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Zhang Y, Wang L, Zeng J, Shen W. Research advances in polyphenols from Chinese herbal medicine for the prevention and treatment of chronic obstructive pulmonary disease: a review. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03945-y. [PMID: 40035820 DOI: 10.1007/s00210-025-03945-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 02/17/2025] [Indexed: 03/06/2025]
Abstract
Chronic obstructive pulmonary disease (COPD) is a global health problem due to its high death and morbidity worldwide, which is characterized by an incompletely reversible limitation in airflow that is not fully reversible. Unfortunately, Western medical treatments are unable to reverse the progressive decline in lung function. Importantly, polyphenolic compounds isolated from Chinese herbal medicine exhibited therapeutic/interventional effects on COPD in preclinical studies. This review systematically analyzed the pathogenesis of COPD, such as inflammation, oxidative stress, protease/antiprotease imbalance, aging, cell death, and dysbiosis of gut microbiota. Moreover, this review summarized the regulatory mechanisms of natural polyphenolic compounds for the treatment of COPD. Several studies have demonstrated that natural polyphenolic compounds have therapeutic effects on COPD by regulating various biological processes, such as anti-inflammatory, reduction of oxidative damage, anti-cell death, and inhibition of airway hyperglycemia. Mechanistically, this review found that the promising effects of natural polyphenolic compounds on COPD were mainly achieved through modulating the NF-κB and MAPK inflammatory pathways, the Nrf2 oxidative stress pathway, and the SIRT1/PGC-1α lung injury pathway. Furthermore, this review analyzed the efficacy and safety of natural polyphenolic compounds for the treatment of COPD in clinical trials, and discussed their challenges and future development directions. In conclusion, this review combined the latest literature to illustrate the various pathogenesis and interrelationships of COPD in the form of graphs, texts, and tables, and sorted out the functional role and mechanisms of natural polyphenols in treating COPD, with a view to providing new ideas and plans for the in-depth research on COPD and the systemic treatment of COPD with Chinese herbal medicine.
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Affiliation(s)
- Yang Zhang
- Department of General Practice Medicine, The Second Affiliated Hospital of Kunming Medical University, No. 374 Dianmian Avenue, Wuhua District, Kunming, 650101, China
| | - Lijuan Wang
- Department of Nuclear Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China
| | - Jinyi Zeng
- Department of General Practice Medicine, The Second Affiliated Hospital of Kunming Medical University, No. 374 Dianmian Avenue, Wuhua District, Kunming, 650101, China
| | - Wen Shen
- Department of General Practice Medicine, The Second Affiliated Hospital of Kunming Medical University, No. 374 Dianmian Avenue, Wuhua District, Kunming, 650101, China.
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2
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Lee J, Mohammad N, Han K, Flagg-Dowie T, Magallon M, Brantly ML, Serban KA. Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency. Front Immunol 2025; 16:1543729. [PMID: 40013145 PMCID: PMC11861504 DOI: 10.3389/fimmu.2025.1543729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 01/27/2025] [Indexed: 02/28/2025] Open
Abstract
Neutrophilic inflammation and a high level of free α-defensins are main features of chronic airway inflammation in alpha-1 antitrypsin-deficient (AATD) individuals. Despite the antimicrobial activities of α-defensins by direct bacterial killing and by modulation of immune responses, AATD individuals are paradoxically burdened by recurrent exacerbation triggered by bacterial infections, frequently with nontypeable Haemophilus influenzae (NTHi). Previous studies demonstrated that high, rather than low α-defensin level could modulate the local pro-inflammatory milieu of bronchial epithelial cells and macrophages promoting chronic inflammation and lower pathogen phagocytosis. IgG-mediated phagocytosis and NTHi adherence, engulfment and phagocytosis were measured in human alveolar macrophages and monocyte-derived macrophages (MDM) isolated from patients with AATD and from healthy individuals. A high concentration of free α-defensins induced NTHi adherence to MDMs but decreased IgG-mediated phagocytosis by MDMs. The decreased phagocytosis was associated with TLR4 activation, downstream signaling via NF-κB p65 and marked increased secretion of inflammatory cytokines, CXCL8, IL-1b, and TNFα by the α-defensin-treated and NTHi-infected MDMs. Exogenous AAT treatment and TLR4 inhibitor decreased TNFα expression in α-defensin-treated cells. Dampening the downstream effects of a high concentration of α-defensins may render AAT and TLR4 inhibitors as potential therapies to decrease NTHi colonization and increase its clearance by phagocytosis in AATD individuals.
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Affiliation(s)
- Jungnam Lee
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
| | - Naweed Mohammad
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
| | - Kyudong Han
- Department of Microbiology, College of Bio-convergence, Dankook University, Cheonan, Republic of Korea
- Center for Bio-Medical Engineering Core Facility, Dankook University, Cheonan, Republic of Korea
| | - Tammy Flagg-Dowie
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
| | - Maria Magallon
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
| | - Mark L. Brantly
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
| | - Karina A. Serban
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, United States
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Tu Y, Chen Y, Li X, Wang Y, Fang B, Ren Y, Wang C. Advances in acute COPD exacerbation: clarifying specific immune mechanisms of infectious and noninfectious factors. Ther Adv Respir Dis 2025; 19:17534666241308408. [PMID: 40098281 PMCID: PMC11915264 DOI: 10.1177/17534666241308408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025] Open
Abstract
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the main cause of hospitalization and death of patients with chronic obstructive pulmonary disease. This is largely due to bacterial resistance caused by clinical antibiotic abuse and the limited efficacy of current treatment strategies in managing noninfectious AECOPD, which presents a significant challenge for clinicians. Therefore, it is urgent for clinical treatment and prevention of AECOPD to fully understand the specific mechanism of AECOPD in the immune system and master the key differences between infectious factors and noninfectious factors. This article systematically discusses AECOPD triggered by various factors, including the activation of immune system, the recruitment and activation of inflammatory cells and the role of specific inflammatory responses, and through a comprehensive review of the literature, this article expounds the existing targeted diagnosis and treatment methods and technologies at different stages in order to provide new ideas and strategies for clinical prevention and treatment of AECOPD.
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Affiliation(s)
- Yadan Tu
- Department of Classic Chinese Medicine, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing, China
- Classic Department of Traditional Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Yong Chen
- Department of Classic Chinese Medicine, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing, China
- Classic Department of Traditional Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Xuanhan Li
- Department of Classic Chinese Medicine, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing, China
- Classic Department of Traditional Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Yigang Wang
- Department of Classic Chinese Medicine, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing, China
- Classic Department of Traditional Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Bangjiang Fang
- Emergency Department, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi Ren
- Department of Classic Chinese Medicine, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing 400021, China
- Classic Department of Traditional Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Chenghu Wang
- Department of Classic Chinese Medicine, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing, China
- Classic Department of Traditional Chinese Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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Sharma G, Gupta DP, Ganguly K, Anand MP, Srivastava S. Meta-Analysis and DIA-MS-Based Proteomic Investigation of COPD Patients and Asymptomatic Smokers in the Indian Population. J Proteome Res 2024; 23:4973-4987. [PMID: 39436829 DOI: 10.1021/acs.jproteome.4c00463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Chronic obstructive pulmonary disease (COPD) is India's second largest cause of death and is largely caused by smoking. Asymptomatic smokers develop COPD due to genetic, environmental, and molecular variables, making early screening crucial. Data-independent acquisition mass spectrometry (DIA-MS) based-proteomics offers an unbiased method to analyze proteomic profiles. This study is the first to use DIA-based proteomics to analyze individual serum samples from three distinct male cohorts: healthy individuals (n = 10), asymptomatic smokers (n = 10), and COPD patients (n = 10). This comprehensive approach identified 667 proteins with a 1% false discovery rate. Differentially expressed proteins included 40 in the normal versus asymptomatic comparison, 88 in the COPD versus normal comparison, and 40 in the COPD versus asymptomatic comparison. Among them, protein-associated genes such as PRDX6, ELANE, PRKCSH, PRTN3, and MNDA could help differentiate COPD from asymptomatic smokers, while ELANE, H3-3A, IGHE, SLC4A1, and SERPINA11 could differentiate COPD from healthy subjects. Pathway enrichment and protein-protein interaction analyses revealed significant alterations in hemostasis, immune system functions, fibrin clot formation, and post-translational protein modifications. Key proteins were validated using a parallel reaction monitoring assay. DIA data are available via ProteomeXchange with identifier PXD055242. Our findings reveal key protein classifiers in COPD patients, asymptomatic smokers, and healthy individuals, helping clinicians understand disease pathobiology and improve disease management and quality of life.
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Affiliation(s)
- Gautam Sharma
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Maharashtra 400076, India
| | - Debarghya Pratim Gupta
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Maharashtra 400076, India
| | - Koustav Ganguly
- Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Mahesh Padukudru Anand
- Department of Respiratory Medicine, JSS Medical College, JSSAHER, Mysore, Karnataka 570015, India
| | - Sanjeeva Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Maharashtra 400076, India
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Sandhu KK, Scott A, Tatler AL, Belchamber KBR, Cox MJ. Macrophages and the microbiome in chronic obstructive pulmonary disease. Eur Respir Rev 2024; 33:240053. [PMID: 39631929 PMCID: PMC11615662 DOI: 10.1183/16000617.0053-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/22/2024] [Indexed: 12/07/2024] Open
Abstract
COPD is a heterogeneous disease of the lungs characterised by restricted airflow. Chronic inflammation and recurrent bacterial infections are known to be important driving factors in exacerbations of this disease. Despite a marked increase in the number of alveolar macrophages present in the lungs of COPD patients, there is evidence of reduced clearance of pathogenic bacteria, leading to recurrent infection, exacerbation and subsequent lung function decline. This is thought to be attributed to a defect in the phagocytic capability of both alveolar and monocyte-derived macrophages in COPD. In addition to this defect, there is apparent selectivity in bacterial uptake by COPD macrophages because certain pathogenic genera, such as Haemophilus, Moraxella and Streptococcus, are taken up more readily than others. The respiratory microbiome plays a key role in regulating the host immune response both in health and during chronic inflammation. In patients with COPD, there are distinct changes in the composition of the respiratory microbiome, particularly the lower respiratory tract, where dominance of clinically relevant pathogenic species is commonly observed. Whether there are links between these changes in the microbiome and dysfunctional macrophage phagocytosis has not yet been widely studied. This review aims to discuss what is currently known about these phenomena and to explore interactions between macrophages and the respiratory microbiome.
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Affiliation(s)
- Karanjot K Sandhu
- Department of Microbes, Infection and Microbiomes, Institute of Microbiology and Infection, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
- Department of Inflammation and Ageing, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
| | - Aaron Scott
- Department of Inflammation and Ageing, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
| | - Amanda L Tatler
- Centre for Respiratory Research, School of Medicine, University of Nottingham, Nottingham, UK
- Biodiscovery Institute, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham, UK
| | - Kylie B R Belchamber
- Department of Inflammation and Ageing, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
- These authors contributed equally
| | - Michael J Cox
- Department of Microbes, Infection and Microbiomes, Institute of Microbiology and Infection, School of Infection, Inflammation and Immunity, College of Medicine and Health, University of Birmingham, Birmingham, UK
- These authors contributed equally
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6
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Abrham Y, Zeng S, Lin W, Lo C, Beckert A, Evans L, Dunn M, Giang B, Thakkar K, Roman J, Blanc PD, Arjomandi M. Self-report underestimates the frequency of the acute respiratory exacerbations of COPD but is associated with BAL neutrophilia and lymphocytosis: an observational study. BMC Pulm Med 2024; 24:433. [PMID: 39223571 PMCID: PMC11367895 DOI: 10.1186/s12890-024-03239-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
RATIONALE Research studies typically quantify acute respiratory exacerbation episodes (AECOPD) among people with chronic obstructive pulmonary disease (COPD) based on self-report elicited by survey questionnaire. However, AECOPD quantification by self-report could be inaccurate, potentially rendering it an imprecise tool for identification of those with exacerbation tendency. OBJECTIVE Determine the agreement between self-reported and health records-documented quantification of AECOPD and their association with airway inflammation. METHODS We administered a questionnaire to elicit the incidence and severity of respiratory exacerbations in the three years preceding the survey among current or former heavy smokers with or without diagnosis of COPD. We then examined electronic health records (EHR) of those with COPD and those without (tobacco-exposed persons with preserved spirometry or TEPS) to determine whether the documentation of the three-year incidence of moderate to very severe respiratory exacerbations was consistent with self-report using Kappa Interrater statistic. A subgroup of participants also underwent bronchoalveolar lavage (BAL) to quantify their airway inflammatory cells. We further used multivariable regressions analysis to estimate the association between respiratory exacerbations and BAL inflammatory cell composition with adjustment for covariates including age, sex, height, weight, smoking status (current versus former) and burden (pack-years). RESULTS Overall, a total of 511 participants completed the questionnaire, from whom 487 had EHR available for review. Among the 222 participants with COPD (70 ± 7 years-old; 96% male; 70 ± 38 pack-years smoking; 42% current smoking), 57 (26%) reported having any moderate to very severe AECOPD (m/s-AECOPD) while 66 (30%) had EHR documentation of m/s-AECOPD. However, 42% of those with EHR-identified m/s-AECOPD had none by self-report, and 33% of those who reported m/s-AECOPD had none by EHR, suggesting only moderate agreement (Cohen's Kappa = 0.47 ± 0.07; P < 0.001). Nevertheless, self-reported and EHR-identified m/s-AECOPD events were both associated with higher BAL neutrophils (ß ± SEM: 3.0 ± 1.1 and 1.3 ± 0.5 per 10% neutrophil increase; P ≤ 0.018) and lymphocytes (0.9 ± 0.4 and 0.7 ± 0.3 per 10% lymphocyte increase; P ≤ 0.041). Exacerbation by either measure combined was associated with a larger estimated effect (3.7 ± 1.2 and 1.0 ± 0.5 per 10% increase in neutrophils and lymphocytes, respectively) but was not statistically significantly different compared to the self-report only approach. Among the 184 TEPS participants, there were fewer moderate to very severe respiratory exacerbations by self-report (n = 15 or 8%) or EHR-documentation (n = 9 or 5%), but a similar level of agreement as those with COPD was observed (Cohen's Kappa = 0.38 ± 0.07; P < 0.001). DISCUSSION While there is modest agreement between self-reported and EHR-identified m/s-AECOPD, events are missed by relying on either method alone. However, m/s-AECOPD quantified by self-report or health records is associated with BAL neutrophilia and lymphocytosis.
