957 results found
Kumar P, Zavala-Reyes JC, Kalaiarasan G, et al., 2023, Characteristics of fine and ultrafine aerosols in the London underground., Science of the Total Environment, Vol: 858, ISSN: 0048-9697
Underground railway systems are recognised spaces of increased personal pollution exposure. We studied the number-size distribution and physico-chemical characteristics of ultrafine (PM0.1), fine (PM0.1-2.5) and coarse (PM2.5-10) particles collected on a London underground platform. Particle number concentrations gradually increased throughout the day, with a maximum concentration between 18:00 h and 21:00 h (local time). There was a maximum decrease in mass for the PM2.5, PM2.5-10 and black carbon of 3.9, 4.5 and ~ 21-times, respectively, between operable (OpHrs) and non-operable (N-OpHrs) hours. Average PM10 (52 μg m-3) and PM2.5 (34 μg m-3) concentrations over the full data showed levels above the World Health Organization Air Quality Guidelines. Respiratory deposition doses of particle number and mass concentrations were calculated and found to be two- and four-times higher during OpHrs compared with N-OpHrs, reflecting events such as train arrival/departure during OpHrs. Organic compounds were composed of aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs) which are known to be harmful to health. Specific ratios of PAHs were identified for underground transport that may reflect an interaction between PAHs and fine particles. Scanning transmission electron microscopy (STEM) chemical maps of fine and ultrafine fractions show they are composed of Fe and O in the form of magnetite and nanosized mixtures of metals including Cr, Al, Ni and Mn. These findings, and the low air change rate (0.17 to 0.46 h-1), highlight the need to improve the ventilation conditions.
Allam VSRR, Pavlidis S, Liu G, et al., 2022, Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma., Thorax
BACKGROUND: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. METHODS: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. RESULTS: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. CONCLUSION: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophi
Hashemian SM, Mortaz E, Shafigh N, et al., 2022, Effectiveness of Borage plus syrup (BPS) on COVID-19 patients in intensive care units, Frontiers in Nutrition, ISSN: 2296-861X
Introduction: COVID-19 (coronovirus disease-2019) still causes a high rate of death globally with no definite curative treatment described. The traditional plant Borage (Borago officinalis L.) is a good source of gamma-linolenic (GLA). We hypothesized that Borage plus syrup (BPS) would be beneficial in severe COVID-19 patients within an intensice care unit (ICU) setting. Methods: A pilot single centre, randomized trial with no placebo was undertaken. 60 PCR-positive severe COVID-19 participants admitted to ICU from June 2020- Dec 2020 at Masih Daneshvari Hospital Tehran-Iran gave informed consent. The participants were randomly assigned to either Borage Plus Syrup (BPS, 5ml for 5 days) (n=30) or standard care (IFN- and favipiravir) as a control group (n=30). Pao2/Fio2, serum ferritin, CRP, bilirubin, IL-6, TNF-α, ALT, AST, PCT and serum IL-8 was measured upon admission and on release. Results: All the measured parameters decreased significantly with BPS treatment . In the control group, most parameters significantly improved apart from AST and PCT. In addition, the suppression of serum TNF levels in the BPS group was greater than that seen in the control group (P≤0.05). Moreover, the length of ICU stay was significantly lower in the BPS group compared with the control group (P≤0.05). Conclusion: Our study shows that addition of BPS to the standard treatment regime of COVID-19 patients in ICU improved outcomes and reduced the length of ICU treatment. Natural products could be considered as new approaches for reducting the harmful consequences of COVID-19.
