scholarly journals Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Terence Ho ◽  
Matthew Nichols ◽  
Gayatri Nair ◽  
Katherine Radford ◽  
Melanie Kjarsgaard ◽  
...  
Keyword(s):  
Immune Cell ◽  
Population Level ◽  
Chronic Obstructive ◽  
Iron Loading ◽  
Experimental Conditions ◽  
Obstructive Pulmonary Disease ◽  
Excess Iron ◽  
Iron Sequestration ◽  
Pulmonary Macrophages

Abstract Background Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated. Objectives To assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on cellular immune function, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD. Methods Intra- and extracellular iron was measured in cell-line-derived and in freshly isolated sputum macrophages under various experimental conditions including treatment with exogenous IL-6 and hepcidin. Bacterial uptake and killing were compared in the presence or absence of iron-loading. A prospective cohort of COPD patients with defined sputum hemosiderin indices were monitored to determine the annual rate of severe infectious exacerbations. Results Gene expression studies suggest that airway macrophages have the requisite apparatus of the hepcidin-ferroportin axis. IL-6 and hepcidin play roles in pulmonary iron sequestration, though IL-6 appears to exert its effect via a hepcidin-independent mechanism. Iron-loaded macrophages had reduced uptake of COPD-relevant organisms and were associated with higher growth rates. Infectious exacerbations were predicted by sputum hemosiderin index (β = 0.035, p = 0.035). Conclusions We demonstrate in-vitro and population-level evidence that excess iron in pulmonary macrophages may contribute to recurrent airway infection in COPD. Specifically, IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation.

scholarly journals What are the respiratory effects of e-cigarettes?

BMJ ◽  
2019 ◽  
pp. l5275 ◽  
Author(s):  
Jeffrey E Gotts ◽  
Sven-Eric Jordt ◽  
Rob McConnell ◽  
Robert Tarran
Keyword(s):  
Current Knowledge ◽  
Respiratory Health ◽  
Electronic Cigarettes ◽  
Population Level ◽  
Chronic Obstructive ◽  
Tobacco Products ◽  
Obstructive Pulmonary Disease ◽  
Biologic Effects ◽  
Chronic Smoking

ABSTRACT Electronic cigarettes (e-cigarettes) are alternative, non-combustible tobacco products that generate an inhalable aerosol containing nicotine, flavors, propylene glycol, and vegetable glycerin. Vaping is now a multibillion dollar industry that appeals to current smokers, former smokers, and young people who have never smoked. E-cigarettes reached the market without either extensive preclinical toxicology testing or long term safety trials that would be required of conventional therapeutics or medical devices. Their effectiveness as a smoking cessation intervention, their impact at a population level, and whether they are less harmful than combustible tobacco products are highly controversial. Here, we review the evidence on the effects of e-cigarettes on respiratory health. Studies show measurable adverse biologic effects on organ and cellular health in humans, in animals, and in vitro. The effects of e-cigarettes have similarities to and important differences from those of cigarettes. Decades of chronic smoking are needed for development of lung diseases such as lung cancer or chronic obstructive pulmonary disease, so the population effects of e-cigarette use may not be apparent until the middle of this century. We conclude that current knowledge of these effects is insufficient to determine whether the respiratory health effects of e-cigarette are less than those of combustible tobacco products.

MiR-195-5p inhibits the development of chronic obstructive pulmonary disease via targeting siglec1

2020 ◽  
Vol 39 (10) ◽  
pp. 1333-1344
Author(s):  
S Li ◽  
L Jiang ◽  
Y Yang ◽  
J Cao ◽  
Q Zhang ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Pulmonary Macrophages ◽  
Pro Inflammatory Cytokines