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Affiliation(s)
- Yorusaliem Abrham
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Siyang Zeng
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, USA
| | - Wendy Lin
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, USA
| | - Colin Lo
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, USA
| | - Alexander Beckert
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Laurel Evans
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Michelle Dunn
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Brian Giang
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Krish Thakkar
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Julian Roman
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Paul D Blanc
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Mehrdad Arjomandi
- Medical Service, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA.
- Department of Medicine, University of California, San Francisco, CA, USA.
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7
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Murphy MP, Hunt D, Herron M, McDonnell J, Alshuhoumi R, McGarvey LP, Fabré A, O’Brien H, McCarthy C, Martin SL, McElvaney NG, Reeves EP. Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:75-85. [PMID: 38758115 PMCID: PMC11212725 DOI: 10.4049/jimmunol.2300658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 04/12/2024] [Indexed: 05/18/2024]
Abstract
In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.
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Affiliation(s)
- Mark P. Murphy
- Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - David Hunt
- Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Malcolm Herron
- Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Jake McDonnell
- Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Rashed Alshuhoumi
- Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Lorcan P. McGarvey
- Wellcome–Wolfson Centre for Experimental Medicine, School of Medicine Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
- Department of Respiratory Medicine, Royal Victoria Hospital; Belfast Health Social Care Trust, Belfast, United Kingdom
| | - Aurelie Fabré
- Department of Histopathology, St. Vincent’s University Hospital and Department of Medicine, University College Dublin, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Helen O’Brien
- Department of Respiratory Medicine, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland
| | - Cormac McCarthy
- School of Medicine, University College Dublin, Dublin, Ireland
- Department of Respiratory Medicine, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland
| | - S. Lorraine Martin
- Biomolecular Sciences Research Group, School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom
| | - Noel G. McElvaney
- Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Emer P. Reeves
- Pulmonary Clinical Science, Department of Anaesthesia and Critical Care Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
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8
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Kim GD, Lim EY, Shin HS. Macrophage Polarization and Functions in Pathogenesis of Chronic Obstructive Pulmonary Disease. Int J Mol Sci 2024; 25:5631. [PMID: 38891820 PMCID: PMC11172060 DOI: 10.3390/ijms25115631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD), the major leading cause of mortality worldwide, is a progressive and irreversible respiratory condition characterized by peripheral airway and lung parenchymal inflammation, accompanied by fibrosis, emphysema, and airflow limitation, and has multiple etiologies, including genetic variance, air pollution, and repetitive exposure to harmful substances. However, the precise mechanisms underlying the pathogenesis of COPD have not been identified. Recent multiomics-based evidence suggests that the plasticity of alveolar macrophages contributes to the onset and progression of COPD through the coordinated modulation of numerous transcription factors. Therefore, this review focuses on understanding the mechanisms and functions of macrophage polarization that regulate lung homeostasis in COPD. These findings may provide a better insight into the distinct role of macrophages in COPD pathogenesis and perspective for developing novel therapeutic strategies targeting macrophage polarization.
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Affiliation(s)
- Gun-Dong Kim
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Republic of Korea; (G.-D.K.); (E.Y.L.)
| | - Eun Yeong Lim
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Republic of Korea; (G.-D.K.); (E.Y.L.)
| | - Hee Soon Shin
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Republic of Korea; (G.-D.K.); (E.Y.L.)
- Department of Food Biotechnology, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea
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9
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Carlier FM, Detry B, Lecocq M, Collin AM, Planté-Bordeneuve T, Gérard L, Verleden SE, Delos M, Rondelet B, Janssens W, Ambroise J, Vanaudenaerde BM, Gohy S, Pilette C. The memory of airway epithelium damage in smokers and COPD patients. Life Sci Alliance 2024; 7:e202302341. [PMID: 38158219 PMCID: PMC10756916 DOI: 10.26508/lsa.202302341] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 01/03/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD), a devastating and irreversible lung disease, causes structural and functional defects in the bronchial epithelium, the (ir)reversibility of which remains unexplored in vitro. This study aimed to investigate the persistence of COPD-related epithelial defects in long-term airway epithelial cultures derived from non-smokers, smokers, and COPD patients. Barrier function, polarity, cell commitment, epithelial-to-mesenchymal transition, and inflammation were evaluated and compared with native epithelium characteristics. The role of inflammation was explored using cytokines. We show that barrier dysfunction, compromised polarity, and lineage abnormalities observed in smokers and COPD persisted for up to 10 wk. Goblet cell hyperplasia was associated with recent cigarette smoke exposure. Conversely, increased IL-8/CXCL-8 release and abnormal epithelial-to-mesenchymal transition diminished over time. These ex vivo observations matched surgical samples' abnormalities. Cytokine treatment induced COPD-like changes in control cultures and reactivated epithelial-to-mesenchymal transition in COPD cells. In conclusion, these findings suggest that the airway epithelium of smokers and COPD patients retains a multidimensional memory of its original state and previous cigarette smoke-induced injuries, maintaining these abnormalities for extended periods.
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Affiliation(s)
- François M Carlier
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
- Department of Pneumology, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
- Lung Transplant Centre, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
| | - Bruno Detry
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Marylène Lecocq
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Amandine M Collin
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Thomas Planté-Bordeneuve
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Ludovic Gérard
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Stijn E Verleden
- Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Monique Delos
- Department of Pathology, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
| | - Benoît Rondelet
- Lung Transplant Centre, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
- Deparment of Cardiovascular and Thoracic Surgery, CHU Mont-Godinne UCL Namur, Yvoir, Belgium
| | - Wim Janssens
- Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Jérôme Ambroise
- Centre de Technologies Moléculaires Appliquées, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Bart M Vanaudenaerde
- Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Sophie Gohy
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
- Department of Pneumology, Cliniques Universitaires St-Luc, Brussels, Belgium
- Cystic Fibrosis Reference Center, Cliniques Universitaires St-Luc, Brussels, Belgium
| | - Charles Pilette
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
- Department of Pneumology, Cliniques Universitaires St-Luc, Brussels, Belgium
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10
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Russo S, Kwiatkowski M, Wolters JC, Gerding A, Hermans J, Govorukhina N, Bischoff R, Melgert BN. Effects of lysine deacetylase inhibitor treatment on LPS responses of alveolar-like macrophages. J Leukoc Biol 2024; 115:435-449. [PMID: 37811856 DOI: 10.1093/jleuko/qiad121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 10/10/2023] Open
Abstract
Macrophages are key immune cells that can adapt their metabolic phenotype in response to different stimuli. Lysine deacetylases are important enzymes regulating inflammatory gene expression and lysine deacetylase inhibitors have been shown to exert anti-inflammatory effects in models of chronic obstructive pulmonary disease. We hypothesized that these anti-inflammatory effects may be associated with metabolic changes in macrophages. To validate this hypothesis, we used an unbiased and a targeted proteomic approach to investigate metabolic enzymes, as well as liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry, to quantify metabolites in combination with the measurement of functional parameters in primary murine alveolar-like macrophages after lipopolysaccharide-induced activation in the presence or absence of lysine deacetylase inhibition. We found that lysine deacetylase inhibition resulted in reduced production of inflammatory mediators such as tumor necrosis factor α and interleukin 1β. However, only minor changes in macrophage metabolism were observed, as only one of the lysine deacetylase inhibitors slightly increased mitochondrial respiration while no changes in metabolite levels were seen. However, lysine deacetylase inhibition specifically enhanced expression of proteins involved in ubiquitination, which may be a driver of the anti-inflammatory effects of lysine deacetylase inhibitors. Our data illustrate that a multiomics approach provides novel insights into how macrophages interact with cues from their environment. More detailed studies investigating ubiquitination as a potential driver of lysine deacetylase inhibition will help developing novel anti-inflammatory drugs for difficult-to-treat diseases such as chronic obstructive pulmonary disease.
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Affiliation(s)
- Sara Russo
- Department of Analytical Biochemistry, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands
| | - Marcel Kwiatkowski
- Functional Proteo-Metabolomics, Department of Biochemistry, University of Innsbruck, Innrain 80-82, Innsbruck 6020, Austria
| | - Justina C Wolters
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands
| | - Albert Gerding
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands
| | - Jos Hermans
- Department of Analytical Biochemistry, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands
| | - Natalia Govorukhina
- Department of Analytical Biochemistry, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands
| | - Rainer Bischoff
- Department of Analytical Biochemistry, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands
| | - Barbro N Melgert
- Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands
- Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands
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11
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Lea S, Higham A, Beech A, Singh D. How inhaled corticosteroids target inflammation in COPD. Eur Respir Rev 2023; 32:230084. [PMID: 37852657 PMCID: PMC10582931 DOI: 10.1183/16000617.0084-2023] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/05/2023] [Indexed: 10/20/2023] Open
Abstract
Inhaled corticosteroids (ICS) are the most commonly used anti-inflammatory drugs for the treatment of COPD. COPD has been previously described as a "corticosteroid-resistant" condition, but current clinical trial evidence shows that selected COPD patients, namely those with increased exacerbation risk plus higher blood eosinophil count (BEC), can benefit from ICS treatment. This review describes the components of inflammation modulated by ICS in COPD and the reasons for the variation in response to ICS between individuals. There are corticosteroid-insensitive inflammatory pathways in COPD, such as bacteria-induced macrophage interleukin-8 production and resultant neutrophil recruitment, but also corticosteroid-sensitive pathways including the reduction of type 2 markers and mast cell numbers. The review also describes the mechanisms whereby ICS can skew the lung microbiome, with reduced diversity and increased relative abundance, towards an excess of proteobacteria. BEC is a biomarker used to enable the selective use of ICS in COPD, but the clinical outcome in an individual is decided by a complex interacting network involving the microbiome and airway inflammation.
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Affiliation(s)
- Simon Lea
- Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Andrew Higham
- Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Augusta Beech
- Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Dave Singh
- Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- Medicines Evaluation Unit, Manchester University NHS Foundation Trust, Manchester, UK
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12
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Graf J, Trautmann-Rodriguez M, Sabnis S, Kloxin AM, Fromen CA. On the path to predicting immune responses in the lung: Modeling the pulmonary innate immune system at the air-liquid interface (ALI). Eur J Pharm Sci 2023; 191:106596. [PMID: 37770004 PMCID: PMC10658361 DOI: 10.1016/j.ejps.2023.106596] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/01/2023] [Accepted: 09/24/2023] [Indexed: 10/03/2023]
Abstract
Chronic respiratory diseases and infections are among the largest contributors to death globally, many of which still have no cure, including chronic obstructive pulmonary disorder, idiopathic pulmonary fibrosis, and respiratory syncytial virus among others. Pulmonary therapeutics afford untapped potential for treating lung infection and disease through direct delivery to the site of action. However, the ability to innovate new therapeutic paradigms for respiratory diseases will rely on modeling the human lung microenvironment and including key cellular interactions that drive disease. One key feature of the lung microenvironment is the air-liquid interface (ALI). ALI interface modeling techniques, using cell-culture inserts, organoids, microfluidics, and precision lung slices (PCLS), are rapidly developing; however, one major component of these models is lacking-innate immune cell populations. Macrophages, neutrophils, and dendritic cells, among others, represent key lung cell populations, acting as the first responders during lung infection or injury. Innate immune cells respond to and modulate stromal cells and bridge the gap between the innate and adaptive immune system, controlling the bodies response to foreign pathogens and debris. In this article, we review the current state of ALI culture systems with a focus on innate immune cells and suggest ways to build on current models to add complexity and relevant immune cell populations.
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Affiliation(s)
- Jodi Graf
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA
| | | | - Simone Sabnis
- Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA
| | - April M Kloxin
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA; Department of Materials Science and Engineering, University of Delaware, Newark, DE 19716, USA.
| | - Catherine A Fromen
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA.