Agache I, Shamji MH, Kermani NZ, et al., 2022, Multidimensional endotyping using nasal proteomics predicts molecular phenotypes in the asthmatic airways, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749
BACKGROUND: Unsupervised clustering of biomarkers derived from non-invasive samples such as nasal fluid is less evaluated as a tool for describing asthma endotypes. OBJECTIVE: To evauate whether protein expression in nasal fluid would identify distinct clusters of asthmatics with specific lower airway molecular phenotypes. METHODS: Unsupervised clustering of 168 nasal inflammatory and immune proteins and Shapley values was used to stratify 43 severe asthmatic patients (ENDANA) using a two 'modelling blocks' machine learning (ML) approach. This algorithm was also applied to nasal brushings transcriptomics from U-BIOPRED. Feature reduction and functional gene analysis were used to compare proteomic and transcriptomic clusters. Gene set variation analysis (GSVA) provided enrichment scores (ESs) of the ENDANA protein signature within U-BIOPRED sputum and blood. RESULTS: The nasal protein ML model identified two severe asthma endotypes, which were replicated in U-BIOPRED nasal transcriptomics. Cluster 1 patients had significant airway obstruction, small airways disease, air trapping, decreased diffusing capacity and increased oxidative stress, although only 4/18 were current smokers. Shapley identified 20 cluster-defining proteins. Forty-one proteins were significantly higher in Cluster 1. Pathways associated with proteomic and transcriptomic clusters were linked to Th1, Th2, neutrophil, JAK-STAT, TLR and infection activation. GSVA analysis of the nasal protein and gene signatures were enriched in subjects with sputum neutrophilic/mixed granulocytic asthma and in subjects with a molecular phenotype found in sputum neutrophil-high subjects. CONCLUSIONS: Protein or gene analysis may indicate molecular phenotypes within the asthmatic lower airway and provide a simple, non-invasive test for non-T2 asthma that is currently unavailable.
Xuan S, Li Y, Wu Y, et al., 2022, Langerin-expressing dendritic cells in pulmonary immune-related diseases, Frontiers of Medicine, Vol: 9, ISSN: 1673-7342
Dendritic cells (DCs) are "frontline" immune cells dedicated to antigen presentation. They serve as an important bridge connecting innate and adaptive immunity, and express various receptors for antigen capture. DCs are divided into various subclasses according to their differential expression of cell surface receptors and different subclasses of DCs exhibit specific immunological characteristics. Exploring the common features of each sub-category has became the focus of many studies. There are certain amounts of DCs expressing langerin in airways and peripheral lungs while the precise mechanism by which langerin+ DCs drive pulmonary disease is unclear. Langerin-expressing DCs can be further subdivided into numerous subtypes based on the co-expressed receptors, but here, we identify commonalities across these subtypes that point to the major role of langerin. Better understanding is required to clarify key disease pathways and determine potential new therapeutic approaches.
Li C, Li B, Yang Y, et al., 2022, Stratified treatment of localized cervical esophageal squamous cell carcinoma induced by neoadjuvant immunotherapy plus chemotherapy (SCENIC), Journal of Thoracic Disease, Vol: 14, Pages: 3277-3284, ISSN: 2072-1439
Iemoli E, Ortolani VGR, Preziosi D, et al., 2022, Failure of desensitization with Pfizer-BioNTech COVID-19 vaccine in two asthmatic patients., Eur Ann Allergy Clin Immunol, Vol: 54, Pages: 240-241, ISSN: 1764-1489
Summary: Since December 2020, in various countries of the world, many cases of severe allergic reactions after administration of PfizerBioNTech COVID-19 vaccine, were reported. A great concern has arisen among the doctors who administer the vaccine and the allergic patients who undergo vaccinations. In Italy guidelines were published in order to stratify the risk in the allergic population. In mRNA vaccines, the component currently suspected of causing allergic reactions is the polyethylene glycol excipient (PEG or macrogol). In patients who have shown an immediate allergic reaction to vaccine and who are negative to skin tests for PEG, desensitization with the same vaccine is proposed. In this paper we describe two cases of asthma after the first COVID vaccine administration in which desensitization has failed.
