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Journal ArticleDOI

Cellular and molecular mechanisms of asthma and COPD.

01 Jul 2017-Clinical Science (PORTLAND PRESS LTD)-Vol. 131, Iss: 13, pp 1541-1558
TL;DR: The inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted to better understand the underlying cellular and molecular mechanisms in order to develop new treatments in areas of unmet need.
Abstract: Asthma and chronic obstructive pulmonary disease (COPD) both cause airway obstruction and are associated with chronic inflammation of the airways. However, the nature and sites of the inflammation differ between these diseases, resulting in different pathology, clinical manifestations and response to therapy. In this review, the inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted. These differences account for the differences in clinical manifestations of asthma and COPD and their response to therapy. Although asthma and COPD are usually distinct, there are some patients who show an overlap of features, which may be explained by the coincidence of two common diseases or distinct phenotypes of each disease. It is important to better understand the underlying cellular and molecular mechanisms of asthma and COPD in order to develop new treatments in areas of unmet need, such as severe asthma, curative therapy for asthma and effective anti-inflammatory treatments for COPD.
Citations
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Journal ArticleDOI
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012 and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

2,853 citations

Journal ArticleDOI
TL;DR: Drugs that target the cytokines that drive asthma and chronic obstructive pulmonary disease offer relief to some people with these diseases, however, further success will require a better understanding of the disease mechanisms and selection of the right drug for the right patient.
Abstract: Cytokines play a key role in orchestrating and perpetuating the chronic airway inflammation in asthma and chronic obstructive pulmonary disease (COPD), making them attractive targets for treating these disorders. Asthma and some cases of COPD are mainly driven by type 2 immune responses, which comprise increased airway eosinophils, T helper 2 (TH2) cells and group 2 innate lymphoid cells (ILC2s) and the secretion of IL-4, IL-5 and IL-13. Clinical trials of antibodies that block these interleukins have shown reduced acute exacerbations and oral corticosteroid use and improvements in lung function and symptoms in selected patients. More recent approaches that block upstream cytokines, such as thymic stromal lymphopoietin (TSLP), show promise in improving patient outcome. Importantly, the clinical trials in cytokine blockade have highlighted the crucial importance of patient selection for the successful use of these expensive therapies and the need for biomarkers to better predict drug responses.

254 citations

Journal ArticleDOI
TL;DR: This review focuses on inflammaging and its contribution to various age-related diseases such as cardiovascular disease, cancer, neurodegenerative diseases, chronic obstructive pulmonary disease, diabetes, and rheumatoid arthritis.
Abstract: It has been proposed that a chronic state of inflammation correlated with aging known as inflammaging, is implicated in multiple disease states commonly observed in the elderly population. Inflammaging is associated with over-abundance of reactive oxygen species in the cell, which can lead to oxidation and damage of cellular components, increased inflammation, and activation of cell death pathways. This review focuses on inflammaging and its contribution to various age-related diseases such as cardiovascular disease, cancer, neurodegenerative diseases, chronic obstructive pulmonary disease, diabetes, and rheumatoid arthritis. Recently published mechanistic details of the roles of reactive oxygen species in inflammaging and various diseases will also be discussed. Advancements in potential treatments to ameliorate inflammaging, oxidative stress, and consequently, reduce the morbidity of multiple disease states will be explored.

227 citations


Additional excerpts

  • ...Following the activation of PRRs such as TLRs, epithelial cells and immune cells release chemokines that attract the inflammatory cells to the site of inflammation which include Th1 cells, type 1 cytotoxic T cells, monocytes, and neutrophils [182,183]....