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13
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Goncalves B, Eze UA. Sputum induction and its diagnostic applications in inflammatory airway disorders: a review. FRONTIERS IN ALLERGY 2023; 4:1282782. [PMID: 37901763 PMCID: PMC10600502 DOI: 10.3389/falgy.2023.1282782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 09/26/2023] [Indexed: 10/31/2023] Open
Abstract
Sputum induction is a technique that covers the induction and the subsequent processing of the expectorate primarily for the analysis of cells and different inflammatory biomarkers present in the airways to further understand the pathophysiology of different inflammatory respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD) as well as the diagnosis of lung diseases such as lung cancer, tuberculosis, and Pneumocystis jirovecii pneumonia. It is a non-invasive, safe, cost-effective, and reliable technique reported to exhibit a high success rate. However, due to being technically demanding and time-consuming and having the need of employing trained staff, this technique is only used in restricted research centres and in limited centres of clinical use. When the sputum is collected after induction, the primary goal is to obtain a differential cell count and evaluate the molecular biomarkers of airway inflammation such as eosinophil cationic protein, eosinophil-derived neurotoxin, major basic protein, tryptase, cytokine production [e.g., interleukin (IL)-5], albumin, and fibrinogen. In addition, cytospins from the processed sputum are used for immunocytochemical staining of cellular products such as EG-2 reactive protein, granulocyte-macrophage colony-stimulating factor, tumour necrosis factor alpha, and IL-8 that play significant roles in understanding the pathophysiology of inflammatory airway diseases. Nowadays, this technique can be further used by performing an additional analysis such as flow cytometry and in situ hybridisation on the sputum supernatant to investigate more the immune response and pathophysiological process of such various respiratory diseases. In addition, the application of sputum fluid phase to assess the biomarkers could be used more routinely in pathological laboratories for diagnosing lung cancer, COPD, and asthma as well as for monitoring lung cancer progression and asthma and COPD treatment, allowing for early detection and a better treatment provided by the clinicians.
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Affiliation(s)
- Beatriz Goncalves
- NIHR Leicester Biomedical Research Centre, Department of Respiratory Sciences, Glenfield Hospital, Leicester, United Kingdom
- Leicester School of Allied Health Sciences, Faculty of Health and Life Sciences, De Montfort University, Leicester, United Kingdom
| | - Ukpai A. Eze
- Leicester School of Allied Health Sciences, Faculty of Health and Life Sciences, De Montfort University, Leicester, United Kingdom
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14
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Arora A, Singh A. Exploring the role of neutrophils in infectious and noninfectious pulmonary disorders. Int Rev Immunol 2023; 43:41-61. [PMID: 37353973 DOI: 10.1080/08830185.2023.2222769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/31/2023] [Indexed: 06/25/2023]
Abstract
With the change in global environment, respiratory disorders are becoming more threatening to the health of people all over the world. These diseases are closely linked to performance of immune system. Within the innate arm of immune system, Neutrophils are an important moiety to serve as an immune defense barrier. They are one of the first cells recruited to the site of infection and plays a critical role in pathogenesis of various pulmonary diseases. It is established that the migration and activation of neutrophils can lead to inflammation either directly or indirectly and this inflammation caused is very crucial for the clearance of pathogens and resolution of infection. However, the immunopathological mechanisms involved to carry out the same is very complex and not well understood. Despite there being studies concentrating on the role of neutrophils in multiple respiratory diseases, there is still a long way to go in order to completely understand the complexity of the participation of neutrophils and mechanisms involved in the development of these respiratory diseases. In the present article, we have reviewed the literature to comprehensively provide an insight in the current development and advancements about the role of neutrophils in infectious respiratory disorders including viral respiratory disorders such as Coronavirus disease (COVID-19) and bacterial pulmonary disorders with a focused review on pulmonary tuberculosis as well as in noninfectious disorders like Chronic obstructive pulmonary disease (COPD) and asthma. Also, future directions into research and therapeutic targets have been discussed for further exploration.
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Affiliation(s)
- Alisha Arora
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Archana Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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15
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Kotlyarov S. The Role of Smoking in the Mechanisms of Development of Chronic Obstructive Pulmonary Disease and Atherosclerosis. Int J Mol Sci 2023; 24:8725. [PMID: 37240069 PMCID: PMC10217854 DOI: 10.3390/ijms24108725] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Tobacco smoking is a major cause of chronic obstructive pulmonary disease (COPD) and atherosclerotic cardiovascular disease (ASCVD). These diseases share common pathogenesis and significantly influence each other's clinical presentation and prognosis. There is increasing evidence that the mechanisms underlying the comorbidity of COPD and ASCVD are complex and multifactorial. Smoking-induced systemic inflammation, impaired endothelial function and oxidative stress may contribute to the development and progression of both diseases. The components present in tobacco smoke can have adverse effects on various cellular functions, including macrophages and endothelial cells. Smoking may also affect the innate immune system, impair apoptosis, and promote oxidative stress in the respiratory and vascular systems. The purpose of this review is to discuss the importance of smoking in the mechanisms underlying the comorbid course of COPD and ASCVD.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
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16
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Behl TA, Stamford BA, Moffatt RJ. The Effects of Smoking on the Diagnostic Characteristics of Metabolic Syndrome: A Review. Am J Lifestyle Med 2023; 17:397-412. [PMID: 37304742 PMCID: PMC10248373 DOI: 10.1177/15598276221111046] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2023] Open
Abstract
Metabolic syndrome is a growing epidemic that increases the risk for cardiovascular disease, diabetes, stroke, and mortality. It is diagnosed by the presence of three or more of the following risk factors: 1) obesity, with an emphasis on central adiposity, 2) high blood pressure, 3) hyperglycemia, 4) dyslipidemia, with regard to reduced high-density lipoprotein concentrations, and 5) dyslipidemia, with regard to elevated triglycerides. Smoking is one lifestyle factor that can increase the risk for metabolic syndrome as it has been shown to exert negative effects on abdominal obesity, blood pressure, blood glucose concentrations, and blood lipid profiles. Smoking may also negatively affect other factors that influence glucose and lipid metabolism including lipoprotein lipase, adiponectin, peroxisome proliferator-activated receptors, and tumor necrosis factor-alpha. Some of these smoking-related outcomes may be reversed with smoking cessation, thus reducing the risk for metabolic disease; however, metabolic syndrome risk may initially increase post cessation, possibly due to weight gain. Therefore, these findings warrant the need for more research on the development and efficacy of smoking prevention and cessation programs.
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Affiliation(s)
- Taylor A. Behl
- Department of Nutrition and Integrative Physiology, Florida State
University, Tallahassee, FL, USA (TAB); School of Business, Education,
and Mathematics, Flagler College, St Augustine, FL, USA (TAB); Department of Kinesiology and
Integrative Physiology, Hanover College, Hanover, IN, USA (BAS); and Human Performance Development
Group, Tallahassee, FL, USA (BAS, RJM)
| | - Bryant A. Stamford
- Department of Nutrition and Integrative Physiology, Florida State
University, Tallahassee, FL, USA (TAB); School of Business, Education,
and Mathematics, Flagler College, St Augustine, FL, USA (TAB); Department of Kinesiology and
Integrative Physiology, Hanover College, Hanover, IN, USA (BAS); and Human Performance Development
Group, Tallahassee, FL, USA (BAS, RJM)
| | - Robert J. Moffatt
- Department of Nutrition and Integrative Physiology, Florida State
University, Tallahassee, FL, USA (TAB); School of Business, Education,
and Mathematics, Flagler College, St Augustine, FL, USA (TAB); Department of Kinesiology and
Integrative Physiology, Hanover College, Hanover, IN, USA (BAS); and Human Performance Development
Group, Tallahassee, FL, USA (BAS, RJM)
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17
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Neutrophil Extracellular Traps in Airway Diseases: Pathological Roles and Therapeutic Implications. Int J Mol Sci 2023; 24:ijms24055034. [PMID: 36902466 PMCID: PMC10003347 DOI: 10.3390/ijms24055034] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can contribute to the pathogenesis of airway diseases. NETs are known to be directly cytotoxic to the lung epithelium and endothelium, highly involved in acute lung injury, and implicated in disease severity and exacerbation. This review describes the role of NET formation in airway diseases, including chronic rhinosinusitis, and suggests that targeting NETs could be a therapeutic strategy for airway diseases.
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18
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SERPINA1 and More? A Putative Genetic Contributor to Pulmonary Dysfunction in Alpha-1 Antitrypsin Deficiency. J Clin Med 2023; 12:jcm12051708. [PMID: 36902496 PMCID: PMC10003154 DOI: 10.3390/jcm12051708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/23/2023] Open
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a common inherited disorder associated with an increased risk of pulmonary disease. Its clinical presentation, including the nature and severity of organ involvement, is highly variable and unpredictable and is not as strongly linked to genotype and environmental exposure (e.g., smoking history) as might be expected. Significant differences were observed within matched populations of severe AATD patients regarding risk of complications, age at onset, and disease course, including the dynamics of lung function decline. Genetic factors are among the putative modifiers contributing to the clinical variability in AATD, yet their role remains elusive. Here, we review and summarise our current understanding of epigenetic and genetic modifiers of pulmonary dysfunction in subjects with AATD.
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19
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Kim JH, Kim JW, Kim CY, Jeong JS, Ko JW, Kim TW. Green tea extract ameliorates macrophage-driven emphysematous lesions in chronic obstructive pulmonary disease induced by cigarette smoke condensate. Phytother Res 2023; 37:1366-1376. [PMID: 36729048 DOI: 10.1002/ptr.7745] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 12/14/2022] [Accepted: 01/21/2023] [Indexed: 02/03/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) is an important lung disease characterized by complicated symptoms including emphysema. We aimed to explore the mechanisms underlying the protective effect of green tea extract (GTE) on cigarette smoke condensate (CSC)-induced emphysema by demonstrating the reduction of macrophage-induced protease expression through GTE treatment in vivo and in vitro. Mice were intranasally administered 50 mg/kg CSC once a week for 4 weeks, and doses of 100 or 300 mg/kg GTE were administered orally once daily for 4 weeks. GTE significantly reduced macrophage counts in bronchoalveolar lavage fluid and emphysematous lesions in lung tissues in CSC-exposed mice. In addition, GTE suppressed CSC-induced extracellular signal-regulated kinase (ERK)/activator protein (AP)-1 phosphorylation followed by matrix metalloproteinases (MMP)-9 expression as revealed by western blotting, immunohistochemistry, and zymography in CSC-instilled mice. These underlying mechanisms related to reduced protease expression were confirmed in NCI-H292 cells stimulated by CSC. Taken together, GTE effectively inhibits macrophage-driven emphysematous lesions induced by CSC treatment, and these protective effects of GTE are closely related to the ERK/AP-1 signaling pathway, followed by a reduced protease/antiprotease imbalance. These results suggest that GTE can be used as a supplementary agent for the prevention of emphysema progression in COPD patients.
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Affiliation(s)
- Jin-Hwa Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Jeong-Won Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Chang-Yeop Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Ji-Soo Jeong
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Je-Won Ko
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
| | - Tae-Won Kim
- College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University, Daejeon, Republic of Korea
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20
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Protective Effects of Chestnut ( Castanea crenata) Inner Shell Extract in Macrophage-Driven Emphysematous Lesion Induced by Cigarette Smoke Condensate. Nutrients 2023; 15:nu15020253. [PMID: 36678124 PMCID: PMC9867500 DOI: 10.3390/nu15020253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/27/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Chestnut (Castanea crenata) inner shell extract (CIE), a curative herb in Korea, has diverse pharmacological effects against various diseases including pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease (COPD). However, its molecular mechanisms of anti-emphysematous effects are still not fully elucidated. In the present study, we elucidate the efficacy of CIE against emphysematous lesion progression in a cigarette smoke condensate (CSC)-instilled mice and CSC-stimulated H292 cell line. The mice are administered CSC via intranasal instillation at 7-day intervals for 1 month after 1 week of pretreatment with CIE. CIE (100 or 300 mg/kg) is administered by oral gavage for 1 month. CIE decreased the macrophage count in bronchoalveolar lavage fluid and the severity of emphysematous lesions in lung tissue. Additionally, CIE suppressed the phosphatidylinositol 3-kinase/protein kinase B/nuclear factor kappa B signal pathway and thereby downregulated matrix metalloprotease-9 expression, which was confirmed in CSC-stimulated H292 cells. Thus, CIE effectively inhibited CSC-induced macrophage-driven emphysema progression in airways; this inhibition was associated with the suppression of protease-antiprotease imbalance. Our results propose that CIE has the potential for the alleviation of COPD.