Adcock I, Badi Y, salcman B, et al., 2022, IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma, Allergy, ISSN: 0105-4538
Mortaz E, Movassaghi M, Bassir A, et al., 2022, Evaluation of myeloid-derived suppressor cells in the blood of Iranian COVID-19 patients, Iranian Journal Of Allergy, Asthma and Immunology, Vol: 21, Pages: 467-477, ISSN: 1735-1502
The cytokine storm and lymphopenia are reported in coronavirus disease 2019 (COVID-19). Myeloid-derived suppressive cells (MDSCs) exist in two different forms, granulocyte (G-MDSCs) and monocytic (M-MDSCs), that both suppress T-cell function. In COVID-19, the role of chemokines such as interleukin (IL)-8 in recruiting MDSCs is unclear. A recent report has correlated IL-8 and MDSCs with poor clinical outcomes in melanoma patients. In the current study, we evaluated the frequency of MDSCs and their correlation with serum IL-8 levels in severe COVID-19 patients from Iran. Thirty-seven severe patients (8 on ventilation, 29 without ventilation), thirteen moderate COVID-19 patients, and eight healthy subjects participated in this study between 10th April 2020 and 9th March 2021. Clinical and biochemical features, serum, and whole blood were obtained. CD14, CD15, CD11b, and HLA-DR expression on MDSCs was measured by flow cytometry. COVID-19 patients compared to healthy subjects had a greater frequency of M-MDSCs (12.7±13.3% vs 0.19±0.20%,), G-MDSCs (15.8±12.6% vs 0.35±0.40%,) and total-MDSCs (27.5±17.3% vs 0.55±0.41%,). M-MDSC (16.8±15.8% vs 5.4±4.8%,) and total-MDSC (33.3±18.5% vs 17.3±13.3%) frequency was higher in non- ventilated compared to moderate COVID-19 subjects. Serum IL-8 levels were higher in patients with COVID-19 than in normal healthy subjects (6.4±7.8 vs. 0.10±00 pg/mL). Ventilated patients (15.7±6.7 pg/mL), non-ventilated patients (5.7±2.7 pg/mL) and moderate patients (2.8±3.0 pg/mL) had significantly different levels of IL-8. A negative correlation was found between the frequency of G-MDSCs and the international normalized ratio (INR) test (r=-0.39), and between the frequency of total-MDSCs and oxygen saturation (%) (r=-0.39). COVID-19 patients with severe non-ventilated disease had the highest levels of M-MDSCs. In addition to systemic MDSC
Mumby S, Kermani NZ, Garnett JP, et al., 2022, CEACAM5 is an IL-13-regulated epithelial gene that mediates transcription in type-2 (T2) high severe asthma, ALLERGY, Vol: 77, Pages: 3463-3466, ISSN: 0105-4538
Di Stefano A, Dossena F, Gnemmi I, et al., 2022, Decreased humoral immune response in the bronchi of rapid decliners with chronic obstructive pulmonary disease., Respiratory Research, Vol: 23, Pages: 1-13, ISSN: 1465-9921
BACKGROUND: Identification of COPD patients with a rapid decline in FEV1 is of particular interest for prognostic and therapeutic reasons. OBJECTIVE: To determine the expression of markers of inflammation in COPD patients with rapid functional decline in comparison to slow or no decliners. METHODS: In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the expression and localization of inflammatory markers was measured in bronchial biopsies of patients with no lung functional decline (FEV1% + 30 ± 43 ml/year, n = 21), slow (FEV1% ml/year, - 40 ± 19, n = 14) and rapid decline (FEV1% ml/year, - 112 ± 53, n = 15) using immunohistochemistry. ELISA test was used for polymeric immunoglobulin receptor (pIgR) quantitation "in vitro". RESULTS: The expression of secretory IgA was significantly reduced in bronchial epithelium (p = 0.011) and plasma cell numbers was significantly reduced in the bronchial lamina propria (p = 0.017) of rapid decliners compared to no decliners. Bronchial inflammatory cell infiltration, CD4, CD8, CD68, CD20, NK, neutrophils, eosinophils, mast cells, pIgR, was not changed in epithelium and lamina propria of rapid decliners compared to other groups. Plasma cells/mm2 correlated positively with scored total IgA in lamina propria of all patients. "In vitro" stimulation of 16HBE cells with LPS (10 μg/ml) and IL-8 (10 ng/ml) induced a significant increase while H2O2 (100 μM) significantly decreased pIgR epithelial expression. CONCLUSION: These data show an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria. These findings may help in the prognosti
