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

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.

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Cigarette Smoke Suppresses the Surface Expression ofc-kitand FcεRI on Mast Cells

Mediators of Inflammation ◽

10.1155/2013/813091 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

M. E. Givi ◽

B. R. Blokhuis ◽

C. A. Da Silva ◽

I. Adcock ◽

J. Garssen ◽

...

Keyword(s):

Bone Marrow ◽

Mast Cells ◽

Cigarette Smoke ◽

Inflammatory Cells ◽

Surface Expression ◽

Chronic Obstructive ◽

Independent Manner ◽

Obstructive Pulmonary Disease ◽

Short Term Exposure ◽

And Function

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. COPD is mostly associated with cigarette smoking. Cigarette smoke contains over 4,700 chemical compounds, including free radicals and LPS (a Toll-Like Receptor 4 agonist) at concentrations which may contribute to the pathogenesis of diseases like COPD. We have previously shown that short-term exposure to cigarette smoke medium (CSM) can stimulate several inflammatory cells via TLR4 and that CSM reduces the degranulation of bone-marrow-derived mast cells (BMMCs). In the current study, the effect of CSM on mast cells maturation and function was investigated. Coculturing of BMMC with CSM during the development of bone marrow progenitor cells suppressed the granularity and the surface expression ofc-kitand FcεRI receptors. Stimulation with IgE/antigen resulted in decreased degranulation and release of Th1 and Th2 cytokines. The effects of CSM exposure could not be mimicked by the addition of LPS to the culture medium. In conclusion, this study shows that CSM may affect mast cell development and subsequent response to allergic activation in a TLR4-independent manner.

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

Respiratory Research ◽

10.1186/s12931-021-01705-z ◽

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.

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

BioMed Research International ◽

10.1155/2019/2025636 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 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.

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Cigarette smoke exposure alters phosphodiesterases in human structural lung cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00319.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. L59-L64 ◽

Cited By ~ 6

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.

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

Marine Drugs ◽

10.3390/md17120673 ◽

2019 ◽

Vol 17 (12) ◽

pp. 673 ◽

Cited By ~ 8

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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Dendritic cells induce Tc1 cell differentiation via the CD40/CD40L pathway in mice after exposure to cigarette smoke

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00002.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. L581-L589 ◽

Cited By ~ 7

Author(s):

Liang-Jian Kuang ◽

Ting-Ting Deng ◽

Qin Wang ◽

Shi-Lin Qiu ◽

Yi Liang ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Differentiation ◽

Cigarette Smoke ◽

Lung Damage ◽

Chronic Obstructive ◽

Wild Type ◽

Control Groups ◽

Obstructive Pulmonary Disease

Dendritic cells and CD8+ T cells participate in the pathology of chronic obstructive pulmonary disease, including emphysema, but little is known of the involvement of the CD40/CD40L pathway. We investigated the role of the CD40/CD40L pathway in Tc1 cell differentiation induced by dendritic cells in a mouse model of emphysema, and in vitro. C57BL/6J wild-type and CD40−/− mice were exposed to cigarette smoke (CS) or not (control), for 24 wk. In vitro experiments involved wild-type and CD40−/− dendritic cells treated with CS extract (CSE) or not. Compared with the control groups, the CS mice (both wild type and CD40−/−) had a greater percentage of lung dendritic cells and higher levels of major histocompatability complex (MHC) class I molecules and costimulatory molecules CD40 and CD80. Relative to the CS CD40−/− mice, the CS wild type showed greater signs of lung damage and Tc1 cell differentiation. In vitro, the CSE-treated wild-type cells evidenced more cytokine release (IL-12/p70) and Tc1 cell differentiation than did the CSE-treated CD40−/− cells. Exposure to cigarette smoke increases the percentage of lung dendritic cells and promotes Tc1 cell differentiation via the CD40/CD40L pathway. Blocking the CD40/CD40L pathway may suppress development of emphysema in mice exposed to cigarette smoke.