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21
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Mir MA, Bashir M, Ishfaq. Role of the CXCL8–CXCR1/2 Axis in Cancer and Inflammatory Diseases. CYTOKINE AND CHEMOKINE NETWORKS IN CANCER 2023:291-329. [DOI: 10.1007/978-981-99-4657-0_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Chami HA, Houjeij N, Makki M, Itani L, Tamim H, Al Mulla A, Celli B, Zeineldine S. Increased airway resistance among exclusive waterpipe smokers detected using impulse oscillometry. Ann Thorac Med 2023; 18:23-30. [PMID: 36968332 PMCID: PMC10034824 DOI: 10.4103/atm.atm_165_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 11/05/2022] [Indexed: 01/26/2023] Open
Abstract
INTRODUCTION Waterpipe smoking is increasing in popularity, yet the evidence implicating waterpipe smoking in lung disease is limited. We hypothesized that impulse oscillometry (IOS) would detect airway abnormalities in waterpipe smokers (WPS). METHODS We studied 210 participants, 40 years or older, from the community, of whom 92 were exclusive WPS and 118 were never-smokers. Waterpipe smoking history was assessed using a validated questionnaire. All participants underwent spirometry, and IOS and absolute and percentage predicted results (for age, sex, height, and weight) were compared between WPS and nonsmokers. The association of IOS parameters with waterpipe smoking duration and extent (waterpipe smoked/day * smoking duration) was evaluated using linear regression. RESULTS WPS smoked on average 1.8 ± 1.2 waterpipes/day, over an average duration of 23.3 ± 39.8 years. WPS and nonsmokers were largely asymptomatic and had similar age, body mass index, sex distribution, and spirometric values. Nevertheless, WPS had higher IOS measured resistance at 5Hz compared to nonsmokers, (0.53 ± 0.2 vs. 0.48 ± 0.2 kPa/L/s, P = 0.03) and higher percentage-predicted resistance (124.5 ± 36.3 vs. 115.7% ± 35.6%, P = 0.04). Waterpipe smoking duration was also associated with resistance (β = 0.04 kPa/L/s/year, P = 0.01) and with percentage-predicted resistance (β = 0.05/year, P = 0.02). Waterpipe smoking extent was associated with resistance (β = 0.009 kPa/L/s/waterpipe-year, P = 0.04), while the association with percentage-predicted resistance was near significance (β = 0.009/waterpipe-year, P = 0.07). CONCLUSIONS Waterpipe smoking is associated with increased airway resistance assessed by IOS but not by spirometry in largely asymptomatic individuals from the community.
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Affiliation(s)
- Hassan A. Chami
- School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America, Beirut, Lebanon
- Department of Medicine and Clinical Research Institute, American University of Beirut, Beirut, Lebanon
| | - Nourhan Houjeij
- Department of Nephrology, Saint Louis University, St Louis, Missouri, United States of America
| | - Maha Makki
- Department of Medicine and Clinical Research Institute, American University of Beirut, Beirut, Lebanon
| | - Lina Itani
- Department of Medicine and Clinical Research Institute, American University of Beirut, Beirut, Lebanon
| | - Hani Tamim
- Department of Medicine and Clinical Research Institute, American University of Beirut, Beirut, Lebanon
- College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia
| | - Ahmad Al Mulla
- Tobacco Control Center, WHO Collaborative Center, Department of Medicine, Hamad Medical Corporation, Doha, Qatar
| | - Bartolome Celli
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Salah Zeineldine
- Department of Medicine and Clinical Research Institute, American University of Beirut, Beirut, Lebanon
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23
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Xie T, Huang R, Deng D, Tang P, Fu Y, Zheng Y, Wan Y. Cryptotanshinone Reverses Corticosteroid Insensitivity by Inhibition of Phosphoinositide-3-Kinase-δ in Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis 2023; 18:797-809. [PMID: 37180749 PMCID: PMC10171224 DOI: 10.2147/copd.s405757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/30/2023] [Indexed: 05/16/2023] Open
Abstract
Purpose Corticosteroid insensitivity has become a major barrier in the treatment of chronic obstructive pulmonary disease (COPD). It is known that oxidative stress reduces the expression and activity of histone deacetylase (HDAC)-2 by activating phosphoinositide-3-kinase-δ(PI3Kδ)/Akt pathway, which is a common mechanism. The aim of this study was to investigate whether cryptotanshinone (CPT) can improve corticosteroid sensitivity and to investigate the molecular mechanisms by which this occurs. Patients and Methods Corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) collected from COPD patients, or in human monocytic U937 monocytic cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-α (TNFα)-induced interleukin 8 (IL-8) production in the presence or absence of cryptotanshinone. PI3K/Akt activity (measured as the relative ratio of phosphorylated Akt at Ser-473 to total Akt) and HDAC2 expression levels were determined by western blotting. HDAC activity was evaluated by a Fluo-Lys HDAC activity assay kit in U937 monocytic cells. Results Both PBMCs in patients with COPD and U937 cells exposed to CSE were found to be insensitive to dexamethasone, accompanied by increased phosphorylated Akt (pAkt) and decreased HDAC2 protein expression. The pretreatment of cryptotanshinone restored their sensitivity to dexamethasone, and simultaneously downregulated the level of phosphorylated Akt and upregulated the level of HDAC2 protein. Pretreatment with cryptotanshinone or IC87114 reversed the decrease in HDAC activity in CSE-stimulated U937 cells. Conclusion Cryptotanshinone restores corticosteroid sensitivity induced by oxidative stress via inhibition of PI3Kδ and is a potential treatment for corticosteroid-insensitive diseases such as COPD.
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Affiliation(s)
- Tao Xie
- Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China
| | - Rong Huang
- Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China
| | - Daishuo Deng
- Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China
| | - Peipei Tang
- Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai’an, Jiangsu, People’s Republic of China
| | - Yufeng Fu
- Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai’an, Jiangsu, People’s Republic of China
| | - Yulong Zheng
- Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China
- Correspondence: Yulong Zheng; Yufeng Wan, Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China, Tel +86 137 7670 7363; +86 158 0523 0282, Fax +86 517 8087 1636; +86 517 8087 1616, Email ;
| | - Yufeng Wan
- Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China
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Giri A, Rahman I, Sundar IK. Circadian clock-based therapeutics in chronic pulmonary diseases. Trends Pharmacol Sci 2022; 43:1014-1029. [PMID: 36302705 PMCID: PMC9756397 DOI: 10.1016/j.tips.2022.09.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 11/11/2022]
Abstract
The circadian clock is the biochemical oscillator that orchestrates the observable circadian rhythms in physiology and behavior. Disruption of the circadian clock in the lungs during chronic pulmonary diseases is considered one of the key etiological risk factors that drive pathobiology. Preclinical studies support that pharmacological manipulation of the circadian clock is a conceivable approach for the development of novel clock-based therapeutics. Despite recent advances, no effort has been undertaken to integrate novel findings for the treatment and management of chronic lung diseases. We, therefore, recognize the need to discuss the candidate clock genes that can be potentially targeted for therapeutic intervention. Here, we aim to create the first roadmap that will advance the development of circadian- clock-based therapeutics that may provide better outcomes in treating chronic pulmonary diseases.
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Affiliation(s)
- Allan Giri
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Irfan Rahman
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
| | - Isaac Kirubakaran Sundar
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
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25
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Tejwani V, Woo H, Liu C, Tillery AK, Gassett AJ, Kanner RE, Hoffman EA, Martinez FJ, Woodruff PG, Barr RG, Fawzy A, Koehler K, Curtis JL, Freeman CM, Cooper CB, Comellas AP, Pirozzi C, Paine R, Tashkin D, Krishnan JA, Sack C, Putcha N, Paulin LM, Zusman M, Kaufman JD, Alexis NE, Hansel NN. Black carbon content in airway macrophages is associated with increased severe exacerbations and worse COPD morbidity in SPIROMICS. Respir Res 2022; 23:310. [PMID: 36376879 PMCID: PMC9664618 DOI: 10.1186/s12931-022-02225-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 10/19/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Airway macrophages (AM), crucial for the immune response in chronic obstructive pulmonary disease (COPD), are exposed to environmental particulate matter (PM), which they retain in their cytoplasm as black carbon (BC). However, whether AM BC accurately reflects environmental PM2.5 exposure, and can serve as a biomarker of COPD outcomes, is unknown. METHODS We analyzed induced sputum from participants at 7 of 12 sites SPIROMICS sites for AM BC content, which we related to exposures and to lung function and respiratory outcomes. Models were adjusted for batch (first vs. second), age, race (white vs. non-white), income (<$35,000, $35,000~$74,999, ≥$75,000, decline to answer), BMI, and use of long-acting beta-agonist/long-acting muscarinic antagonists, with sensitivity analysis performed with inclusion of urinary cotinine and lung function as covariates. RESULTS Of 324 participants, 143 were current smokers and 201 had spirometric-confirmed COPD. Modeled indoor fine (< 2.5 μm in aerodynamic diameter) particulate matter (PM2.5) and urinary cotinine were associated with higher AM BC. Other assessed indoor and ambient pollutant exposures were not associated with higher AM BC. Higher AM BC was associated with worse lung function and odds of severe exacerbation, as well as worse functional status, respiratory symptoms and quality of life. CONCLUSION Indoor PM2.5 and cigarette smoke exposure may lead to increased AM BC deposition. Black carbon content in AMs is associated with worse COPD morbidity in current and former smokers, which remained after sensitivity analysis adjusting for cigarette smoke burden. Airway macrophage BC, which may alter macrophage function, could serve as a predictor of experiencing worse respiratory symptoms and impaired lung function.
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Affiliation(s)
- Vickram Tejwani
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.
- Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, A90, 44195, Cleveland, OH, USA.
| | - Han Woo
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Chen Liu
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Anna K Tillery
- Center for Environmental Medicine, Asthma, and Lung Biology, Division of Allergy and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Amanda J Gassett
- Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA
| | - Richard E Kanner
- Division of Respiratory, Critical Care and Occupational Medicine, University of Utah, Salt Lake City, UT, USA
| | - Eric A Hoffman
- Department of Radiology, Medicine and Biomedical Engineering, University of Iowa, Iowa City, IA, USA
| | - Fernando J Martinez
- Division of Pulmonology and Critical Care Medicine, Weill-Cornell Medical Center, Cornell University, New York, NY, USA
| | - Prescott G Woodruff
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA
| | - R Graham Barr
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Ashraf Fawzy
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Kirsten Koehler
- Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Jeffrey L Curtis
- Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
- Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Christine M Freeman
- Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
- Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Christopher B Cooper
- Division of Pulmonary and Critical Care Medicine, University of California Los Angeles Medical Center, Los Angeles, CA, USA
| | - Alejandro P Comellas
- Division of Pulmonary, Critical Care, and Occupational Medicine, College of Medicine, University of Iowa, Iowa City, IA, USA
| | | | - Robert Paine
- University of Utah Hospital, Salt Lake City, UT, USA
| | - Donald Tashkin
- Division of Pulmonary and Critical Care Medicine, University of California Los Angeles Medical Center, Los Angeles, CA, USA
| | - Jerry A Krishnan
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Coralynn Sack
- Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA
| | - Nirupama Putcha
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Laura M Paulin
- Pulmonary/Critical Care, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
| | - Marina Zusman
- Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA
| | - Joel D Kaufman
- Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA
| | - Neil E Alexis
- Center for Environmental Medicine, Asthma, and Lung Biology, Division of Allergy and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nadia N Hansel
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
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Cho J, Johnson BD, Watt KD, Niven AS, Yeo D, Kim CH. Exercise training attenuates pulmonary inflammation and mitochondrial dysfunction in a mouse model of high-fat high-carbohydrate-induced NAFLD. BMC Med 2022; 20:429. [PMID: 36348343 PMCID: PMC9644617 DOI: 10.1186/s12916-022-02629-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 10/24/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) can lead to pulmonary dysfunction that is associated with pulmonary inflammation. Moreover, little is known regarding the therapeutic role of exercise training on pulmonary pathophysiology in NAFLD. The present study aimed to investigate the effect of exercise training on high-fat high-carbohydrate (HFHC)-induced pulmonary dysfunction in C57BL/6 mice. METHODS Male C57BL/6 mice (N = 40) were fed a standard Chow (n = 20) or an HFHC (n = 20) diet for 15 weeks. After 8 weeks of dietary treatment, they were further assigned to 4 subgroups for the remaining 7 weeks: Chow (n = 10), Chow plus exercise (Chow+EX, n = 10), HFHC (n = 10), or HFHC plus exercise (HFHC+EX, n = 10). Both Chow+EX and HFHC+EX mice were subjected to treadmill running. RESULTS Chronic exposure to the HFHC diet resulted in obesity with hepatic steatosis, impaired glucose tolerance, and elevated liver enzymes. The HFHC significantly increased fibrotic area (p < 0.001), increased the mRNA expression of TNF-α (4.1-fold, p < 0.001), IL-1β (5.0-fold, p < 0.001), col1a1 (8.1-fold, p < 0.001), and Timp1 (6.0-fold, p < 0.001) in the lung tissue. In addition, the HFHC significantly altered mitochondrial function (p < 0.05) along with decreased Mfn1 protein levels (1.8-fold, p < 0.01) and increased Fis1 protein levels (1.9-fold, p < 0.001). However, aerobic exercise training significantly attenuated these pathophysiologies in the lungs in terms of ameliorating inflammatory and fibrogenic effects by enhancing mitochondrial function in lung tissue (p < 0.001). CONCLUSIONS The current findings suggest that exercise training has a beneficial effect against pulmonary abnormalities in HFHC-induced NAFLD through improved mitochondrial function.
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Affiliation(s)
- Jinkyung Cho
- Department of Cardiovascular Disease, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.,Department of Sport Science, Korea Institute of Sport Science, Seoul, Republic of Korea
| | - Bruce D Johnson
- Department of Cardiovascular Disease, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | - Kymberly D Watt
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Alexander S Niven
- Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Dongwook Yeo
- Department of Cardiovascular Disease, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | - Chul-Ho Kim
- Department of Cardiovascular Disease, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
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Dey D, Mondal P, Moitra S, Saha GK, Podder S. Association of Interleukin 6 and Interleukin 8 genes polymorphisms with house dust mite-induced nasal-bronchial allergy in a sample of Indian patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00348-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Genetic background of nasal-bronchial allergy (NBA) is well documented. House Dust Mites (HDMs) are reported to elicit NBA symptoms. Susceptibility to HDM sensitization varies considerably from person to person. Interleukin 6 (IL 6) and Interleukin 8 (IL 8) are studied previously for genetic association with several diseases. To the best of our knowledge, the genetic association of HDM-induced NBA has not been largely reported from India. The aim of our present study was to evaluate any possible association of IL 6 and IL 8 gene polymorphisms with HDM-induced NBA in an Indian population.
