also highlight the use of experimental models for better understanding these mechanisms of pathogenesis. We outline the urgency for revised dust control strategies, and the need for evidence-based identification of safe level exposures using clinical and experimental studies to better protect workers’ health.
    Type of Medium: Online Resource
    ISSN: 0905-9180 , 1600-0617
    URL: Article
    DOI: 10.1183/16000617.0250-2021
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2022
    detail.hit.zdb_id: 2202947-3
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