scholarly journals Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression

2017 ◽  
Vol 49 (5) ◽  
pp. 1602006 ◽  
Author(s):  
Antonino Di Stefano ◽  
Fabio L.M. Ricciardolo ◽  
Gaetano Caramori ◽  
Ian M. Adcock ◽  
Kian Fan Chung ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Bacterial Load ◽  
Airflow Obstruction ◽  
Adaptor Protein ◽  
Inflammatory Cells ◽  
Primary Response ◽  
Chronic Obstructive ◽  
Bronchial Mucosa ◽  
Bronchial Epithelial ◽  
Bronchial Inflammation

Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was measured by quantitative real-time PCR.TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4+ and CD8+ cells and airflow obstruction. NOD1 expression correlated with CD8+ cells. The bronchial load of P. aeruginosa was directly correlated, but H. influenzae inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells.Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and P. aeruginosa bacterial load, may play a role in the pathogenesis of COPD.

scholarly journals The Toll-Like Receptor 5 agonist flagellin prevents Non-typeable Haemophilus influenzae-induced infection in cigarette smoke-exposed mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0236216
Author(s):  
Magdiel Pérez-Cruz ◽  
Bachirou Koné ◽  
Rémi Porte ◽  
Christophe Carnoy ◽  
Julien Tabareau ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Cigarette Smoke ◽  
Pathogenic Bacteria ◽  
Bacterial Load ◽  
Inflammatory Cells ◽  
Chronic Obstructive ◽  
Toll Like Receptor ◽  
Copd Exacerbations ◽  
Toll Like Receptor 5 ◽  
Stimulation Of

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. The major bacterial cause of COPD exacerbations is non-typeable Haemophilus influenzae (NTHi). 25 to over 80% of cases are associated with NTHi. This susceptibility to infection involves a defective production of interleukin (IL)-22 which plays an important role in mucosal defense. Prophylactic administration of flagellin, a Toll-like receptor 5 (TLR5) agonist, protects healthy mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might prevent COPD exacerbations. Mice chronically exposed to cigarette smoke (CS), which presented COPD symptoms, were infected with NTHi and intraperitoneally treated with recombinant flagellin following a prophylactic or therapeutic protocol. Compared with control, cigarette smoke-exposed mice treated with flagellin showed a lower bacterial load in the airways, the lungs and the blood. This protection was associated with an early neutrophilia, a lower production of pro-inflammatory cytokines and an increased IL-22 production. Flagellin treatment decreased the recruitment of inflammatory cells and the lung damages related to exacerbation. Morover, the protective effect of flagellin against NTHi was altered by treatment with anti-IL-22 blocking antibodies in cigarette smoke-exposed mice and in Il22-/- mice. The effect of flagellin treatment did not implicated the anti-bacterial peptides calgranulins and defensin-β2. This study shows that stimulation of innate immunity by a TLR5 ligand is a potent antibacterial treatment in CS-exposed mice, suggesting innovative therapeutic strategies against acute exacerbation in COPD.

scholarly journals Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala

2019 ◽  
Vol 9 (12) ◽  
pp. 361 ◽  
Author(s):  
Michal Bajo ◽  
Reesha R. Patel ◽  
David M. Hedges ◽  
Florence P. Varodayan ◽  
Roman Vlkolinsky ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Motor Coordination ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Gaba Release ◽  
Primary Response ◽  
Central Amygdala ◽  
Gabaergic Transmission ◽  
Whole Cell Patch Clamp

Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced sedation, and ethanol-induced deficits in motor coordination. In this study, we examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala (CeA) of male mice using whole-cell patch-clamp recordings in combination with pharmacological (AS-1, a mimetic that prevents MyD88 recruitment by IL-1R) and genetic (Myd88 knockout mice) approaches. We demonstrate through both approaches that IL-1β and ethanol’s modulatory effects at CeA GABA synapses are not dependent on MyD88. Myd88 knockout potentiated IL-1β’s actions in reducing postsynaptic GABAA receptor function. Pharmacological inhibition of MyD88 modulates IL-1β’s action at CeA GABA synapses similar to Myd88 knockout mice. Additionally, ethanol-induced CeA GABA release was greater in Myd88 knockout mice compared to wildtype controls. Thus, MyD88 is not essential to IL-1β or ethanol regulation of CeA GABA synapses but plays a role in modulating the magnitude of their effects, which may be a potential mechanism by which it regulates ethanol-related behaviors.

scholarly journals Role of Lipid Rafts and Flagellin in Invasion of Colonic Epithelial Cells by Shiga-Toxigenic Escherichia coli O113:H21