Methods
IL 6 (− 572G/C, − 597G/A) and IL 8 polymorphisms (− 251A/T, + 781C/T) were analyzed in a HDM-sensitized group (N = 372) and a control group (N = 110). Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR–RFLP) based genotyping was done. Chi-square test and Fisher’s exact tests were applied for statistical analysis.
Results
IL 6 − 597G/A and IL 8 + 781C/T were not associated with HDM-sensitization, while IL 6 − 72G/C and IL 8 − 51A/T showed significant associations in terms of both genotype and allele frequencies. For both the SNPs, minor allele frequencies were significantly higher in the patients compared to the control. Moreover, IL 6 -572G/C and IL 8 -251A/T were found to be strongly linked with HDM sensitization and severity.
Conclusion
This is probably the pioneer study to describe the association of IL 6 and IL 8 polymorphisms with HDM sensitization in any Indian population. The results suggested that IL 6 -572G/C and IL 8 -251A/T may exert a risk of HDM sensitization leading to NBA.
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Shin DU, Eom JE, Song HJ, Jung SY, Nguyen TV, Lim KM, Chai OH, Kim HJ, Kim GD, Shin HS, Lee SY. Camellia sinensis L. Alleviates Pulmonary Inflammation Induced by Porcine Pancreas Elastase and Cigarette Smoke Extract. Antioxidants (Basel) 2022; 11:antiox11091683. [PMID: 36139757 PMCID: PMC9495585 DOI: 10.3390/antiox11091683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/25/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
Cigarette smoke (CS) is the major factor in the development of chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. Furthermore, although Camellia sinensis (CN) has been known as an anti-inflammatory material, the effect of CN has not yet been known on pulmonary inflammation in COPD. Thus, we investigated the protective effects of Camellia sinensis L. extract (CLE) against pulmonary inflammation in porcine pancreas elastase (PPE) and a cigarette smoke extract (CSE)-induced COPD mouse model. Oral administration of CLE suppressed the symptoms such as infiltration of immune cells, cytokines/chemokines secretion, mucus hypersecretion, and injuries of the lung parenchyma. Increased inflammatory responses in COPD are mediated by various immune cells such as airway epithelial cells, neutrophils, and alveolar macrophages. Thus, we investigated the effect and mechanisms of CLE in H292, HL-60, and MH-S cells. The CLE inhibited the expression of IL-6, IL-8, MUC5AC and MUC5B on CSE/LPS-stimulated H292 cells and also suppressed the formation of neutrophil extracellular traps and secretion of neutrophil elastase by inhibiting reactive oxygen species in PMA-induced HL-60 cells. In particular, the CLE suppressed the release of cytokines and chemokines caused by activating the nuclear factor kappa-light-chain-enhancer of activated B via the activation of nuclear factor erythroid-2-related factor 2 and the heme oxygenase-1 pathway in CSE/LPS-stimulated MH-S cells. Therefore, we suggest that the CLE administration be the effective approach for treating or preventing chronic pulmonary diseases such as COPD induced by CS.
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Affiliation(s)
- Dong-Uk Shin
- Department of Food Biotechnology, Korea University of Science and Technology (UST), Daejeon 34113, Korea
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Korea
| | - Ji-Eun Eom
- Food Function Infrastructure Team, Korea Food Research Institute (KFRI), Wanju 55365, Korea
| | - Hyeon-Ji Song
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Korea
- Department of Food Science and Technology, Jeonbuk National University, Jeonju 54896, Korea
| | - Sun Young Jung
- Department of Food Biotechnology, Korea University of Science and Technology (UST), Daejeon 34113, Korea
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Korea
| | - Thi Van Nguyen
- Department of Anatomy, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Kyung Min Lim
- Department of Food Biotechnology, Korea University of Science and Technology (UST), Daejeon 34113, Korea
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Korea
| | - Ok Hee Chai
- Department of Anatomy, Institute of Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Hyun-Jin Kim
- Division of Applied Life Science (BK21 Four), Department of Food Science and Technology, Institute of Agriculture and Life Science, Gyeongsang National University, 501 Jinjudaero, Jinju 52828, Korea
- EZmass. Co., Ltd., 501 Jinjudaero, Jinju 55365, Korea
| | - Gun-Dong Kim
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Korea
| | - Hee Soon Shin
- Department of Food Biotechnology, Korea University of Science and Technology (UST), Daejeon 34113, Korea
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Korea
- Correspondence: (H.S.S.); (S.-Y.L.); Tel.: +82-63-219-9296 (H.S.S.); +82-63-219-9348 (S.-Y.L.)
| | - So-Young Lee
- Department of Food Biotechnology, Korea University of Science and Technology (UST), Daejeon 34113, Korea
- Division of Food Functionality Research, Korea Food Research Institute (KFRI), Wanju 55365, Korea
- Correspondence: (H.S.S.); (S.-Y.L.); Tel.: +82-63-219-9296 (H.S.S.); +82-63-219-9348 (S.-Y.L.)
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Marzec JM, Nadadur SS. Inflammation resolution in environmental pulmonary health and morbidity. Toxicol Appl Pharmacol 2022; 449:116070. [PMID: 35618031 PMCID: PMC9872158 DOI: 10.1016/j.taap.2022.116070] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/04/2022] [Accepted: 05/14/2022] [Indexed: 02/07/2023]
Abstract
Inflammation and resolution are dynamic processes comprised of inflammatory activation and neutrophil influx, followed by mediator catabolism and efferocytosis. These critical pathways ensure a return to homeostasis and promote repair. Over the past decade research has shown that diverse mediators play a role in the active process of resolution. Specialized pro-resolving mediators (SPMs), biosynthesized from fatty acids, are released during inflammation to facilitate resolution and are deficient in a variety of lung disorders. Failed resolution results in remodeling and cellular deposition through pro-fibrotic myofibroblast expansion that irreversibly narrows the airways and worsens lung function. Recent studies indicate environmental exposures may perturb and deregulate critical resolution pathways. Environmental xenobiotics induce lung inflammation and generate reactive metabolites that promote oxidative stress, injuring the respiratory mucosa and impairing gas-exchange. This warrants recognition of xenobiotic associated molecular patterns (XAMPs) as new signals in the field of inflammation biology, as many environmental chemicals generate free radicals capable of initiating the inflammatory response. Recent studies suggest that unresolved, persistent inflammation impacts both resolution pathways and endogenous regulatory mediators, compromising lung function, which over time can progress to chronic lung disease. Chronic ozone (O3) exposure overwhelms successful resolution, and in susceptible individuals promotes asthma onset. The industrial contaminant cadmium (Cd) bioaccumulates in the lung to impair resolution, and recurrent inflammation can result in chronic obstructive pulmonary disease (COPD). Persistent particulate matter (PM) exposure increases systemic cardiopulmonary inflammation, which reduces lung function and can exacerbate asthma, COPD, and idiopathic pulmonary fibrosis (IPF). While recurrent inflammation underlies environmentally induced pulmonary morbidity and may drive the disease process, our understanding of inflammation resolution in this context is limited. This review aims to explore inflammation resolution biology and its role in chronic environmental lung disease(s).
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Affiliation(s)
- Jacqui M Marzec
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Srikanth S Nadadur
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
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30
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Varney V, Quirke G, Witwit A, Bansal A. Longstanding hypersensitivity pneumonitis and its response to roflumilast: A review of its likely immunological effects. Respir Med Case Rep 2022; 39:101701. [PMID: 35942000 PMCID: PMC9356264 DOI: 10.1016/j.rmcr.2022.101701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/29/2022] [Accepted: 07/05/2022] [Indexed: 12/04/2022] Open
Abstract
We describe the case of a 42yr old man with evidence of hypersensitivity pneumonitis referred with cough and breathlessness for several years which had further deteriorated in the prior 12 months. He had known atopic asthma without evidence of activation. A chest CT scan showed widespread ground glass change in his lung fields. He had feather bedding at home and in his youth cleaned aviaries. His forced vital capacity and lung volumes were reduced along with oxygen saturations at rest (92% on air), overnight (83% on air) and upon walking (78%). Steroids were commenced for a total of 6 months with little consistent improvement in symptoms or objective measures and with no change in his CT scan appearance. As a result, a trial of roflumilast (a phosphodiesterase-4 inhibitor) was commenced due to its range of immunological effects and in order to avoid long-term immune suppression with mycophenolate motefil in a young patient. On roflumilast treatment his cough and breathlessness improved at 4 weeks and the chest crackles cleared. An interval Chest CT scan showed resolution of the ground glass change with improved CT scores that are maintained 2 yrs. All oxygen measures improved and nocturnal oxygen was discontinued. His Lung function has remained largely stable on roflumilast and symptoms of cough and breathlessness have resolved. This case report reviews the immunology of hypersensitivity pneumonitis and the likely actions of Roflumilast relevant to this condition. It is the first published case report documenting its use in hypersensitivity pneumonitis.
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Affiliation(s)
- V.A. Varney
- Respiratory + Allergy & Immunology, St Helier Hospital, Wrythe Lane, Carshalton, Surrey, SM51AA, UK
| | - G. Quirke
- Respiratory Dept, St Helier Hospital, Wrythe Lane, Carshalton, Surrey, SM51AA, UK
| | - Alaa Witwit
- Dept of Radiology, St Helier Hospital, Wrythe Lane, Carshalton, Surrey, SM51AA, UK
| | - A.S. Bansal
- Dept of Immunology, St Helier Hospital, Wrythe Lane, Carshalton, Surrey, SM51AA, UK
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Baker JR, Fenwick PS, Koss CK, Owles HB, Elkin SL, Fine JS, Thomas M, Kasmi KC, Barnes PJ, Donnelly LE. Imbalance between IL-36 receptor agonist and antagonist drives neutrophilic inflammation in COPD. JCI Insight 2022; 7:155581. [PMID: 35763349 PMCID: PMC9462491 DOI: 10.1172/jci.insight.155581] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 06/24/2022] [Indexed: 11/17/2022] Open
Abstract
Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared to control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and further induced by a viral mimetic, whereas IL-36RA is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, that was inhibited by exogenous IL-36RA. The use of a therapeutic antibody that inhibits binding to the IL-36 receptor (IL-36R) attenuated IL-36γ driven inflammation and cellular cross talk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising new therapeutic strategy in the treatment of COPD.
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Affiliation(s)
- Jonathan R Baker
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter S Fenwick
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Carolin K Koss
- Boehringer Ingelheim Pharma GmbH & Co KG,, Biberach an der Riß, Germany
| | - Harriet B Owles
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Sarah L Elkin
- Department of Respiratory Medicine, Imperial College Healthcare Trust, London, United Kingdom
| | - Jay S Fine
- Immunology and Respiratory Diseases, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, United States of America
| | - Matthew Thomas
- Department of Immunology and Respiratory, Boehringer Ingelheim Pharma GmbH & Co KG,, Biberach an der Riß, Germany
| | - Karim C Kasmi
- Department of Immunology and Respiratory, Boehringer Ingelheim Pharma GmbH & Co KG,, Biberach an der Riß, Germany
| | - Peter J Barnes
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Louise E Donnelly
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
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Lea S, Beech A, Baker J, Gaskell R, Pindolia D, Dikwa AB, Shah R, Singh D. Differential responses of COPD macrophages to respiratory bacterial pathogens. ERJ Open Res 2022; 8:00044-2022. [PMID: 35923420 PMCID: PMC9339767 DOI: 10.1183/23120541.00044-2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/04/2022] [Indexed: 11/08/2022] Open
Abstract
COPD patients have increased susceptibility to airway bacterial colonisation. Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are three of the most common respiratory bacterial species in COPD. H. influenzae colonisation, but not other bacteria, in COPD patients is associated with higher sputum neutrophil counts. Alveolar macrophages are key in clearance of bacteria as well as releasing mediators to recruit and activate other immune cells in response to infection. The aim was to characterise differences in COPD macrophage responses to H. influenzae, M. catarrhalisand S. pneumoniae, focusing on release of inflammatory and chemotactic mediators, and apoptosis regulation. Lung macrophages and monocyte-derived macrophages from COPD patients and control subjects were exposed to H. influenzae, M. catarrhalisor S. pneumoniae. Cytokine secretion (tumour necrosis factor-α, interleukin (IL)-6, CXCL8, CCL5 and IL-1β) were measured by ELISA and quantitative reverse transcriptase PCR (RT-qPCR), and apoptosis genes MCL-1, BCL-2, BAX and BAK1 by RT-qPCR. Apoptosis and reactive oxygen species (ROS) release were also measured. Macrophages responded differentially to the bacterial species, with increased, prolonged production of the neutrophil chemoattractant CXCL8 in response to H. influenzae and M. catarrhalis but not S. pneumoniae. S. pneumoniae initiated macrophage apoptosis and ROS release, H. influenzae and M. catarrhalis did not and increased anti-apoptosis gene expression (BCL-2 5.5-fold and MCL-1 2.4-fold, respectively). Differential cytokine responses of macrophages to these bacterial species can explain neutrophilic airway inflammation associated with H. influenzae, but not S. pneumoniae in COPD. Furthermore, delayed macrophage apoptosis is a potential mechanism contributing to inability to clear H. influenzae. Differential cytokine responses of macrophages to Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae can explain neutrophilic airway inflammation associated with H. influenzae but not S. pneumoniae in COPDhttps://bit.ly/3950HVZ
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He G, Dong T, Yang Z, Branstad A, Huang L, Jiang Z. Point-of-care COPD diagnostics: biomarkers, sampling, paper-based analytical devices, and perspectives. Analyst 2022; 147:1273-1293. [PMID: 35113085 DOI: 10.1039/d1an01702k] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) has become the third leading cause of global death. Insufficiency in early diagnosis and treatment of COPD, especially COPD exacerbations, leads to a tremendous economic burden and medical costs. A cost-effective and timely prevention requires decentralized point-of-care diagnostics at patients' residences at affordable prices. Advances in point-of-care (POC) diagnostics may offer new solutions to reduce medical expenditures by measuring salivary and blood biomarkers. Among them, paper-based analytical devices have been the most promising candidates due to their advantages of being affordable, biocompatible, disposable, scalable, and easy to modify. In this review, we present salivary and blood biomarkers related to COPD endotypes and exacerbations, summarize current technologies to collect human whole saliva and whole blood samples, evaluate state-of-the-art paper-based analytical devices that detect COPD biomarkers in saliva and blood, and discuss existing challenges with outlooks on future paper-based POC systems for COPD diagnosis and management.