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Dendritic cells inversely regulate airway inflammation in cigarette smoke-exposed mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00251.2014 ◽

2016 ◽

Vol 310 (1) ◽

pp. L95-L102 ◽

Cited By ~ 3

Author(s):

Masoumeh Ezzati Givi ◽

Peyman Akbari ◽

Louis Boon ◽

Vladimir S. Puzovic ◽

Gillina F. G. Bezemer ◽

...

Keyword(s):

Dendritic Cells ◽

Airway Inflammation ◽

Cigarette Smoke ◽

Lung Tissue ◽

Inflammatory Cells ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Crucial Feature ◽

Plasmacytoid Dcs ◽

Lung Tissue Damage

The recruitment and activation of inflammatory cells into the respiratory system is considered a crucial feature in the pathophysiology of chronic obstructive pulmonary disease (COPD). Because dendritic cells (DCs) have a pivotal role in the onset and regulation of immune responses, we investigated the effect of modulating DC subsets on airway inflammation by acute cigarette smoke (CS) exposure. CS-exposed mice (5 days) were treated with fms-like tyrosine kinase 3 ligand (Flt3L) and 120g8 antibody to increase total DC numbers and deplete plasmacytoid DCs (pDCs), respectively. Flt3L treatment decreased the number of inflammatory cells in the bronchoalveolar lavage (BALF) of the smoke-exposed mice and increased these in lung tissue. DC modulation reduced IL-17 and increased IL-10 levels, which may be responsible for the suppression of the BALF cells. Furthermore, depletion of pDCs led to increased infiltration of alveolar macrophages while restricting the presence of CD103+ DCs. This study suggests that DC subsets may differentially and compartment-dependent influence the inflammation induced by CS. pDC may play a role in preventing the pathogenesis of CS by inhibiting the alveolar macrophage migration to lung and increasing CD103+ DCs at inflammatory sites to avoid extensive lung tissue damage.

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The role of oxidative stress in lung injury induced by cigarette smoke

Biologia ◽

10.2478/s11756-006-0135-4 ◽

2006 ◽

Vol 61 (6) ◽

Cited By ~ 5

Author(s):

Zuzana Kluchová ◽

Ružena Tkáčová

Keyword(s):

Oxidative Stress ◽

Cigarette Smoking ◽

Lung Injury ◽

Cigarette Smoke ◽

Current Knowledge ◽

Inflammatory Cells ◽

Systemic Circulation ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Markers Of Oxidative Stress

AbstractOxidative stress is a damaging process resulting from an imbalance between excessive generation of oxidant compounds and insufficient antioxidant defence mechanisms. Oxidative stress plays a crucial role in the initiation and progression of cigarette smoke-induced lung injury, deterioration in lung functions, and development of chronic obstructive pulmonary disease (COPD). In smokers and in patients with COPD, the increased oxidant burden derives from cigarette smoke per se, and from activated inflammatory cells releasing enhanced amounts of reactive oxygen and nitrogen species (ROS, RNS, respectively). Although mild oxidative stress resulting from cigarette smoking leads to the upregulation of the antioxidative enzymes synthesis in the lungs, high levels of ROS and RNS observed in patients with COPD overwhelm the antioxidant enzymes capacities, resulting in oxidant-mediated lung injury and cell death. In addition, depletion of antioxidative systems in the systemic circulation was consistently observed in such patients. The imbalance between the generation of ROS/RNS and antioxidant capacities — the state of “oxidative stress” — is one of the major pathophysiologic hallmarks in the development of COPD. Detrimental effects of oxidative stress include impairment of membrane functions, inactivation of membrane-bound receptors and enzymes, and increased tissue permeability. In addition, oxidative stress aggravates the inflammatory processes in the lungs, and contributes to the worsening of the protease-antiprotease imbalance. Several markers of oxidative stress, such as increases in lipid peroxidation products and reductions in glutathione peroxidase activity, have been shown to be related to the reductions in pulmonary functions. In the present article we review the current knowledge about the vicious cycle of cigarette smoking, oxidative stress, and inflammation in the pathogenesis of COPD.

