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 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 A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated Pneumococcal Mouse Infections

2015 ◽  
Vol 59 (10) ◽  
pp. 6064-6072 ◽  
Author(s):  
Rémi Porte ◽  
Delphine Fougeron ◽  
Natalia Muñoz-Wolf ◽  
Julien Tabareau ◽  
Anne-France Georgel ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Combination Treatment ◽  
Intranasal Administration ◽  
Pathogenic Bacteria ◽  
Bacterial Load ◽  
Pneumococcal Infection ◽  
Toll Like Receptor ◽  
Content Type ◽  
Toll Like Receptor 5 ◽  
Stimulation Of

ABSTRACTProphylactic intranasal administration of the Toll-like receptor 5 (TLR5) agonist flagellin protects mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might improve the therapeutic index of antibiotics for the treatment ofStreptococcus pneumoniaerespiratory infections in mice. Intranasal administration of flagellin was combined with either oral administration of amoxicillin or intraperitoneal injection of trimethoprim-sulfamethoxazole to treatS. pneumoniae-infected animals. Compared with standalone treatments, the combination of antibiotic and flagellin resulted in a lower bacterial load in the lungs and greater protection againstS. pneumoniaedissemination and was associated with an early increase in neutrophil infiltration in the airways. The antibiotic-flagellin combination treatment was, however, not associated with any exacerbation of inflammation. Moreover, combination treatment was more efficacious than standalone antibiotic treatments in the context of post-influenza virus pneumococcal infection. Lastly, TLR5 signaling was shown to be mandatory for the efficacy of the combined antibacterial therapy. This report is the first to show that combining antibiotic treatment with the stimulation of mucosal innate immunity is a potent antibacterial strategy against pneumonia.

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 Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice

2015 ◽  
Vol 308 (1) ◽  
pp. L96-L103 ◽  
Author(s):  
Loes E. M. Kistemaker ◽  
Ronald P. van Os ◽  
Albertina Dethmers-Ausema ◽  
I. Sophie T. Bos ◽  
Machteld N. Hylkema ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cigarette Smoke ◽  
Neutrophil Migration ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Chronic Obstructive ◽  
Wild Type ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Relative Contribution

Anticholinergics, blocking the muscarinic M3 receptor, are effective bronchodilators for patients with chronic obstructive pulmonary disease. Recent evidence from M3 receptor-deficient mice (M3R−/−) indicates that M3 receptors also regulate neutrophilic inflammation in response to cigarette smoke (CS). M3 receptors are present on almost all cell types, and in this study we investigated the relative contribution of M3 receptors on structural cells vs. inflammatory cells to CS-induced inflammation using bone marrow chimeric mice. Bone marrow chimeras (C56Bl/6 mice) were generated, and engraftment was confirmed after 10 wk. Thereafter, irradiated and nonirradiated control animals were exposed to CS or fresh air for four consecutive days. CS induced a significant increase in neutrophil numbers in nonirradiated and irradiated control animals (4- to 35-fold). Interestingly, wild-type animals receiving M3R−/− bone marrow showed a similar increase in neutrophil number (15-fold). In contrast, no increase in the number of neutrophils was observed in M3R−/− animals receiving wild-type bone marrow. The increase in keratinocyte-derived chemokine (KC) levels was similar in all smoke-exposed groups (2.5- to 5.0-fold). Microarray analysis revealed that fibrinogen-α and CD177, both involved in neutrophil migration, were downregulated in CS-exposed M3R−/− animals receiving wild-type bone marrow compared with CS-exposed wild-type animals, which was confirmed by RT-qPCR (1.6–2.5 fold). These findings indicate that the M3 receptor on structural cells plays a proinflammatory role in CS-induced neutrophilic inflammation, whereas the M3 receptor on inflammatory cells does not. This effect is probably not mediated via KC release, but may involve altered adhesion and transmigration of neutrophils via fibrinogen-α and CD177.

scholarly journals Nontypeable Haemophilus influenzae Clearance by Alveolar Macrophages Is Impaired by Exposure to Cigarette Smoke

2009 ◽  
Vol 77 (10) ◽  
pp. 4232-4242 ◽  
Author(s):  
Pau Martí-Lliteras ◽  
Verónica Regueiro ◽  
Pau Morey ◽  
Derek W. Hood ◽  
Carles Saus ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Cigarette Smoke ◽  
Alveolar Macrophages ◽  
Respiratory Diseases ◽  
Actin Polymerization ◽  
Respiratory Infections ◽  
Chronic Obstructive ◽  
Pi3k Signaling ◽  
Macrophage Phagocytosis ◽  
Tnf Α