Thorsen J, Stokholm J, Rasmussen MA, et al., 2022, Asthma and Wheeze Severity and the Oropharyngeal Microbiota in Children and Adolescents., Ann Am Thorac Soc
RATIONALE: There is a major unmet need for improving the care of children and adolescents with severe asthma and wheeze. Identification of factors contributing to disease severity may lead to improved diagnostics, biomarkers, or therapies. The airway microbiota may be such a key factor. OBJECTIVE: To compare the oropharyngeal airway microbiota of children and adolescents with severe and mild/moderate asthma/wheeze. METHODS: Oropharyngeal swab samples from school-age and pre-school children in the European U-BIOPRED multicenter study of severe asthma, all receiving severity-appropriate treatment, were examined using 16S rRNA gene sequencing. Bacterial taxa were defined as Amplicon Sequence Variants (ASVs). RESULTS: We analysed 241 samples from four cohorts; A) 86 school-age children with severe asthma, B) 39 school-age children with mild/moderate asthma, C) 65 pre-school children with severe wheeze and D) 51 pre-school children with mild/moderate wheeze. The most common bacteria were Streptococcus (mean relative abundance 33.5%), Veillonella (10.3%), Haemophilus (7.0%), Prevotella (5.9%) and Rothia (5.5%). Age group (school-age versus pre-school) was associated with the microbiota in beta-diversity analysis (F=3.32, p=0.011) and in a differential abundance analysis (28 significant ASVs). Among all children, we found no significant difference in the microbiota between children with severe and mild/moderate asthma/wheeze in a univariable beta-diversity analysis (F=1.99, p=0.08, n=241), but a significant difference in a multivariable model (F=2.66, p=0.035), including number of exacerbations in the previous year. Age was also significant when expressed as a Microbial Maturity Score (Spearman Rho 0.39, p=4.6e-10), however this score was not associated with asthma/wheeze severity. CONCLUSION: There was a modest difference in the oropharyngeal airway microbiota between children with severe and mild/moderate asthma/wheeze across all children but not in individual age groups
Marshall DC, Al Omari O, Goodall R, et al., 2022, Trends in prevalence, mortality, and disability-adjusted life-years relating to chronic obstructive pulmonary disease in Europe: an observational study of the global burden of disease database, 2001-2019, BMC Pulmonary Medicine, Vol: 22, ISSN: 1471-2466
IntroductionChronic Obstructive Pulmonary Disease (COPD) is associated with significant mortality and well-defined aetiological factors. Previous reports indicate that mortality from COPD is falling worldwide. This study aims to assess the burden of COPD using prevalence, mortality, and disability-adjusted life years (DALYs) between 2001 and 2019 in 28 European countries (the European Union and the United Kingdom).MethodsWe extracted COPD data from the Global Burden of Disease database based on the International Classification of Diseases versions 10 (J41, 42, 43, 44 and 47). Age-standardised prevalence rates (ASPRs), age-standardised mortality rates (ASMRs), and DALYs were analysed for European countries by sex for each year (2001–2019) and reported per 100,000 population. We used Joinpoint regression analysis to quantify changing trends in the burden of COPD.ResultsIn 2019, the median ASPR across Europe was 3230/100,000 for males and 2202/100,000 for females. Between 2001 and 2019, the median percentage change in ASPR was − 9.7% for males and 4.3% for females. 23/28 countries demonstrated a decrease in ASPRs in males, and 11/28 demonstrated a decrease in females. The median percentage change in ASMR between 2001 and 2019 was − 27.5% for males and − 10.4% for females. 25/28 and 19/28 countries demonstrated a decrease in ASMR in males and females, respectively.ConclusionIn the EU between 2001 and 2019 COPD prevalence has overall increased in females but continues to decrease in males and in some countries, female prevalence now exceeds that of males. COPD mortality in the EU has decreased overall between 2001 and 2019; however, this decrease is not universal, particularly in females, and therefore remains a substantial source of amenable mortality.