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Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00317.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. L514-L522 ◽

Cited By ~ 61

Author(s):

Christopher S. Stevenson ◽

Kevin Coote ◽

Ruth Webster ◽

Helinor Johnston ◽

Hazel C. Atherton ◽

...

Keyword(s):

Cigarette Smoke ◽

Neutrophil Migration ◽

Neutrophil Infiltration ◽

Lavage Fluid ◽

Whole Body ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Rat Growth ◽

Inflammatory Changes

Repetitive, acute inflammatory insults elicited by cigarette smoke (CS) contribute to the development of chronic obstructive pulmonary disease (COPD), a disorder associated with lung inflammation and mucus hypersecretion. Presently, there is a poor understanding of the acute inflammatory mechanisms involved in this process. The aims of this study were to develop an acute model to investigate temporal inflammatory changes occurring after CS exposure. Rats were exposed to whole body CS (once daily) generated from filtered research cigarettes. Initial studies indicated the generation of a neutrophilic/mucus hypersecreting lung phenotype in <4 days. Subsequent studies demonstrated that just two exposures to CS (15 h apart) elicited a robust inflammatory/mucus hypersecretory phenotype that was used to investigate mechanisms driving this response. Cytokine-induced neutrophil chemoattractants (CINCs) 1–3, the rat growth-related oncogene-α family homologs, and IL-1β demonstrated time-dependent increases in lung tissue or lavage fluid over the 24-h period following CS exposure. The temporal changes in the neutrophil chemokines, CINCs 1–3, mirrored increases in neutrophil infiltration, indicative of a role in neutrophil migration. In addition, a specific CXCR2 antagonist, SB-332235, effectively inhibited CS-induced neutrophilia in a dose-dependent manner, supporting this conclusion. This modeling of the response of the rat airways to acute CS exposure indicates 1) as few as two exposures to CS will induce a phenotype with similarities to COPD and 2) a novel role for CINCs in the generation of this response. These observations represent a paradigm for the study of acute, repetitive lung insults that contribute to the development of chronic disease.

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Isoflavone Aglycones Attenuate Cigarette Smoke-Induced Emphysema via Suppression of Neutrophilic Inflammation in a COPD Murine Model

Nutrients ◽

10.3390/nu11092023 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2023 ◽

Cited By ~ 1

Author(s):

Kazuya Kojima ◽

Kazuhisa Asai ◽

Hiroaki Kubo ◽

Arata Sugitani ◽

Yohkoh Kyomoto ◽

...

Keyword(s):

Cigarette Smoke ◽

Murine Model ◽

Inflammatory Cells ◽

Lavage Fluid ◽

Control Group ◽

Chronic Obstructive ◽

Gene Expressions ◽

Neutrophilic Inflammation ◽

Cytokines And Chemokines ◽

Smoking Group

Chronic obstructive pulmonary disease (COPD), a lung disease caused by chronic exposure to cigarette smoke, increases the number of inflammatory cells such as macrophages and neutrophils and emphysema. Isoflavone is a polyphenolic compound that exists in soybeans. Daidzein and genistein, two types of isoflavones, have been reported to have anti-inflammatory effects in various organs. We hypothesized that the daidzein-rich soy isoflavone aglycones (DRIAs) attenuate cigarette smoke-induced emphysema in mice. Mice were divided into four groups: the (i) control group, (ii) isoflavone group, (iii) smoking group, and (iv) isoflavone + smoking group. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and the airspace enlargement using the mean linear intercept (MLI) were determined 12 weeks after smoking exposure. Expressions of neutrophilic inflammatory cytokines and chemokines were also examined. In the isoflavone + smoking group, the number of neutrophils in BALF and MLI was significantly less than that in the smoking group. Furthermore, the gene-expressions of TNF-α and CXCL2 (MIP-2) in the isoflavone + smoking group were significantly less than those in the smoking group. Supplementation of the COPD murine model with DRIAs significantly attenuates pathological changes of COPD via suppression of neutrophilic inflammation.

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