ABSTRACT Nontypeable Haemophilus influenzae (NTHI) is an opportunistic gram-negative pathogen that causes respiratory infections and is associated with progression of respiratory diseases. Cigarette smoke is a main risk factor for development of respiratory infections and chronic respiratory diseases. Glucocorticoids, which are anti-inflammatory drugs, are still the most common therapy for these diseases. Alveolar macrophages are professional phagocytes that reside in the lung and are responsible for clearing infections by the action of their phagolysosomal machinery and promotion of local inflammation. In this study, we dissected the interaction between NTHI and alveolar macrophages and the effect of cigarette smoke on this interaction. We showed that alveolar macrophages clear NTHI infections by adhesion, phagocytosis, and phagolysosomal processing of the pathogen. Bacterial uptake requires host actin polymerization, the integrity of plasma membrane lipid rafts, and activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Parallel to bacterial clearance, macrophages secrete tumor necrosis factor alpha (TNF-α) upon NTHI infection. In contrast, exposure to cigarette smoke extract (CSE) impaired alveolar macrophage phagocytosis, although NTHI-induced TNF-α secretion was not abrogated. Mechanistically, our data showed that CSE reduced PI3K signaling activation triggered by NTHI. Treatment of CSE-exposed cells with the glucocorticoid dexamethasone reduced the amount of TNF-α secreted upon NTHI infection but did not compensate for CSE-dependent phagocytic impairment. The deleterious effect of cigarette smoke was observed in macrophage cell lines and in human alveolar macrophages obtained from smokers and from patients with chronic obstructive pulmonary disease.

scholarly journals Cigarette Smoke Induced Lung Barrier Dysfunction, EMT, and Tissue Remodeling: A Possible Link between COPD and Lung Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Wei Hou ◽  
Siyi Hu ◽  
Chunyan Li ◽  
Hanbin Ma ◽  
Qi Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Fine Particulate Matter ◽  
Inflammatory Cells ◽  
Chronic Obstructive ◽  
Vascular Networks ◽  
Barrier Dysfunction ◽  
Obstructive Pulmonary Disease ◽  
Lung Cancer Patients

Chronic obstructive pulmonary disease (COPD) and lung cancer, closely related to smoking, are major lung diseases affecting millions of individuals worldwide. The generated gas mixture of smoking is proved to contain about 4,500 components such as carbon monoxide, nicotine, oxidants, fine particulate matter, and aldehydes. These components were considered to be the principle factor driving the pathogenesis and progression of pulmonary disease. A large proportion of lung cancer patients showed a history of COPD, which demonstrated that there might be a close relationship between COPD and lung cancer. In the early stages of smoking, lung barrier provoked protective response and DNA repair are likely to suppress these changes to a certain extent. In the presence of long-term smoking exposure, these mechanisms seem to be malfunctioned and lead to disease progression. The infiltration of inflammatory cells to mucosa, submucosa, and glandular tissue caused by inhaled cigarette smoke is responsible for the destruction of matrix, blood supply shortage, and epithelial cell death. Conversely, cancer cells have the capacity to modulate the proliferation of epithelial cells and produce of new vascular networks. Comprehension understanding of mechanisms responsible for both pathologies is necessary for the prevention and treatment of COPD and lung cancer. In this review, we will summarize related articles and give a glance of possible mechanism between cigarette smoking induced COPD and lung cancer.

scholarly journals Cigarette smoke exposure alters phosphodiesterases in human structural lung cells

2020 ◽  
Vol 318 (1) ◽  
pp. L59-L64 ◽  
Author(s):  
Haoxiao Zuo ◽  
Alen Faiz ◽  
Maarten van den Berge ◽  
Senani N. H. Rathnayake Mudiyanselage ◽  
Theo Borghuis ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Cyclic Nucleotides ◽  
Complex Mixture ◽  
Inflammatory Cells ◽  
Pde4 Inhibitor ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Pde Inhibition ◽  
Never Smokers

Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli, which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in preclinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally, the expression and distribution of PDE3A and PDE4D in human lung tissues was examined. This study reveals that chronic CS exposure modulates the expression of various PDE members. Thus, CS exposure may change the levels of intracellular cyclic nucleotides and thereby impact the efficiency of PDE-targeted therapies.

scholarly journals Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema through Nrf2 Activation in Mice

Marine Drugs ◽  
2019 ◽  
Vol 17 (12) ◽  
pp. 673 ◽  
Author(s):  
Hiroaki Kubo ◽  
Kazuhisa Asai ◽  
Kazuya Kojima ◽  
Arata Sugitani ◽  
Yohkoh Kyomoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cigarette Smoke ◽  
Defense Mechanism ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Obstructive Pulmonary Disease ◽  
Suppression Effect

Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key cellular defense mechanism against oxidative stress. Recent studies have shown that astaxanthin protects against oxidative stress via Nrf2. In this study, we investigated the emphysema suppression effect of astaxanthin via Nrf2 in mice. Mice were divided into four groups: control, smoking, astaxanthin, and astaxanthin + smoking. The mice in the smoking and astaxanthin + smoking groups were exposed to cigarette smoke for 12 weeks, and the mice in the astaxanthin and astaxanthin + smoking groups were fed a diet containing astaxanthin. Significantly increased expression levels of Nrf2 and its target gene, heme oxygenase-1 (HO-1), were found in the lung homogenates of astaxanthin-fed mice. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was significantly decreased, and emphysema was significantly suppressed. In conclusion, astaxanthin protects against oxidative stress via Nrf2 and ameliorates cigarette smoke-induced emphysema. Therapy with astaxanthin directed toward activating the Nrf2 pathway has the potential to be a novel preventive and therapeutic strategy for COPD.

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