Kole TM, Vanden Berghe E, Kraft M, et al., 2022, Predictors and associations of the persistent airflow limitation phenotype in asthma: a post-hoc analysis of the ATLANTIS study., The Lancet Respiratory Medicine, ISSN: 2213-2600
BACKGROUND: Persistent airflow limitation (PAL) occurs in a subset of patients with asthma. Previous studies on PAL in asthma have included relatively small populations, mostly restricted to severe asthma, or have no included longitudinal data. The aim of this post-hoc analysis was to investigate the determinants, clinical implications, and outcome of PAL in patients with asthma who were included in the ATLANTIS study. METHODS: In this post-hoc analysis of the ATLANTIS study, we assessed the prevalence, clinical characteristics, and implications of PAL across the full range of asthma severity. The study population included patients aged 18-65 years who had been diagnosed with asthma at least 6 months before inclusion. We defined PAL as a post-bronchodilator FEV1/forced vital capacity (FVC) of less than the lower limit of normal at recruitment. Asthma severity was defined according to the Global Initiative for Asthma. We used Mann-Whitney U test, t test, or χ2 test to analyse differences in baseline characteristics between patients with and without PAL. Logistic regression was used for multivariable analysis of the associations between PAL and baseline data. Cox regression was used to analyse risk of exacerbation in relation to PAL, and a linear mixed-effects model was used to analyse change in FEV1 over time in patients with versus patients without PAL. Results were validated in the U-BIOPRED cohort. FINDINGS: Between June 30, 2014 and March 3, 2017, 773 patients were enrolled in the ATLANTIS study of whom 760 (98%) had post-bronchodilator FEV1/FVC data available. Of the included patients with available data, mean age was 44 years (SD 13), 441 (58%) of 760 were women, 578 (76%) were never-smokers, and 248 (33%) had PAL. PAL was not only present in patients with severe asthma, but also in 21 (16%) of 133 patients with GINA step 1 and 24 (29%) of 83 patients with GINA step 2. PAL was independently associated with older age at baseline (46 years in PAL group vs 43
Lakhdar R, Mumby S, Abubakar-Waziri H, et al., 2022, Lung toxicity of particulates and gaseous pollutants using ex-vivo airway epithelial cell culture systems, ENVIRONMENTAL POLLUTION, Vol: 305, ISSN: 0269-7491
Adcock I, Mumby S, 2022, Recent evidence from omic analysis for redox signalling and mitochondrial oxidative stress in COPD, Journal of Inflammation, Vol: 19, ISSN: 1476-9255
COPD is driven by exogenous and endogenous oxidative stress derived from inhaled cigarette smoke, air pollution and reactive oxygen species from dysregulated mitochondria in activated inflammatory cells within the airway and lung. This is compounded by the loss in antioxidant defences including FOXO and NRF2 and other antioxidant transcription factors together with various key enzymes that attenuate oxidant effects. Oxidative stress enhances inflammation; airway remodelling including fibrosis and emphysema; post-translational protein modifications leading to autoantibody generation; DNA damage and cellular senescence. Recent studies using various omics technologies in the airways, lungs and blood of COPD patients has emphasised the importance of oxidative stress, particularly that derived from dysfunctional mitochondria in COPD and its role in immunity, inflammation, mucosal barrier function and infection. Therapeutic interventions targeting oxidative stress should overcome the deleterious pathologic effects of COPD if targeted to the lung. We require novel, more efficacious antioxidant COPD treatments among which mitochondria-targeted antioxidants and Nrf2 activators are promising.