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Affiliation(s)
- Guozhen He
- Chongqing Key Laboratory of Micro-Nano Systems and Smart Transduction, Chongqing Key Laboratory of Colleges and Universities on Micro-Nano Systems Technology and Smart Transducing, Collaborative Innovation Center on Micro-Nano Transduction and Intelligent Eco-Internet of Things, Chongqing Academician and Expert Workstation, Chongqing Technology and Business University, Nan'an District, Chongqing 400067, China.,Department of Microsystems (IMS), Faculty of Technology, Natural Sciences and Maritime Sciences, University of South-Eastern Norway, Postboks 235, 3603 Kongsberg, Norway.
| | - Tao Dong
- Department of Microsystems (IMS), Faculty of Technology, Natural Sciences and Maritime Sciences, University of South-Eastern Norway, Postboks 235, 3603 Kongsberg, Norway.
| | - Zhaochu Yang
- Chongqing Key Laboratory of Micro-Nano Systems and Smart Transduction, Chongqing Key Laboratory of Colleges and Universities on Micro-Nano Systems Technology and Smart Transducing, Collaborative Innovation Center on Micro-Nano Transduction and Intelligent Eco-Internet of Things, Chongqing Academician and Expert Workstation, Chongqing Technology and Business University, Nan'an District, Chongqing 400067, China
| | - Are Branstad
- University of Southeast Norway (USN), School of Business, Box 235, 3603 Kongsberg, Norway
| | - Lan Huang
- Chongqing Key Laboratory of Micro-Nano Systems and Smart Transduction, Chongqing Key Laboratory of Colleges and Universities on Micro-Nano Systems Technology and Smart Transducing, Collaborative Innovation Center on Micro-Nano Transduction and Intelligent Eco-Internet of Things, Chongqing Academician and Expert Workstation, Chongqing Technology and Business University, Nan'an District, Chongqing 400067, China
| | - Zhuangde Jiang
- Chongqing Key Laboratory of Micro-Nano Systems and Smart Transduction, Chongqing Key Laboratory of Colleges and Universities on Micro-Nano Systems Technology and Smart Transducing, Collaborative Innovation Center on Micro-Nano Transduction and Intelligent Eco-Internet of Things, Chongqing Academician and Expert Workstation, Chongqing Technology and Business University, Nan'an District, Chongqing 400067, China
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Been T, Traboulsi H, Paoli S, Alakhtar B, Mann KK, Eidelman DH, Baglole CJ. Differential impact of JUUL flavors on pulmonary immune modulation and oxidative stress responses in male and female mice. Arch Toxicol 2022; 96:1783-1798. [PMID: 35254488 DOI: 10.1007/s00204-022-03269-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 02/23/2022] [Indexed: 12/17/2022]
Abstract
JUUL is a popular e-cigarette brand that manufactures e-liquids in a variety of flavors, such as mango and mint. Despite their popularity, the pulmonary effects of flavored JUUL e-liquids that are aerosolized and subsequently inhaled are not known. Therefore, the purpose of this study was to evaluate if acute exposure to JUUL e-cigarette aerosols in three popular flavors elicits an immunomodulatory or oxidative stress response in mice. We first developed a preclinical model that mimics human use patterns of e-cigarettes using 1 puff/min or 4 puffs/min exposure regimes. Based on cotinine levels, these exposures were representative of light/occasional and moderate JUUL users. We then exposed C57BL/6 mice to JUUL e-cigarette aerosols in mango, mint, and Virginia tobacco flavors containing 5% nicotine for 3 days, and assessed the inflammatory and oxidative stress response in the lungs and blood. In response to the 1 puff/min regime (light/occasional user), there were minimal changes in BAL cell composition or lung mRNA expression. However, at 4 puffs/min (moderate user), mint-flavored JUUL significantly increased lung neutrophils, while mango-flavored JUUL significantly increased Tnfα and Il13 mRNA in the lungs. Both the 1- and 4 puffs/min regimes significantly increased oxidative stress markers in the blood, indicating systemic effects. Thus, JUUL products are not inert; even short-term inhalation of flavored JUUL e-cigarette aerosols differentially causes immune modulation and oxidative stress responses.
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Affiliation(s)
- Terek Been
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.,Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Hussein Traboulsi
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada.,Department of Medicine, McGill University, Montreal, QC, Canada
| | - Sofia Paoli
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.,Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Bayan Alakhtar
- Division of Experimental Medicine, McGill University, Montreal, QC, Canada
| | - Koren K Mann
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.,Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada
| | - David H Eidelman
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada.,Department of Medicine, McGill University, Montreal, QC, Canada
| | - Carolyn J Baglole
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada. .,Research Institute of the McGill University Health Centre, Montreal, QC, Canada. .,Department of Medicine, McGill University, Montreal, QC, Canada. .,Department of Pathology, McGill University, Montreal, QC, Canada.
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Finicelli M, Digilio FA, Galderisi U, Peluso G. The Emerging Role of Macrophages in Chronic Obstructive Pulmonary Disease: The Potential Impact of Oxidative Stress and Extracellular Vesicle on Macrophage Polarization and Function. Antioxidants (Basel) 2022; 11:antiox11030464. [PMID: 35326114 PMCID: PMC8944669 DOI: 10.3390/antiox11030464] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 12/20/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is one of the most common airway diseases, and it is considered a major global health problem. Macrophages are the most representative immune cells in the respiratory tract, given their role in surveying airways, removing cellular debris, immune surveillance, and resolving inflammation. Macrophages exert their functions by adopting phenotypical changes based on the stimuli they receive from the surrounding tissue. This plasticity is described as M1/M2 macrophage polarization, which consists of a strictly coordinated process leading to a difference in the expression of surface markers, the production of specific factors, and the execution of biological activities. This review focuses on the role played by macrophages in COPD and their implication in inflammatory and oxidative stress processes. Particular attention is on macrophage polarization, given macrophage plasticity is a key feature in COPD. We also discuss the regulatory influence of extracellular vesicles (EVs) in cell-to-cell communications. EV composition and cargo may influence many COPD-related aspects, including inflammation, tissue remodeling, and macrophage dysfunctions. These findings could be useful for better addressing the role of macrophages in the complex pathogenesis and outcomes of COPD.
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Affiliation(s)
- Mauro Finicelli
- Research Institute on Terrestrial Ecosystems (IRET), National Research Council of Italy (CNR), Via Pietro Castellino 111, 80131 Naples, Italy;
- Correspondence: (M.F.); (G.P.); Tel.: +39-0816132553 (M.F.); +39-0816132280 (G.P.)
| | - Filomena Anna Digilio
- Research Institute on Terrestrial Ecosystems (IRET), National Research Council of Italy (CNR), Via Pietro Castellino 111, 80131 Naples, Italy;
| | - Umberto Galderisi
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy;
| | - Gianfranco Peluso
- Research Institute on Terrestrial Ecosystems (IRET), National Research Council of Italy (CNR), Via Pietro Castellino 111, 80131 Naples, Italy;
- Faculty of Medicine and Surgery, Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
- Correspondence: (M.F.); (G.P.); Tel.: +39-0816132553 (M.F.); +39-0816132280 (G.P.)
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Giordano L, Gregory AD, Pérez Verdaguer M, Ware SA, Harvey H, DeVallance E, Brzoska T, Sundd P, Zhang Y, Sciurba FC, Shapiro SD, Kaufman BA. Extracellular Release of Mitochondrial DNA: Triggered by Cigarette Smoke and Detected in COPD. Cells 2022; 11:369. [PMID: 35159179 PMCID: PMC8834490 DOI: 10.3390/cells11030369] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/13/2022] [Accepted: 01/18/2022] [Indexed: 12/17/2022] Open
Abstract
Cigarette smoke (CS) is the most common risk factor for chronic obstructive pulmonary disease (COPD). The present study aimed to elucidate whether mtDNA is released upon CS exposure and is detected in the plasma of former smokers affected by COPD as a possible consequence of airway damage. We measured cell-free mtDNA (cf-mtDNA) and nuclear DNA (cf-nDNA) in COPD patient plasma and mouse serum with CS-induced emphysema. The plasma of patients with COPD and serum of mice with CS-induced emphysema showed increased cf-mtDNA levels. In cell culture, exposure to a sublethal dose of CSE decreased mitochondrial membrane potential, increased oxidative stress, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles (EVs). Mitochondrial DNA release into EVs occurred concomitantly with increased expression of markers that associate with DNA damage responses, including DNase III, DNA-sensing receptors (cGAS and NLRP3), proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-18, and CXCL2), and markers of senescence (p16 and p21); the majority of the responses are also triggered by cytosolic DNA delivery in vitro. Exposure to a lethal CSE dose preferentially induced mtDNA and nDNA release in the cell debris. Collectively, the results of this study associate markers of mitochondrial stress, inflammation, and senescence with mtDNA release induced by CSE exposure. Because high cf-mtDNA is detected in the plasma of COPD patients and serum of mice with emphysema, our findings support the future study of cf-mtDNA as a marker of mitochondrial stress in response to CS exposure and COPD pathology.
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Affiliation(s)
- Luca Giordano
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (S.A.W.); (H.H.)
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (E.D.); (T.B.); (P.S.)
| | - Alyssa D. Gregory
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (A.D.G.); (Y.Z.); (F.C.S.); (S.D.S.)
| | - Mireia Pérez Verdaguer
- Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA;
| | - Sarah A. Ware
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (S.A.W.); (H.H.)
| | - Hayley Harvey
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (S.A.W.); (H.H.)
| | - Evan DeVallance
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (E.D.); (T.B.); (P.S.)
| | - Tomasz Brzoska
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (E.D.); (T.B.); (P.S.)
- Division of Hematology/Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Prithu Sundd
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (E.D.); (T.B.); (P.S.)
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (A.D.G.); (Y.Z.); (F.C.S.); (S.D.S.)
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yingze Zhang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (A.D.G.); (Y.Z.); (F.C.S.); (S.D.S.)
| | - Frank C. Sciurba
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (A.D.G.); (Y.Z.); (F.C.S.); (S.D.S.)
| | - Steven D. Shapiro
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; (A.D.G.); (Y.Z.); (F.C.S.); (S.D.S.)
| | - Brett A. Kaufman
- Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (S.A.W.); (H.H.)
- Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (E.D.); (T.B.); (P.S.)