2012 ◽  
Vol 80 (8) ◽  
pp. 2858-2867 ◽  
Author(s):  
Trisha J. Rogers ◽  
Cheleste M. Thorpe ◽  
Adrienne W. Paton ◽  
James C. Paton
Keyword(s):  
Escherichia Coli ◽  
Lipid Rafts ◽  
Kinase Inhibitor ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Primary Response ◽  
Serine Kinase ◽  
Neuraminidase Treatment ◽  
Asialo Gm1

ABSTRACTShiga-toxigenicEscherichia coli(STEC) O113:H21 strains that lack the locus of enterocyte effacement (LEE) efficiently invade eukaryotic cellsin vitro, unlike LEE-positive O157:H7 strains. We used afliCdeletion mutant of the O113:H21 STEC strain 98NK2 (98NK2ΔfliC) to show that invasion of colonic epithelial (HCT-8) cells is heavily dependent on production of flagellin, even though adherence to the cells was actually enhanced in the mutant. Flagellin binds and signals through Toll-like receptor 5 (TLR5), but there was no evidence that either TLR5, the adaptor protein myeloid differentiation primary response gene 88 (MyD88), or the serine kinase interleukin-1 receptor-associated kinase (IRAK) were required for invasion of HCT-8 cells by strain 98NK2, as judged by transfection, RNA knockdown, or inhibitor studies. However, pretreatment of cells with anti-asialo-GM1 significantly decreased 98NK2 invasion (by 40.8%), while neuraminidase treatment (which cleaves terminal sialic acid residues, thus converting GM1 into asialo-GM1) significantly increased invasion (by 70.7%). Pretreatment of HCT-8 cells with either the cholesterol-depleting agent methyl-β-cyclodextrin (MβCD) or the tyrosine kinase inhibitor genistein significantly decreased invasion by 98NK2, indicating a potential role for lipid rafts in the invasion mechanism. Confocal microscopy also showed invading 98NK2 colocalized with lipid raft markers caveolin-1 and GM1. Interestingly, anti-asialo-GM1, neuraminidase, MβCD, and genistein have similar effects on the vestigial level of STEC invasion seen for STEC strain 98NK2ΔfliC, indicating that lipid rafts mediate a common step in flagellin-dependent and flagellin-independent cellular invasion.

scholarly journals The Toll-Like Receptor 5 agonist flagellin prevents Non-typeable Haemophilus influenzae-induced exacerbations in cigarette smoke-exposed mice

2020 ◽  
Author(s):  
Magdiel Pérez-Cruz ◽  
Bachirou Koné ◽  
Rémi Porte ◽  
Christophe Carnoy ◽  
Julien Tabareau ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Cigarette Smoke ◽  
Pathogenic Bacteria ◽  
Bacterial Load ◽  
Inflammatory Cells ◽  
Chronic Obstructive ◽  
Toll Like Receptor ◽  
Copd Exacerbations ◽  
Toll Like Receptor 5 ◽  
Stimulation Of

AbstractChronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. The major bacterial cause of COPD exacerbations is non-typeable Haemophilus influenzae (NTHi). This susceptibility to infection involves a defective production of interleukin (IL)-22 which plays an important role in mucosal defense. Prophylactic administration of flagellin, a Toll-like receptor 5 (TLR5) agonist, protects healthy mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might prevent COPD exacerbations due to NTHi. Mice were chronically exposed to cigarette smoke and then infected with NTHi. According our preventive or therapeutic protocol, flagellin was administered intraperitoneally. Cigarette smoke-exposed mice treated with flagellin showed a lower bacterial load in the airways, the lungs and the blood. This protection was associated with an early neutrophilia, a lower production of pro-inflammatory cytokines and an increased IL-22 production. Flagellin treatment decreased the recruitment of inflammatory cells and the lung damages related to exacerbation. Protective effect of flagellin against NTHi was altered by treatment with anti-IL-22 blocking antibodies in cigarette smoke-exposed mice and in Il22−/− mice. Flagellin treatment also amplified the production of the β-defensin2 anti-bacterial peptides. This study shows that stimulation of innate immunity by a TLR5 ligand is a potent antibacterial treatment in cigarette smoke exposed mice, suggesting innovative therapeutic strategies against acute exacerbation in COPD.

scholarly journals Bruceine D ameliorates the balance of Th1/Th2 in a mouse model of ovalbumin-induced allergic asthma via inhibiting the NOTCH pathway

2021 ◽  
Vol 49 (6) ◽  
pp. 73-79
Author(s):  
Ying Nie ◽  
Bangkun Yang ◽  
Junfeng Hu ◽  
Lingling Zhang ◽  
Zhimin Ma
Keyword(s):  
Notch Signaling ◽  
Allergic Asthma ◽  
Airflow Obstruction ◽  
Bronchial Hyperresponsiveness ◽  
Notch Pathway ◽  
Bioactive Compound ◽  
Inflammatory Cells ◽  
Cell Infiltration ◽  
Inflammatory Disorder ◽  
Bronchial Inflammation