Chronic obstructive pulmonary disease (COPD), characterized by chronic inflammation, is a recognized global health crisis. Sialic acid-binding immunoglobulin-like lectin 1 (siglec1 or CD169), mainly expressed in macrophages and dendritic cells, is markedly upregulated after encountering pathogens or under acute/chronic inflammation conditions. However, it is rarely reported that whether siglec1 plays a role in the development of COPD. In this study, we found that siglec1 had higher expression in the lungs from COPD rats and in peripheral blood mononuclear cells (PBMCs) from COPD patients. Knockdown of siglec1 in vivo and in vitro dramatically decreased pro-inflammatory cytokines production in pulmonary macrophages and alleviated pulmonary inflammatory responses in COPD rats as well as inactivated nuclear factor kappa B (NF-κB) signaling. In addition, we identified a new microRNA, miR-195-5p, which has never explored in COPD, was lower expressed in COPD rats and PBMC of COPD patients, and could negatively modulate siglec1 expression in macrophages. Moreover, overexpression of miR-195-5p via miR-195-5p mimics in vitro and in vivo could significantly alleviate pro-inflammatory cytokines production in pulmonary macrophages and pulmonary inflammatory responses in COPD rats. Together, our findings suggested that miR-195-5p inhibited the development of COPD via targeting siglec1, which might become a therapeutic target to improve COPD.

scholarly journals ILC2 Cells Promote Th2 Cell Differentiation in AECOPD Through Activated Notch-GATA3 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Jiang ◽  
Ren Cai ◽  
Jing Wang ◽  
Zheng Li ◽  
Dan Xu ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Peripheral Blood ◽  
Culture Supernatant ◽  
Th2 Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Protein Levels ◽  
Th2 Cell

This study is to investigate the capacity of type 2 innate lymphoid cells (ILC2s) in regulating the Th2 type adaptive immune response of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The study enrolled healthy people, stable chronic obstructive pulmonary disease (COPD) patients, and AECOPD patients. Flow cytometry was used to detect Th2 and ILC2 cells in the peripheral blood. In addition, ILC2s from the peripheral blood of AECOPD patients were stimulated with PBS, IL-33, Jagged1, DAPT, IL-33+Jagged1, IL-33+DAPT, and IL-33+Jagged-1+DAP in vitro. The levels of cytokines in the culture supernatant were detected by ELISA and the culture supernatant was used to culture CD4 + T cells. The mRNA and protein levels of Notch1, hes1, GATA3, RORα, and NF-κB of ILC2s were detected by real-time PCR and Western blot. The proportion of Th2 and ILC2s was significantly increased in the peripheral blood of AECOPD patients, alone with the increased Notch1, hes1, and GATA3 mRNA levels. In vitro results showed that the mRNA and protein levels of Notch1, hes1, GATA3 and NF-κB were significantly increased after stimulation with Notch agonist, meanwhile, the level of type 2 cytokines were increased in the supernatant of cells stimulated with Notch agonist, and significantly promoted differentiation of Th2 cells in vitro. Disruption of Notch pathway weakened GATA3 expression and cytokine production, and ultimately affected the differentiation of Th2 cells. In conclusion, our results suggest that ILC2s can promote Th2 cell differentiation in AECOPD via activated Notch-GATA3 signal pathway.

scholarly journals Possible Implication of Hypoxia-mediated Incomplete Neutrophil Extracellular Trap Formation in Pneumonia-induced Exacerbation of Lung Diseases

2021 ◽  
Author(s):  
Sakiko Masuda ◽  
Kurumi Kato ◽  
Misato Ishibashi ◽  
Yuka Nishibata ◽  
Ayako Sugimoto ◽  
...  
Keyword(s):  
Lung Diseases ◽  
Actin Polymerization ◽  
Hypoxia Inducible Factor ◽  
Neutrophil Extracellular Trap ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Hypoxic Conditions ◽  
Pulmonary Arterial ◽  
Underlying Diseases