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Kotlyarov S. Involvement of the Innate Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Int J Mol Sci 2022; 23:985. [PMID: 35055174 PMCID: PMC8778852 DOI: 10.3390/ijms23020985] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/14/2022] [Accepted: 01/15/2022] [Indexed: 01/27/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a common, socially significant disease characterized by progressive airflow limitation due to chronic inflammation in the bronchi. Although the causes of COPD are considered to be known, the pathogenesis of the disease continues to be a relevant topic of study. Mechanisms of the innate immune system are involved in various links in the pathogenesis of COPD, leading to persistence of chronic inflammation in the bronchi, their bacterial colonization and disruption of lung structure and function. Bronchial epithelial cells, neutrophils, macrophages and other cells are involved in the development and progression of the disease, demonstrating multiple compromised immune mechanisms.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
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38
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Pani A, Valeria L, Dugnani S, Scaglione F. Erdosteine enhances antibiotic activity against bacteria within biofilm. Int J Antimicrob Agents 2022; 59:106529. [DOI: 10.1016/j.ijantimicag.2022.106529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 11/05/2022]
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Benson VS, Hartl S, Barnes N, Galwey N, Van Dyke MK, Kwon N. Blood eosinophil counts in the general population and airways disease: a comprehensive review and meta-analysis. Eur Respir J 2022; 59:2004590. [PMID: 34172466 PMCID: PMC8756293 DOI: 10.1183/13993003.04590-2020] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 05/26/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The clinical context for using blood eosinophil (EOS) counts as treatment-response biomarkers in asthma and COPD requires better understanding of EOS distributions and ranges. We describe EOS distributions and ranges published in asthma, COPD, control (non-asthma/COPD) and general populations. METHODS We conducted a comprehensive literature review and meta-analysis of observational studies (January 2008 to November 2018) that included EOS counts in asthma, severe asthma, COPD, control and general populations. Excluded studies had total sample sizes <200, EOS as inclusion criterion, hospitalised population only and exclusively paediatric participants. RESULTS Overall, 91 eligible studies were identified, most had total-population-level data available: asthma (39 studies), severe asthma (12 studies), COPD (23 studies), control (seven studies) and general populations (14 studies); some articles reported data for multiple populations. Reported EOS distributions were right-skewed (seven studies). Reported median EOS counts ranged from 157-280 cells·µL-1 (asthma, 22 studies); 200-400 cells·µL-1 (severe asthma, eight studies); 150-183 cells·µL-1 (COPD, six studies); and 100-160 cells·µL-1 (controls, three studies); and 100-200 cells·µL-1 (general populations, six studies). The meta-analysis showed that observed variability was mostly between studies rather than within studies. Factors reportedly associated with higher blood EOS counts included current smoking, positive skin-prick test, elevated total IgE, comorbid allergic rhinitis, age ≤18 years, male sex, spirometric asthma/COPD diagnosis, metabolic syndrome and adiposity. CONCLUSION EOS distribution and range varied by study population, and were affected by clinical factors including age, smoking history and comorbidities, which, regardless of severity, should be considered during treatment decision-making.
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Affiliation(s)
- Victoria S Benson
- Epidemiology, Value Evidence and Outcomes (VEO), Global Medical R&D, GlaxoSmithKline, Brentford, UK
| | - Sylvia Hartl
- Dept of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for Lung Health, Clinic Penzing, WiGev and Sigmund Freud University, Medical School, Vienna, Austria
| | - Neil Barnes
- Respiratory Therapy Area, GlaxoSmithKline, Brentford, UK
- William Harvey Institute, Barts and The London School of Medicine and Dentistry, London, UK
| | | | - Melissa K Van Dyke
- Epidemiology, Value Evidence and Outcomes (VEO), Global Medical R&D, GlaxoSmithKline, Upper Providence, PA, USA
| | - Namhee Kwon
- Respiratory Research and Development, GlaxoSmithKline, Brentford, UK
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Dobric A, De Luca SN, Spencer SJ, Bozinovski S, Saling MM, McDonald CF, Vlahos R. Novel pharmacological strategies to treat cognitive dysfunction in chronic obstructive pulmonary disease. Pharmacol Ther 2021; 233:108017. [PMID: 34626675 DOI: 10.1016/j.pharmthera.2021.108017] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/19/2021] [Accepted: 10/04/2021] [Indexed: 12/12/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and currently the 3rd largest cause of death in the world, with approximately 3.23 million deaths per year. Globally, the financial burden of COPD is approximately €82 billion per year and causes substantial morbidity and mortality. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and viral and bacterial-induced acute exacerbations (AECOPD). Recent clinical studies have shown that cognitive dysfunction is present in up to 60% of people with COPD, with impairments in executive function, memory, and attention, impacting on important outcomes such as quality of life, hospitalisation and survival. The high prevalence of cognitive dysfunction in COPD may also help explain the insufficient adherence to therapeutic plans and strategies, thus worsening disease progression in people with COPD. However, the mechanisms underlying the impaired neuropathology and cognition in COPD remain largely unknown. In this review, we propose that the observed pulmonary oxidative burden and inflammatory response of people with COPD 'spills over' into the systemic circulation, resulting in damage to the brain and leading to cognitive dysfunction. As such, drugs targeting the lungs and comorbidities concurrently represent an exciting and unique therapeutic opportunity to treat COPD and cognitive impairments, which may lead to the production of novel targets to prevent and reverse the debilitating and life-threatening effects of cognitive dysfunction in COPD.
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Affiliation(s)
- Aleksandar Dobric
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Simone N De Luca
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Sarah J Spencer
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, RMIT University, Melbourne, VIC, Australia
| | - Steven Bozinovski
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Michael M Saling
- Clinical Neuropsychology, The University of Melbourne and Austin Health, VIC, Australia
| | - Christine F McDonald
- Institute for Breathing and Sleep, Austin Health, Melbourne, VIC, Australia; Department of Respiratory & Sleep Medicine, The University of Melbourne and Austin Health, Melbourne, VIC, Australia
| | - Ross Vlahos
- School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
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Bao W, Tian X, Hao H, Jin Y, Xie X, Yin D, Zhang Y, Chen X, Xue Y, Han L, Yang F, Zhang M. Is small airway dysfunction an abnormal phenomenon for patients with normal forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity? Ann Allergy Asthma Immunol 2021; 128:68-77.e1. [PMID: 34551345 DOI: 10.1016/j.anai.2021.09.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/27/2021] [Accepted: 09/11/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND The clinical significance of small airway dysfunction (SAD) determined with spirometry in patients with normal forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) is controversial. OBJECTIVE To determine whether SAD presents histologic abnormalities in the setting of normal computed tomography (CT) imaging and FEV1 and FEV1/FVC. METHODS A cross-sectional study was performed in 64 patients undergoing thoracotomy for pulmonary nodules. Thoracic high-resolution CT (HRCT), bronchodilation test, and fractional exhaled nitric oxide (FENO) and its alveolar component (nitric oxide alveolar concentration [CANO]) were obtained before surgery. Lung pathology and levels of cytokines in lung tissue were measured. The patients were divided into SAD and small airway normal function groups according to forced expiratory flow at 75% and 50% of the FVC (maximal expiratory flow [MEF] 25, MEF50) and maximum midexpiratory flow. RESULTS The MEF50, MEF25, and maximum midexpiratory flow were strongly negatively correlated with CANO (r, -0.42, -0.42, -0.40, respectively; P ≤ .001 for all). The MEFs were mildly negatively correlated with interleukin (IL)-6 and macrophages in lung tissue (r < -0.25, P < .001 for all). The CANO (P < .001), airspace size (mean linear intercept) (P = .02), macrophages (P = .003), IL-6 (P = .003), and IL-8 (P = .008) in lung tissue were higher in patients with SAD (n = 35) than those with small airway normal function (n = 29). A total of 8 patients (22.86%) with SAD and 2 (6.90%) without SAD had pneumatoceles (P = .10). CONCLUSION Patients with pulmonary nodules and SAD were more likely to have abnormal inflammation and emphysematous destruction than patients without SAD. Thus, SAD indicates histologic abnormalities in patients with normal CT imaging and FEV1 and FEV1/FVC.
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Affiliation(s)
- Wuping Bao
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xue Tian
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huijuan Hao
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yubiao Jin
- Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueqian Xie
- Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongning Yin
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingying Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Chen
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yishu Xue
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Han
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fu Yang
- Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Min Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Che L, Yu C, Chen G, Lin J, Xie Z, Xia T, Luo W, Cai X, Liu S. The Inflammatory Response Induced by RELMβ Upregulates IL-8 and IL-1β Expression in Bronchial Epithelial Cells in COPD. Int J Chron Obstruct Pulmon Dis 2021; 16:2503-2513. [PMID: 34511895 PMCID: PMC8421257 DOI: 10.2147/copd.s321877] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/23/2021] [Indexed: 01/04/2023] Open
Abstract
Purpose Chronic obstructive pulmonary disease (COPD) is associated with a complex inflammatory regulatory network. Resistin-like molecule β (RELMβ) is highly expressed in the lungs of COPD patients. We aimed to investigate the proinflammatory effect of RELMβ on airway epithelial cells in COPD. Methods First, a GEO dataset was used to analyze the expression of the RELMβ gene in the COPD and control groups as well as the protein levels of RELMβ in the sera of outpatients with COPD and normal control subjects in our hospital. We also stimulated 16HBE bronchial epithelial cells with recombinant RELMβ protein and analyzed the expression of IL-8 and IL-1β. We upregulated and downregulated the gene expression of RELMβ in 16HBE cells and analyzed the expression of the inflammatory cytokines IL-8 and IL-1β. In addition, we also examined the mechanism by which the p38 MAPK signaling pathway contributed to the regulation of IL-8 and IL-1β expression by RELMβ. Results RELMβ expression was increased in COPD tissues in different data sets and in the serum of COPD patients in our hospital. IL-8 and IL-1β expression was also increased in COPD tissues with high RELMβ gene expression in different data sets. The RELMβ gene was mainly related to inflammatory factors and inflammatory signaling pathways in the PPI regulatory network. Experiments at the cellular level showed that RELMβ promoted the expression of the inflammatory cytokines IL-8 and IL-1β, and this regulation was mediated by the p38 MAPK signaling pathway. Conclusion RELMβ can promote the expression of the inflammatory cytokines IL-8 and IL-1β in bronchial epithelial cells of patients with COPD and exert inflammatory effects. RELMβ may be a potential target for the treatment of COPD.
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Affiliation(s)
- Li Che
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China
| | - Chao Yu
- Department of Pulmonary and Critical Care Medicine, Lu'an People's Hospital of Anhui Province, Lu'an, 237016, People's Republic of China
| | - Guangshu Chen
- Department of Endocrinology, Guangzhou Red Cross Hospital, The Affiliated Hospital of Jinan University, Guangzhou, 510220, People's Republic of China
| | - Jiaxin Lin
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China
| | - Zhefan Xie
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China
| | - Tingting Xia
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China
| | - Wenzhi Luo
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China
| | - Xingdong Cai
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China
| | - Shengming Liu
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People's Republic of China
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Baker JR, Donnelly LE. Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy. Int J Chron Obstruct Pulmon Dis 2021; 16:2227-2242. [PMID: 34354348 PMCID: PMC8331105 DOI: 10.2147/copd.s266394] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 07/19/2021] [Indexed: 11/23/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive lung condition affecting 10% of the global population over 45 years. Currently, there are no disease-modifying treatments, with current therapies treating only the symptoms of the disease. COPD is an inflammatory disease, with a high infiltration of leukocytes being found within the lung of COPD patients. These leukocytes, if not kept in check, damage the lung, leading to the pathophysiology associated with the disease. In this review, we focus on the main leukocytes found within the COPD lung, describing how the release of chemokines from the damaged epithelial lining recruits these cells into the lung. Once present, these cells become active and may be driven towards a more pro-inflammatory phenotype. These cells release their own subtypes of inflammatory mediators, growth factors and proteases which can all lead to airway remodeling, mucus hypersecretion and emphysema. Finally, we describe some of the current therapies and potential new targets that could be utilized to target aberrant leukocyte function in the COPD lung. Here, we focus on old therapies such as statins and corticosteroids, but also look at the emerging field of biologics describing those which have been tested in COPD already and potential new monoclonal antibodies which are under review.
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Affiliation(s)
- Jonathan R Baker
- Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK
| | - Louise E Donnelly
- Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK
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44
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Belchamber KBR, Hughes MJ, Spittle DA, Walker EM, Sapey E. New Pharmacological Tools to Target Leukocyte Trafficking in Lung Disease. Front Immunol 2021; 12:704173. [PMID: 34367163 PMCID: PMC8334730 DOI: 10.3389/fimmu.2021.704173] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/24/2021] [Indexed: 01/13/2023] Open
Abstract
Infection and inflammation of the lung results in the recruitment of non-resident immune cells, including neutrophils, eosinophils and monocytes. This swift response should ensure clearance of the threat and resolution of stimuli which drive inflammation. However, once the threat is subdued this influx of immune cells should be followed by clearance of recruited cells through apoptosis and subsequent efferocytosis, expectoration or retrograde migration back into the circulation. This cycle of cell recruitment, containment of threat and then clearance of immune cells and repair is held in exquisite balance to limit host damage. Advanced age is often associated with detrimental changes to the balance described above. Cellular functions are altered including a reduced ability to traffic accurately towards inflammation, a reduced ability to clear pathogens and sustained inflammation. These changes, seen with age, are heightened in lung disease, and most chronic and acute lung diseases are associated with an exaggerated influx of immune cells, such as neutrophils, to the airways as well as considerable inflammation. Indeed, across many lung diseases, pathogenesis and progression has been associated with the sustained presence of trafficking cells, with examples including chronic diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis and acute infections such as Pneumonia and Pneumonitis. In these instances, there is evidence that dysfunctional and sustained recruitment of cells to the airways not only increases host damage but impairs the hosts ability to effectively respond to microbial invasion. Targeting leukocyte migration in these instances, to normalise cellular responses, has therapeutic promise. In this review we discuss the current evidence to support the trafficking cell as an immunotherapeutic target in lung disease, and which potential mechanisms or pathways have shown promise in early drug trials, with a focus on the neutrophil, as the quintessential trafficking immune cell.