Allergic asthma is a heterogeneous inflammatory disorder triggered by inhaled allergens, leading to airflow obstruction, bronchial inflammation, and airway hyperresponsiveness (AHR). T helper (Th) 2 cell-mediated immune response and airway inflammation are the key features of allergic asthma. Bruceine D (BD) is a bioactive compound extracted from the seeds of Brucea javanica. The present study aimed to investigate the effects of increased doses of BD on AHR, secretion of Th1-/Th2-associated cytokines, and inflammatory cell infiltration in ovalbumin (OVA)-induced allergic asthma mice. The results showed that BD reduced OVA-induced inflam-matory cell infiltration and bronchial hyperresponsiveness into the peribronchial tissues and perivascular areas. Mice treated with BD also showed significantly decreased expressions of Th2-associated cytokines (i.e., interleukin (IL)-4, IL-5, and IL-13) and elevated production of Th1-associated cytokines (i.e., interferon gamma and IL-2) following OVA stimulation. BD treatment dose-dependently inhibited OVA-induced accumulation of inflammatory cells in asth-matic mice. Further analysis revealed that OVA exposure upregulated pulmonary expressions of NOTCH signaling receptors, a group of transmembrane proteins that communicate signals upon binding to transmembrane ligands expressed on adjacent cells, while BD treatment sig-nificantly abolished OVA-induced activation of the NOTCH pathway. In conclusion, BD protected mice against OVA-induced allergic asthma by reducing AHR and restoring the Th1/Th2 balance through the NOTCH signaling pathway. Our findings highlighted the potential of BD as a therapeutic agent for allergic asthma.

scholarly journals MCP-1/CCR2B-dependent loop upregulates MUC5AC and MUC5B in human airway epithelium

2011 ◽  
Vol 300 (2) ◽  
pp. L204-L215 ◽  
Author(s):  
Maria E. Monzon ◽  
Rosanna Malbrán Forteza ◽  
S. Marina Casalino-Matsuda
Keyword(s):  
Airway Epithelium ◽  
Primary Cultures ◽  
Airflow Obstruction ◽  
Inflammatory Cells ◽  
Chronic Obstructive ◽  
Cell Hyperplasia ◽  
Epithelial Surface ◽  
Initial Exposure ◽  
Mucus Hypersecretion

Cigarette smoke represents a major risk factor for the development of chronic obstructive pulmonary disease (COPD), a respiratory condition associated with airflow obstruction, mucus hypersecretion, chronic inflammation, and upregulation of inflammatory mediators such as the monocyte chemotactic protein-1 (MCP-1). MCP-1 through its receptor CCR2 induces chemotaxis and activates 44/42MAPK, a kinase known to play a key role in mucin regulation in bronchial epithelium. In the present study we used differentiated primary cultures of normal human bronchial epithelial (NHBE) cells to test whether MCP-1 through its receptor CCR2 induces mucin upregulation. We have provided evidence that NHBE cells release MCP-1 to the epithelial surface and express the CCR2B isoform of the receptor mainly at the apical pole. In addition, we found that MCP-1 has a novel function in airway epithelium, increasing the two major airway mucins MUC5AC and MUC5B, an effect mediated, at least in part, by a cascade of events initiated by interaction of its receptor CCR2B with Gq subunits in caveolae, followed by PLCβ, PKC, and 44/42MAPK activation. We also have shown that MCP-1 is able to induce its own expression using the same receptor but through a different pathway that involves RhoA GTPase. Furthermore, we found that a single exposure to MCP-1 is enough to induce MCP-1 secretion and sustained mucin upregulation up to 7 days after initial exposure, an effect mediated by CCR2B as confirmed using short hairpin RNA. These results agree with our data in smoker's airway epithelium, where CCR2B is present in MUC5AC- and MUC5B-expressing cells and augmented MCP-1 expression is associated with increased MUC5AC and MUC5B immunolabeling, suggesting that the mechanisms described in primary cell cultures in the present study are operative in vivo. Therefore, therapeutic approaches targeting MCP-1/CCR2B may be useful in preventing not only influx of inflammatory cells to the airways but also mucus hypersecretion and goblet cell hyperplasia.

scholarly journals Serum bilirubin and chronic obstructive pulmonary disease (COPD): a systematic review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
David M. MacDonald ◽  
Ken M. Kunisaki ◽  
Timothy J. Wilt ◽  
Arianne K. Baldomero
Keyword(s):  
Systematic Review ◽  
Health Status ◽  
Lung Function ◽  
Serum Bilirubin ◽  
Respiratory Health ◽  
Airflow Obstruction ◽  
Risk Of Bias ◽  
Chronic Obstructive ◽  
Strength Of Evidence ◽  
Acute Exacerbations