Marshall D, Al Omari O, Goodall R, et al., 2022, Trends in prevalence, mortality, and disability-adjusted life-years relating to Chronic Obstructive Pulmonary Disease in Europe: 2001-2019, BMC Pulmonary Medicine, ISSN: 1471-2466
Introduction:Chronic Obstructive Pulmonary Disease (COPD) is associated with significant mortality and well-defined etiological factors. Previous reports indicate that mortality from COPD is falling worldwide. This study aims to assess the burden of COPD using prevalence, mortality, and disability-adjusted life years (DALYs) between 2001-2019 in 28 European countries (the European Union and the United Kingdom).Methods: We extracted COPD data from the Global Burden of Disease database based on the International Classification of Diseases versions 10 (J41,42,43,44, and 47). Age-standardised prevalence rates (ASPRs), age-standardised mortality rates (ASMRs), and DALYs were analysed for European countries by sex for each year (2001-2019) and reported per 100,000 population. We used Joinpoint regression analysis to quantify changing trends in the burden of COPD.Results:In 2019, the median ASPR across Europe was 3230/100,000 for males and 2202/100,000 for females. Between 2001 and 2019, the median percentage change in ASPR was -9.7% for males and 4.3% for females. 23/28 countries demonstrated a decrease in ASPRs in males, and 11/28 demonstrated a decrease in females. The median percentage change in ASMR between 2001-2019 was -27.5% for males and -10.4% for females. 25/28 and 19/28 countries demonstrated a decrease in ASMR in males and females, respectively.Conclusion:In the EU between 2001 and 2019 COPD prevalence has overall increased in females but continues to decrease in males and in some countries, female prevalence now exceeds that of males. COPD mortality in the EU has decreased overall between 2001 and 2019; however, this decrease is not universal, particularly in females, and therefore remains a substantial source of amenable mortality. Funding:DCM is supported by an NIHR Academic Clinical Fellowship acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. KFC is a Senior Investigator of the National Institu
Liu G, Jarnicki AG, Paudel KR, et al., 2022, Adverse roles of mast cell chymase-1 in chronic obstructive pulmonary disease., Eur Respir J
BACKGROUND: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase-1 (hCMA1) and it's ortholog mCMA1/mouse mast cell (MC) protease-5 (mMCP5) are exocytosed from activated MCs and have adverse roles in numerous disorders, but their role in COPD is unknown. METHODS: We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5-deficient (-/-) mice to evaluate this proteases' role and potential for therapeutic targeting in CS-induced experimental COPD. We also used ex vivo/in vitro studies to define mechanisms. RESULTS: The levels of hCMA1 mRNA and CMA1+ MCs were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated MC numbers and mMCP5 protein were increased in lung tissues of wild-type (WT) mice with experimental COPD. mmcp5 -/- mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of MCs from WT but not mmcp5 -/- mice with WT lung macrophages increased in TNF-α release. It also caused the release of CMA1 from human MCs, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD. CONCLUSION: CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.
Sanchez-Ovando S, Pavlidis S, Kermani NZ, et al., 2022, Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts, RESPIROLOGY, Vol: 27, Pages: 730-738, ISSN: 1323-7799
Nucera F, Mumby S, Paudel KR, et al., 2022, Role of oxidative stress in the pathogenesis of COPD, Minerva Medica, Vol: 113, Pages: 370-404, ISSN: 0026-4806
Chronic inhalation of cigarette smoke is a prominent cause of chronic obstructive pulmonary disease (COPD) and provides an important source of exogenous oxidants. In addition, several inflammatory and structural cells are a source of endogenous oxidants in the lower airways of COPD patients, even in former smokers. This suggests that oxidants play a key role in the pathogenesis of COPD. This oxidative stress is counterbalanced by the protective effects of the various endogenous antioxidant defenses of the lower airways. A large amount of data from animal models and patients with COPD have shown that both the stable phase of the disease, and during exacerbations, have increased oxidative stress in the lower airways compared with age-matched smokers with normal lung function. Thus, counteracting the increased oxidative stress may produce clinical benefits in COPD patients. Smoking cessation is currently the most effective treatment of COPD patients and reduces oxidative stress in the lower airways. In addition, many drugs used to treat COPD have some antioxidant effects, however, it is still unclear if their clinical efficacy is related to pharmacological modulation of the oxidant/antioxidant balance. Several new antioxidant compounds are in development for the treatment of COPD.