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Affiliation(s)
- Kylie B. R. Belchamber
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Michael J. Hughes
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Daniella A. Spittle
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Eloise M. Walker
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Elizabeth Sapey
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
- NIHR Clinical Research Facility Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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45
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Meikle CKS, Creeden JF, McCullumsmith C, Worth RG. SSRIs: Applications in inflammatory lung disease and implications for COVID-19. Neuropsychopharmacol Rep 2021; 41:325-335. [PMID: 34254465 PMCID: PMC8411309 DOI: 10.1002/npr2.12194] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 05/17/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022] Open
Abstract
Selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory properties that may have clinical utility in treating severe pulmonary manifestations of COVID-19. SSRIs exert anti-inflammatory effects at three mechanistic levels: (a) inhibition of proinflammatory transcription factor activity, including NF-κB and STAT3; (b) downregulation of lung tissue damage and proinflammatory cell recruitment via inhibition of cytokines, including IL-6, IL-8, TNF-α, and IL-1β; and (c) direct suppression inflammatory cells, including T cells, macrophages, and platelets. These pathways are implicated in the pathogenesis of COVID-19. In this review, we will compare the pathogenesis of lung inflammation in pulmonary diseases including COVID-19, ARDS, and chronic obstructive pulmonary disease (COPD), describe the anti-inflammatory properties of SSRIs, and discuss the applications of SSRIS in treating COVID-19-associated inflammatory lung disease.
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Affiliation(s)
- Claire Kyung Sun Meikle
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Justin Fortune Creeden
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.,Department of Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Cheryl McCullumsmith
- Department of Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Randall G Worth
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
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46
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Burke H, Wilkinson TMA. Unravelling the mechanisms driving multimorbidity in COPD to develop holistic approaches to patient-centred care. Eur Respir Rev 2021; 30:30/160/210041. [PMID: 34415848 DOI: 10.1183/16000617.0041-2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/06/2021] [Indexed: 01/04/2023] Open
Abstract
COPD is a major cause of morbidity and mortality worldwide. Multimorbidity is common in COPD patients and a key modifiable factor, which requires timely identification and targeted holistic management strategies to improve outcomes and reduce the burden of disease.We discuss the use of integrative approaches, such as cluster analysis and network-based theory, to understand the common and novel pathobiological mechanisms underlying COPD and comorbid disease, which are likely to be key to informing new management strategies.Furthermore, we discuss the current understanding of mechanistic drivers to multimorbidity in COPD, including hypotheses such as multimorbidity as a result of shared common exposure to noxious stimuli (e.g. tobacco smoke), or as a consequence of loss of function following the development of pulmonary disease. In addition, we explore the links to pulmonary disease processes such as systemic overspill of pulmonary inflammation, immune cell priming within the inflamed COPD lung and targeted messengers such as extracellular vesicles as a result of local damage as a cause for multimorbidity in COPD.Finally, we focus on current and new management strategies which may target these underlying mechanisms, with the aim of holistic, patient-centred treatment rather than single disease management.
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Affiliation(s)
- H Burke
- School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK .,University Hospitals Southampton NHS Foundation Trust, Southampton, UK
| | - T M A Wilkinson
- School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.,University Hospitals Southampton NHS Foundation Trust, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
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47
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Proboszcz M, Goryca K, Nejman-Gryz P, Przybyłowski T, Górska K, Krenke R, Paplińska-Goryca M. Phenotypic Variations of Mild-to-Moderate Obstructive Pulmonary Diseases According to Airway Inflammation and Clinical Features. J Inflamm Res 2021; 14:2793-2806. [PMID: 34234506 PMCID: PMC8254142 DOI: 10.2147/jir.s309844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 05/20/2021] [Indexed: 11/24/2022] Open
Abstract
Purpose Asthma and chronic obstructive pulmonary disease (COPD) are complex and heterogeneous inflammatory diseases. We sought to investigate distinct disease profiles based on clinical, cellular and molecular data from patients with mild-to-moderate obstructive pulmonary diseases. Patients and Methods Patients with mild-to-moderate allergic asthma (n=30) and COPD (n=30) were prospectively recruited. Clinical characteristics and induced sputum were collected. In total, 35 mediators were assessed in induced sputum. Logistic regression analysis was conducted to identify the optimal factors that were able to discriminate between asthma and COPD. Further, the data were explored using hierarchical clustering in order to discover and compare clusters of combined samples of asthma and COPD patients. Clinical parameters, cellular composition, and sputum mediators of asthma and COPD were assessed between and within obtained clusters. Results We found five clinical and biochemical variables, namely IL-6, IL-8, CCL4, FEV1/VC ratio pre-bronchodilator (%), and sputum neutrophils (%) that differentiated asthma and COPD and were suitable for discrimination purposes. A combination of those variables yielded high sensitivity and specificity in the differentiation between asthma and COPD, although only FEV1/VC ratio pre-bronchodilator (%) proven significant in the combined model. In cluster analysis, two main clusters were identified: cluster 1, asthma predominant with evidence of eosinophilic airway inflammation and low level of Th1 and Th2 cytokines; and cluster 2, COPD predominant with elevated levels of Th1 and Th2 mediators. Conclusion The inflammatory profile of sputum samples from patients with stable mild-to-moderate asthma and COPD is not disease specific, varies within the disease and might be similar between these diseases. This study highlights the need for phenotyping the mild-to-moderate stages according to their clinical and molecular features.
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Affiliation(s)
- Małgorzata Proboszcz
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Goryca
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Patrycja Nejman-Gryz
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
| | - Tadeusz Przybyłowski
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
| | - Katarzyna Górska
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
| | - Rafał Krenke
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Paplińska-Goryca
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland
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48
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Bennet TJ, Randhawa A, Hua J, Cheung KC. Airway-On-A-Chip: Designs and Applications for Lung Repair and Disease. Cells 2021; 10:1602. [PMID: 34206722 PMCID: PMC8304815 DOI: 10.3390/cells10071602] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 12/22/2022] Open
Abstract
The lungs are affected by illnesses including asthma, chronic obstructive pulmonary disease, and infections such as influenza and SARS-CoV-2. Physiologically relevant models for respiratory conditions will be essential for new drug development. The composition and structure of the lung extracellular matrix (ECM) plays a major role in the function of the lung tissue and cells. Lung-on-chip models have been developed to address some of the limitations of current two-dimensional in vitro models. In this review, we describe various ECM substitutes utilized for modeling the respiratory system. We explore the application of lung-on-chip models to the study of cigarette smoke and electronic cigarette vapor. We discuss the challenges and opportunities related to model characterization with an emphasis on in situ characterization methods, both established and emerging. We discuss how further advancements in the field, through the incorporation of interstitial cells and ECM, have the potential to provide an effective tool for interrogating lung biology and disease, especially the mechanisms that involve the interstitial elements.
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Affiliation(s)
- Tanya J. Bennet
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; (T.J.B.); (A.R.); (J.H.)
- Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Avineet Randhawa
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; (T.J.B.); (A.R.); (J.H.)
- Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Jessica Hua
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; (T.J.B.); (A.R.); (J.H.)
- Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Karen C. Cheung
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; (T.J.B.); (A.R.); (J.H.)
- Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Department of Electrical & Computer Engineering, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
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49
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Carlier FM, de Fays C, Pilette C. Epithelial Barrier Dysfunction in Chronic Respiratory Diseases. Front Physiol 2021; 12:691227. [PMID: 34248677 PMCID: PMC8264588 DOI: 10.3389/fphys.2021.691227] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 05/20/2021] [Indexed: 12/15/2022] Open
Abstract
Mucosal surfaces are lined by epithelial cells, which provide a complex and adaptive module that ensures first-line defense against external toxics, irritants, antigens, and pathogens. The underlying mechanisms of host protection encompass multiple physical, chemical, and immune pathways. In the lung, inhaled agents continually challenge the airway epithelial barrier, which is altered in chronic diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis. In this review, we describe the epithelial barrier abnormalities that are observed in such disorders and summarize current knowledge on the mechanisms driving impaired barrier function, which could represent targets of future therapeutic approaches.
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Affiliation(s)
- François M. Carlier
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
- Department of Pneumology and Lung Transplant, Centre Hospitalier Universitaire UCL Namur, Yvoir, Belgium
| | - Charlotte de Fays
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Charles Pilette
- Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
- Department of Pneumology, Cliniques universitaires St-Luc, Brussels, Belgium
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50
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Sevilla-Montero J, Labrousse-Arias D, Fernández-Pérez C, Fernández-Blanco L, Barreira B, Mondéjar-Parreño G, Alfaro-Arnedo E, López IP, Pérez-Rial S, Peces-Barba G, Pichel JG, Peinado VI, Cogolludo Á, Calzada MJ. Cigarette Smoke Directly Promotes Pulmonary Arterial Remodeling and Kv7.4 Channel Dysfunction. Am J Respir Crit Care Med 2021; 203:1290-1305. [PMID: 33306938 DOI: 10.1164/rccm.201911-2238oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 12/10/2020] [Indexed: 01/10/2023] Open
Abstract
Rationale: Cigarette smoke is considered the chief leading cause of chronic obstructive pulmonary disease (COPD). Its impact on the progressive deterioration of airways has been extensively studied, but its direct effects on the pulmonary vasculature are less known. Objectives: To prove that pulmonary arterial remodeling in patients with COPD is not just a consequence of alveolar hypoxia but also due to the direct effects of cigarette smoke on the pulmonary vascular bed. Methods: We have used different molecular and cell biology approaches, as well as traction force microscopy, wire myography, and patch-clamp techniques in human cells and freshly isolated pulmonary arteries. In addition, we relied on in vivo models and human samples to analyze the effects of cigarette smoke on pulmonary vascular tone alterations. Measurements and Main Results: Cigarette smoke extract exposure directly promoted a hypertrophic, senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to an increase in the proliferative potential of nonexposed cells. Interestingly, these effects were significantly reversed by antioxidants. Furthermore, cigarette smoke extract affected cell contractility and dysregulated the expression and activity of the voltage-gated K+ channel Kv7.4. This contributed to the impairment of vasoconstriction and vasodilation responses. Most importantly, the levels of this channel were diminished in the lungs of smoke-exposed mice, smokers, and patients with COPD. Conclusions: Cigarette smoke directly contributes to pulmonary arterial remodeling through increased cell senescence, as well as vascular tone alterations because of diminished levels and function in the Kv7.4 channel. Strategies targeting these pathways may lead to novel therapies for COPD.
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Affiliation(s)
- Javier Sevilla-Montero
- Biomedical Research Institute La Princesa Hospital, Madrid, Spain
- Department of Medicine, School of Medicine, and
- Doctoral School, Autonoma University of Madrid, Madrid, Spain
| | - David Labrousse-Arias
- Biomedical Research Institute La Princesa Hospital, Madrid, Spain
- Department of Medicine, School of Medicine, and
| | - Cintia Fernández-Pérez
- Biomedical Research Institute La Princesa Hospital, Madrid, Spain
- Department of Medicine, School of Medicine, and
| | - Laura Fernández-Blanco
- Biomedical Research Institute La Princesa Hospital, Madrid, Spain
- Department of Medicine, School of Medicine, and
| | - Bianca Barreira
- Department of Pharmacology and Toxicology, School of Medicine, Complutense University of Madrid, Madrid, Spain
- Biomedical Research Networking Center in Respiratory Diseases, Institute of Health Carlos III, Madrid, Spain
| | - Gema Mondéjar-Parreño
- Department of Pharmacology and Toxicology, School of Medicine, Complutense University of Madrid, Madrid, Spain
- Biomedical Research Networking Center in Respiratory Diseases, Institute of Health Carlos III, Madrid, Spain
| | - Elvira Alfaro-Arnedo
- Lung Cancer and Respiratory Diseases Unit, Biomedical Research Center of La Rioja, Rioja Salud Foundation, Logroño, Spain
| | - Icíar P López
- Lung Cancer and Respiratory Diseases Unit, Biomedical Research Center of La Rioja, Rioja Salud Foundation, Logroño, Spain
| | - Sandra Pérez-Rial
- Biomedical Research Networking Center in Respiratory Diseases, Institute of Health Carlos III, Madrid, Spain
- Respiratory Research Unit, Biomedical Research Unit, Health Research Institute Fundación Jiménez Díaz, Madrid, Spain; and
| | - Germán Peces-Barba
- Biomedical Research Networking Center in Respiratory Diseases, Institute of Health Carlos III, Madrid, Spain
- Respiratory Research Unit, Biomedical Research Unit, Health Research Institute Fundación Jiménez Díaz, Madrid, Spain; and
| | - José G Pichel
- Biomedical Research Networking Center in Respiratory Diseases, Institute of Health Carlos III, Madrid, Spain
- Lung Cancer and Respiratory Diseases Unit, Biomedical Research Center of La Rioja, Rioja Salud Foundation, Logroño, Spain
| | - Víctor Ivo Peinado
- Biomedical Research Networking Center in Respiratory Diseases, Institute of Health Carlos III, Madrid, Spain
- Department of Pulmonary Medicine, Hospital August Pi i Sunyer Biomedical Research Institute, University of Barcelona, Barcelona, Spain
| | - Ángel Cogolludo
- Department of Pharmacology and Toxicology, School of Medicine, Complutense University of Madrid, Madrid, Spain
- Biomedical Research Networking Center in Respiratory Diseases, Institute of Health Carlos III, Madrid, Spain
| | - María J Calzada
- Biomedical Research Institute La Princesa Hospital, Madrid, Spain
- Department of Medicine, School of Medicine, and
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