Abstract When patients with preexisting lung diseases, such as chronic obstructive pulmonary disease, interstitial pneumonitis, and pulmonary arterial hypertension, develop pneumonia, the complication often exacerbates the underlying diseases. Although neutrophil extracellular traps (NETs) are important components of innate immune system, the residue of NETs in the tissue can harm the host. We examined the expression of hypoxia-inducible factor 1α (HIF-1α) and NETs in the lungs of patients with lung diseases complicated with pneumonia, and investigated the properties of NETs generated under hypoxia. This study demonstrated that the amount of NETs in pulmonary lesions was greater in patients with pneumonia than in patients without pneumonia and displayed a positive correlation between the amount of NETs and HIF-1α expression. We further demonstrated that the formation of typical lytic NETs was suppressed and round-shaped NETs were generated under hypoxic conditions in vitro. These round NETs were resistant to digestion by the principal NET regulator, DNase I. Focusing on actin rearrangement in neutrophils stimulated under hypoxic conditions, we found that G-actin polymerization and F-actin degradation—both of which are observed time-dependently under normoxic conditions—were disrupted, suggesting that hypoxia mediated the incomplete NET formation. Moreover, neutrophils stimulated under hypoxic conditions possessed cytotoxicity. Accumulation of neutrophils that form degradation-resistant NETs and possess cytotoxicity, which are generated under hypoxic circumstances, are expected to be involved in exacerbation of underlying lung diseases complicated with pneumonia.

scholarly journals Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jomkuan Theprungsirikul ◽  
Sladjana Skopelja-Gardner ◽  
Ashley S. Burns ◽  
Rachel M. Wierzbicki ◽  
William F. C. Rigby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critical Role ◽  
Chronic Obstructive ◽  
Dependent Manner ◽  
Opsonic Activity ◽  
Obstructive Pulmonary Disease ◽  
Neutrophil Dysfunction ◽  
Chronic Lung Infection

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

scholarly journals Eosinophil-derived IL-13 promotes emphysema

2019 ◽  
Vol 53 (5) ◽  
pp. 1801291 ◽  
Author(s):  
Alfred D. Doyle ◽  
Manali Mukherjee ◽  
William E. LeSuer ◽  
Tyler B. Bittner ◽  
Saif M. Pasha ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Chronic Type ◽  
Obstructive Pulmonary Disease ◽  
Lung Eosinophilia

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.

scholarly journals TheTMEM189gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens

2020 ◽  
Vol 117 (14) ◽  
pp. 7792-7798 ◽  
Author(s):  
Ernst R. Werner ◽  
Markus A. Keller ◽  
Sabrina Sailer ◽  
Katharina Lackner ◽  
Jakob Koch ◽  
...  
Keyword(s):  
Double Bond ◽  
Vinyl Ether ◽  
Desaturase Activity ◽  
Immune Cell ◽  
Transmembrane Protein ◽  
Chemical Properties ◽  
Chronic Obstructive ◽  
Protein Motif ◽  
Obstructive Pulmonary Disease ◽  
Alternative Type

A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, particularly in the brain, cardiac, and immune cell membranes. A decline in these lipids has been observed in such diseases as Alzheimer’s and chronic obstructive pulmonary disease. Plasmalogens contain a characteristic 1-O-alk-1′-enyl ether (vinyl ether) double bond that confers special biophysical, biochemical, and chemical properties to these lipids. However, the genetics of their biosynthesis is not fully understood, since no gene has been identified that encodes plasmanylethanolamine desaturase (E.C. 1.14.99.19), the enzyme introducing the crucial alk-1′-enyl ether double bond. The present work identifies this gene as transmembrane protein 189 (TMEM189). Inactivation of theTMEM189gene in human HAP1 cells led to a total loss of plasmanylethanolamine desaturase activity, strongly decreased plasmalogen levels, and accumulation of plasmanylethanolamine substrates and resulted in an inability of these cells to form labeled plasmalogens from labeled alkylglycerols. Transient expression of TMEM189 protein, but not of other selected desaturases, recovered this deficit. TMEM189 proteins contain a conserved protein motif (pfam10520) with eight conserved histidines that is shared by an alternative type of plant desaturase but not by other mammalian proteins. Each of these histidines is essential for plasmanylethanolamine desaturase activity. Mice homozygous for an inactivatedTmem189gene lacked plasmanylethanolamine desaturase activity and had dramatically lowered plasmalogen levels in their tissues. These results assign theTMEM189gene to plasmanylethanolamine desaturase and suggest that the previously characterized phenotype ofTmem189-deficient mice may be caused by a lack of plasmalogens.