Michaeloudes C, Abubakar-Waziri H, Lakhdar R, et al., 2022, Molecular mechanisms of oxidative stress in asthma, Molecular Aspects of Medicine, Vol: 85, ISSN: 0098-2997
The lungs are exposed to reactive oxygen species oxygen (ROS) produced as a result of inhalation of oxygen, as well as smoke and other air pollutants. Cell metabolism and the NADPH oxidases (Nox) generate low levels of intracellular ROS that act as signal transduction mediators by inducing oxidative modifications of histones, enzymes and transcription factors. Redox signalling is also regulated by localised production and sensing of ROS in mitochondria, the endoplasmic reticulum (ER) and inside the nucleus. Intracellular ROS are maintained at low levels through the action of a battery of enzymatic and non-enzymatic antioxidants. Asthma is a heterogeneous airway inflammatory disease with different immune endotypes; these include atopic or non-atopic Th2 type immune response associated with eosinophilia, or a non-Th2 response associated with neutrophilia. Airway remodelling and hyperresponsiveness accompany the inflammatory response in asthma. Over-production of ROS resulting from infiltrating immune cells, particularly eosinophils and neutrophils, and a concomitant impairment of antioxidant responses lead to development of oxidative stress in asthma. Oxidative stress is augmented in severe asthma and during exacerbations, as well as by air pollution and obesity, and causes oxidative damage of tissues promoting airway inflammation and hyperresponsiveness. Furthermore, deregulated Nox activity, mitochondrial dysfunction, ER stress and/or oxidative DNA damage, resulting from exposure to irritants, inflammatory mediators or obesity, may lead to redox-dependent changes in cell signalling. ROS play a central role in airway epithelium-mediated sensing, development of innate and adaptive immune responses, and airway remodelling and hyperresponsiveness. Nonetheless, antioxidant compounds have proven clinically ineffective as therapeutic agents for asthma, partly due to issues with stability and in vivo metabolism of these compounds. The compartmentalised nature of ROS product
Reinke SN, Naz S, Chaleckis R, et al., 2022, Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study, EUROPEAN RESPIRATORY JOURNAL, Vol: 59, ISSN: 0903-1936
Mortaz E, Garssen J, Adcock IM, 2022, Do Low-density Granulocytes Induce Lymphopenia in Patients with COVID-19?, IRANIAN JOURNAL OF ALLERGY ASTHMA AND IMMUNOLOGY, Vol: 21, Pages: 369-373, ISSN: 1735-1502
Li C, Zhang H, Wei L, et al., 2022, Role of TRPA1/TRPV1 in acute ozone exposure induced murine model of airway inflammation and bronchial hyperresponsiveness, Journal of Thoracic Disease, Vol: 14, ISSN: 2072-1439
Background: Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) mediatethe development of lung injury and inflammation. This study investigated the role and mechanism of theTRPA1/TRPV1 pathway in airway inflammation and bronchial hyperresponsiveness (BHR) induced byacute ozone exposure.Methods: C57BL/6 mice (8–10 weeks) were intraperitoneally injected with phosphate buffered saline(PBS), A967079 (TRPA1 inhibitor) or AMG9810 (TRPV1 inhibitor) 1 h before or after ozone exposure(2.5 ppm, 3 h). BHR, cell counts in bronchoalveolar lavage (BAL) fluid, oxidative stress biomarkers,inflammatory cytokines, TRPA1 and TPRV1 protein levels, mitochondrial dynamics- and mitophagy-relatedprotein levels, and activities of mitochondrial respiratory chain (MRC) in lung were measured.Results: The preventive treatment effect was similar to the therapeutic treatment effect. Both A967079 andAMG9810 intervention suppressed BHR, inflammatory cytokines, total BAL fluid cells, malondialdehyde(MDA) levels and inflammatory cytokines mRNA including Substance P (SP), Keratinocyte-DerivedChemokine (KC), interleukin18 (IL-18) and chemokine (C-X-C motif) ligand 8 (CXCL8) expression, andenhanced reduced glutathione (GSH)/oxidized glutathione (GSSG) levels compared with ozone-exposedmice. A967079 and AMG9810 intervention inhibited dynamin-related protein (DRP1), mitochondrial fissionfactor (MFF), Parkinson protein 2 E3 ubiquitin protein ligase (PARK2) and Sequestosome 1 (SQSTM1)/p62expression, increased Optic atrophy 1 (OPA1), mitofusin 2 (MFN2) and PTEN-induced putative kinase 1(PINK1) expression, and up-regulated the activities of MRC complex III and V in lung tissue.Conclusions: The results show that both TRPA1 and TRPV1 pathways are involved in acute ozoneexposure-induced airway inflammation and BHR and influence oxidative stress, mitochondrial qualitycontrol and MRC activity, which could be a potential target for clinical therapy of respiritory disease