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Journal ArticleDOI
TL;DR: It is found that inflammatory response in COPD is determined by the activation of epithelial cells and macrophages in the respiratory tract, and mechanistic computational models that have been applied in studying the complex physiological and pathological mechanisms of chronic inflammation in different airway diseases are presented.
Abstract: Inflammation in the lung is the body’s natural response to injury. It acts to remove harmful stimuli such as pathogens, irritants, and damaged cells and initiate the healing process. Acute and chronic pulmonary inflammation are seen in different respiratory diseases such as; acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF). In this review, we found that inflammatory response in COPD is determined by the activation of epithelial cells and macrophages in the respiratory tract. Epithelial cells and macrophages discharge transforming growth factor-β (TGF-β), which trigger fibroblast proliferation and tissue remodeling. Asthma leads to airway hyper-responsiveness, obstruction, mucus hyper-production, and airway-wall remodeling. Cytokines, allergens, chemokines, and infectious agents are the main stimuli that activate signaling pathways in epithelial cells in asthma. Mutation of the CF transmembrane conductance regulator (CFTR) gene results in CF. Mutations in CFTR influence the lung epithelial innate immune function that leads to exaggerated and ineffective airway inflammation that fails to abolish pulmonary pathogens. We present mechanistic computational models (based on ordinary differential equations, partial differential equations and agent-based models) that have been applied in studying the complex physiological and pathological mechanisms of chronic inflammation in different airway diseases. The scope of the present review is to explore the inflammatory mechanism in airway diseases and highlight the influence of aging on airways’ inflammation mechanism. The main goal of this review is to encourage research collaborations between experimentalist and modelers to promote our understanding of the physiological and pathological mechanisms that control inflammation in different airway diseases.

155 citations


Cites background from "Cellular and molecular mechanisms o..."

  • ...CXCL9, CXCL10 and CXCL11 act on CXCR3 to attract T helper 1 (TH1) cells and type 1 cytotoxic T (TC1) cells [82]....

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Journal ArticleDOI
TL;DR: Global measures, that aim to reduce exposure to air pollutants, are highly needed in order to improve the outcomes and management of adult and pediatric asthma in addition to the existing guidelines.
Abstract: Asthma is a chronic respiratory disease characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Evidence suggests that air pollution has a negative impact on asthma outcomes in both adult and pediatric populations. The aim of this review is to summarize the current knowledge on the effect of various outdoor and indoor pollutants on asthma outcomes, their burden on its management, as well as to highlight the measures that could result in improved asthma outcomes. Traffic-related air pollution, nitrogen dioxide and second-hand smoking (SHS) exposures represent significant risk factors for asthma development in children. Nevertheless, a causal relation between air pollution and development of adult asthma is not clearly established. Exposure to outdoor pollutants can induce asthma symptoms, exacerbations and decreases in lung function. Active tobacco smoking is associated with poorer asthma control, while exposure to SHS increases the risk of asthma exacerbations, respiratory symptoms and healthcare utilization. Other indoor pollutants such as heating sources and molds can also negatively impact the course of asthma. Global measures, that aim to reduce exposure to air pollutants, are highly needed in order to improve the outcomes and management of adult and pediatric asthma in addition to the existing guidelines.

146 citations


Cites background from "Cellular and molecular mechanisms o..."

  • ...There are high levels of nitric oxide in tobacco smoke generating peroxynitrite, which leads to the inactivation of HDAC-2 via nitration and ubiquitination [135,136]....

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References
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Journal ArticleDOI
Rafael Lozano1, Mohsen Naghavi1, Kyle J Foreman2, Stephen S Lim1  +192 moreInstitutions (95)
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex, using the Cause of Death Ensemble model.

11,809 citations

Journal ArticleDOI
TL;DR: Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles, coupled to a repair or remodeling process that thickens the walls of these airways.
Abstract: Background Chronic obstructive pulmonary disease (COPD) is a major public health problem associated with long-term exposure to toxic gases and particles. We examined the evolution of the pathological effects of airway obstruction in patients with COPD. Methods The small airways were assessed in surgically resected lung tissue from 159 patients — 39 with stage 0 (at risk), 39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Results The progression of COPD was strongly associated with an increase in the volume of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates containing follicles (P=0.003) and the abs...

3,401 citations

Journal ArticleDOI
05 Jun 2014-Nature
TL;DR: The mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions are covered.
Abstract: Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.

2,130 citations

Journal ArticleDOI
TL;DR: A single dose of monoclonal antibody to IL-5 decreased blood eosinophils for up to 16 weeks and sputum eosInophils at 4 weeks, which has considerable therapeutic potential for asthma and allergy, however, the findings question the role of eos inophils in mediating the late asthmatic response and causing airway hyper-responsiveness.

1,824 citations

Journal ArticleDOI
TL;DR: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control and the safety profile of mepolIZumab was similar to that of placebo.
Abstract: BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

1,680 citations

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