Allyl isothiocyanate upregulates MRP1 expression through Notch1 signaling in human bronchial epithelial cells

2020 ◽  
Vol 98 (5) ◽  
pp. 324-331
Author(s):  
Ni-ni Li ◽  
Yan Guo ◽  
Cheng-jun Jiang ◽  
Yuan-yuan Zhou ◽  
Chen-hui Li ◽  
...  
Keyword(s):  
Critical Role ◽  
Allyl Isothiocyanate ◽  
Chronic Obstructive ◽  
Therapeutic Effects ◽  
Mobility Shift ◽  
Obstructive Pulmonary Disease ◽  
Suppression Effect ◽  
Notch1 Signaling ◽  
Mrp1 Expression

Multidrug resistance associated protein-1 (MRP1) and Notch signaling are closely related and both play a critical role in chronic obstructive pulmonary disease (COPD) establishment and progression. The aim of our work was to test whether Notch1 is involved in allyl isothiocyanate (AITC) induced MRP1 expression. We used cigarette smoke extract (CSE) to simulate the smoking microenvironment in vitro. The results demonstrated that CSE led to apoptosis as well as reduced the expression of Notch1, Hes1, and MRP1, while AITC significantly reversed this downregulation. Transfected with Notch1 siRNA downregulated MRP1 expression and activity, aggravated the suppression effect by CSE, and abolished the AITC-induced Notch1, Hes1, and MRP1 expression. Validation of the correlation between Notch1 and MRP1 was implemented by gel-shift assays (electrophoretic mobility shift assay). The result revealed an interaction between a specific promoter region of MRP1 and the intracellular domain of Notch1. In conclusion, Notch1 signaling positively regulated MRP1 in 16HBE cells and AITC induced MRP1 expression and function may be attributed to Notch1 signaling. These findings show that Notch1 and MRP1 might have a potential protective effect in the COPD process and become a new therapeutic target for COPD or other lung diseases. It also provides a theoretical basis for the therapeutic effects of AITC.

scholarly journals Antimicrobial activity of a novel bioengineered honey against non-typeable Haemophilus influenzae biofilms: an in vitro study

2018 ◽  
Vol 71 (6) ◽  
pp. 554-558 ◽  
Author(s):  
Rachel S Newby ◽  
Matthew Dryden ◽  
Raymond N Allan ◽  
Rami J Salib
Keyword(s):  
Haemophilus Influenzae ◽  
Treatment Strategies ◽  
In Vitro Study ◽  
Opportunistic Pathogen ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chronic Respiratory Diseases ◽  
Novel Treatment ◽  
Novel Treatment Strategies

The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) plays an important role in many chronic respiratory diseases including otitis media, chronic rhinosinusitis, cystic fibrosis and chronic obstructive pulmonary disease. Biofilm formation has been implicated in NTHi colonisation, persistence of infection and recalcitrance towards antimicrobials. There is therefore a pressing need for the development of novel treatment strategies that are effective against NTHi biofilm-associated diseases. SurgihoneyRO is a honey-based product that has been bioengineered to enable the slow release of H2O2, a reactive oxygen species to which H. influenzae is susceptible. Treatment of established NTHi biofilms with SurgihoneyRO significantly reduced biofilm viability through enhanced H2O2 production and was shown to be more effective than the conventional antibiotic co-amoxiclav.

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