Masfufa IW, Chung KF, Adcock I, 2022, Clinical characteristic of severe asthma patients with JAK-STAT pathway activation, Publisher: ELSEVIER, Pages: S32-S32, ISSN: 0009-8981
Hoda U, Pavlidis S, Bansal AT, et al., 2022, Clinical and transcriptomic features of persistent exacerbation-prone severe asthma in U-BIOPRED cohort, Clinical and Translational Medicine, Vol: 12, ISSN: 2001-1326
Background: Exacerbation-prone asthma is a feature of severe disease. Yet, the basis for its persistency remains unclear. Objectives: To determine the clinical and transcriptomic features of the frequent-exacerbator (FE) and of persistent FEs (PFE) in U-BIOPRED cohort. Methods: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures.Results: Of 317 patients, 62.4 % were FE of whom 63.6% were PFE, while 37.6% were IE of whom 61.3% were PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE with eczema, short-acting beta-agonist use and asthma control index. CEA Cell Adhesion Molecule 5 (CEACAM5) was the only differentially-expressed transcript in bronchial biopsies between PE and IE. There were no differentially-expressed genes in the other 4 compartments. There were higher expression scores for Type 2 , T-helper type-17 and Type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while higher expression scores of Type 2, Type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE.Conclusion: FE group and its PFE subgroup are associated with poor asthma control while expressing higher Type 1 and Type 2 activation pathways compared to IE and PIE, respectively.
Mortaz E, Nomani M, Adcock I, et al., 2022, Galactooligosaccharides and 2 '-fucosyllactose can directly suppress growth of specific pathogenic microbes and affect phagocytosis of neutrophils, NUTRITION, Vol: 96, ISSN: 0899-9007
Asef A, Ghafaripour HA, Jamaati H, et al., 2022, The role of HLA-DRB1 alleles in pulmonary cystic fibrosis, Iranian Journal Of Allergy, Asthma and Immunology, Vol: 21, Pages: 189-196, ISSN: 1735-1502
Cystic fibrosis (CF) is the most common lethal autosomal recessive disease inwhite Caucasians. It affects many organs including the lung, pancreas, and liver. Whilst CF is a monogenic disease, several studies revealed a complex relationship between genotype and clinical phenotype of diseases.We examined the expression of human leukocyte antigen (HLA) class II alleles among Iranian CF patients with disease-related microbial infection. This study was conducted on 50 hospitalized CF patients (27 males, 23 females aged 15.5±6.5 years), and 50 healthy age-and gender-matched control subjects. 5ml whole blood was harvested and after isolation of genomic DNA, HLA-DRB1 subtypes were determined by single specific primer polymerase chain reaction methods. HLA-DRB1*10 was less frequent and HLA-DRB1*04 and HLA-DRB1*11 wasthe most frequent allele in CF patients, but none reached significance. HLA-DRB1*04 allele was frequently seen among16 CF patients with high serum IgElevels (430.25±219.7 IU/mL) and 27 CF patients that were positive for Pseudomonas aeruginosa colonization. A total of31 CF patients had candida Albicans colonization in whomHLA-DRB1*11 was mostly seen. A total of 3 CF patients had allergic bronchopulmonary aspergillosis and two were diabetic. The DR4 and DR11 serotypes that recognize the HLA-DRB1*04 and HLA-DRB1*11 gene products respectively are not significantly enriched in the Iranian CF population. Further research should be conducted on DR4 and DR11 in CF patients to understand their possible role in infection and IgE expression
Pinkerton JW, Kim RY, Brown AC, et al., 2022, Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma, Journal of Allergy and Clinical Immunology, Vol: 149, Pages: 1270-1280, ISSN: 0091-6749
BACKGROUND: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. OBJECTIVE: We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. METHODS: We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma. RESULTS: Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. CONCLUSION: We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors.
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