Abstract Background Bilirubin is a potent antioxidant and higher serum bilirubin levels have been associated with improved COPD outcomes. We performed a systematic review to evaluate the association between serum bilirubin levels and lung function (FEV1), prevalence/incidence of COPD, acute exacerbations of COPD, respiratory health status, and mortality. Methods MEDLINE® and Embase were searched using Ovid® (search updated October 1st, 2019). We included studies that measured serum bilirubin levels and outcomes of interest in adults with or without underlying lung disease. We excluded studies of those with liver disease or drug-induced elevations in bilirubin. We used the Newcastle–Ottawa scale to assess individual study risk of bias (ROB) and the US Agency for Healthcare Research and Quality—Evidence Based Practice tool to assess overall strength of evidence (SOE). Two authors independently determined eligibility, performed data abstraction, assessed ROB, and determined SOE. Results Thirteen studies (5 low risk of bias, 3 moderate and 5 high risk) were included. We found low strength of evidence for the association between higher bilirubin levels and lower risk of acute exacerbations of COPD (2 studies), mortality (3 studies), COPD diagnosis (4 studies), and lung function (FEV1) (8 studies). We found insufficient evidence on the relationship between serum bilirubin and respiratory health status/exercise capacity (1 study) and airflow obstruction (FEV1/FVC ratio) (4 studies). Conclusion Higher bilirubin levels may be associated with lower mortality and improved COPD outcomes. Randomized trials are needed to evaluate the effect of medications that raise serum bilirubin on COPD outcomes. PROSPERO registration: CRD42019145747.

scholarly journals Loss of IL-33 enhances elastase-induced and cigarette smoke extract-induced emphysema in mice

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daisuke Morichika ◽  
Akihiko Taniguchi ◽  
Naohiro Oda ◽  
Utako Fujii ◽  
Satoru Senoo ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Intratracheal Instillation ◽  
Inflammatory Cells ◽  
Cigarette Smoke Extract ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Porcine Pancreas ◽  
Obstructive Pulmonary Disease ◽  
Quantitative Morphometry ◽  
Cytokines And Chemokines

Abstract Background IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear. Methods We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33−/− mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again. Results Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33−/− mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33−/− and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33−/− mice than WT mice. IL-33−/− mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE. Conclusion These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.

scholarly journals Cardiovascular risk prediction using physical performance measures in COPD: results from a multicentre observational study

BMJ Open ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. e038360
Author(s):  
Jilles M Fermont ◽  
Marie Fisk ◽  
Charlotte E Bolton ◽  
William MacNee ◽  
John R Cockcroft ◽  
...  
Keyword(s):  
Risk Factors ◽  
Physical Performance ◽  
Risk Prediction ◽  
Survival Data ◽  
Airflow Obstruction ◽  
Secondary Outcome ◽  
Chronic Obstructive ◽  
Bode Index ◽  
Gold Stage ◽  
Improved Model

ObjectivesAlthough cardiovascular disease (CVD) is a common comorbidity associated with chronic obstructive pulmonary disease (COPD), it is unknown how to improve prediction of cardiovascular (CV) risk in individuals with COPD. Traditional CV risk scores have been tested in different populations but not uniquely in COPD. The potential of alternative markers to improve CV risk prediction in individuals with COPD is unknown. We aimed to determine the predictive value of conventional CVD risk factors in COPD and to determine if additional markers improve prediction beyond conventional factors.DesignData from the Evaluation of the Role of Inflammation in Chronic Airways disease cohort, which enrolled 729 individuals with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II–IV COPD were used. Linked hospital episode statistics and survival data were prospectively collected for a median 4.6 years of follow-up.SettingFive UK centres interested in COPD.ParticipantsPopulation-based sample including 714 individuals with spirometry-defined COPD, smoked at least 10 pack years and who were clinically stable for >4 weeks.InterventionsBaseline measurements included aortic pulse wave velocity (aPWV), carotid intima–media thickness (CIMT), C reactive protein (CRP), fibrinogen, spirometry and Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity (BODE) Index, 6 min walk test (6MWT) and 4 m gait speed (4MGS) test.Primary and secondary outcome measuresNew occurrence (first event) of fatal or non-fatal hospitalised CVD, and all-cause and cause-specific mortality.ResultsOut of 714 participants, 192 (27%) had CV hospitalisation and 6 died due to CVD. The overall CV risk model C-statistic was 0.689 (95% CI 0.688 to 0.691). aPWV and CIMT neither had an association with study outcome nor improved model prediction. CRP, fibrinogen, GOLD stage, BODE Index, 4MGS and 6MWT were associated with the outcome, independently of conventional risk factors (p<0.05 for all). However, only 6MWT improved model discrimination (C=0.727, 95% CI 0.726 to 0.728).ConclusionPoor physical performance defined by the 6MWT improves prediction of CV hospitalisation in individuals with COPD.Trial registration numberID 11101.

Sign in / Sign up

Export Citation Format

Share Document