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

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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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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Matrine reduces cigarette smoke-induced airway neutrophilic inflammation by enhancing neutrophil apoptosis

Clinical Science ◽

10.1042/cs20180912 ◽

2019 ◽

Vol 133 (4) ◽

pp. 551-564 ◽

Cited By ~ 9

Author(s):

Xuhua Yu ◽

Huei Jiunn Seow ◽

Hao Wang ◽

Desiree Anthony ◽

Steven Bozinovski ◽

...

Keyword(s):

Cigarette Smoke ◽

Lung Inflammation ◽

Therapeutic Potential ◽

Proteolytic Enzymes ◽

Ex Vivo ◽

Lavage Fluid ◽

Airflow Limitation ◽

Chronic Obstructive ◽

Neutrophilic Inflammation ◽

Anti Inflammatory

AbstractChronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and will become the third largest cause of death in the world by 2030. It is well established that an exaggerated inflammatory and oxidative stress response to cigarette smoke (CS) leads to, emphysema, small airway fibrosis, mucus hypersecretion, and progressive airflow limitation. Current treatments have limited efficacy in inhibiting chronic inflammation and consequently do not reverse the pathology that initiates and drives the long-term progression of disease. In particular, there are no effective therapeutics that target neutrophilic inflammation in COPD, which is known to cause tissue damage by degranulation of a suite of proteolytic enzymes including neutrophil elastase (NE). Matrine, an alkaloid compound extracted from Sophora flavescens Ait, has well known anti-inflammatory activity. Therefore, the aim of the present study was to investigate whether matrine could inhibit CS-induced lung inflammation in mice. Matrine significantly reduced CS-induced bronchoalveolar lavage fluid (BALF) neutrophilia and NE activity in mice. The reduction in BALF neutrophils in CS-exposed mice by matrine was not due to reductions in pro-neutrophil cytokines/chemokines, but rather matrine’s ability to cause apoptosis of neutrophils, which we demonstrated ex vivo. Thus, our data suggest that matrine has anti-inflammatory actions that could be of therapeutic potential in treating CS-induced lung inflammation observed in COPD.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00259.2014 ◽

2015 ◽

Vol 308 (1) ◽

pp. L96-L103 ◽

Cited By ~ 12

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.

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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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Dexamethasone and losartan combination treatment protected cigarette smoke-induced COPD in rats

Human & Experimental Toxicology ◽

10.1177/0960327120950012 ◽

2020 ◽

pp. 096032712095001

Author(s):

Samia S Sokar ◽

Esraa H Afify ◽

Enass Y Osman

Keyword(s):

Oxidative Stress ◽

Lung Injury ◽

Cigarette Smoke ◽

Lavage Fluid ◽

Control Group ◽

Chronic Obstructive ◽

Protective Effects ◽

Sprague Dawley ◽

Obstructive Pulmonary Disease ◽

Sprague Dawley Rats

Chronic Obstructive Pulmonary Disease (COPD) is a dangerous prevalent smoking-related disease characterized by abnormal inflammation and oxidative stress and expected to be the third cause of death in the world next decade. Corticosteroids have low effects in decreasing numbers of inflammatory mediators specifically in long-term use. Our study designed to investigate the possible protective effects of combined dexamethasone (Dex) (2mg/kg) and losartan (Los) (30mg/kg angiotensin receptor blocker, it possesses antioxidant and anti-inflammatory properties in lung injury in mice) against cigarette -smoke (CS) induced COPD in rats compared with dexamethasone and losartan. Male Sprague Dawley rats (N = 40) divided into five groups (n = 8): control group, CS group, Dex group, Los group, and Dex +Los group. COPD induced in rats by CS exposure twice daily for 10 weeks. After the specified treatment period, bronchoalveolar lavage fluid (BALF) and lung tissue were collected for measurement of SOD, NO, MDA, ICAM-, MMP-9, CRP, NF-κB and histopathology scoring. Our results indicated that Los+Dex significantly prevent CS-induced COPD emphysema, congested alveoli, and elevation of lung injury parameters in BALF. They also showed a significant decrease in MDA, ICAM-1, MMP-9, CRP, and NF-κB and a significant increase in SOD and NO. In conclusion, adding Los to Dex potentiating their activity in inhibition the progression of COPD based on its activity on oxidative stress, inflammation, and NF-κB protein expression.

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

10.21203/rs.3.rs-52288/v1 ◽

2020 ◽

Author(s):

Daisuke Morichika ◽

Akihiko Taniguchi ◽

Naohiro Oda ◽

Utako Fujii 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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FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01409-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ying Liu ◽

Jiawei Xu ◽

Tian Liu ◽

Jinxiang Wu ◽

Jiping Zhao ◽

...

Keyword(s):

Lung Function ◽

Airway Inflammation ◽

Cigarette Smoke ◽

Airway Remodeling ◽

Critical Factor ◽

Lavage Fluid ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Impaired Lung Function

Abstract Background Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

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Cigarette smoking, emphysema, and damage to alpha 1-proteinase inhibitor

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.266.6.l593 ◽

1994 ◽

Vol 266 (6) ◽

pp. L593-L611 ◽

Cited By ~ 13

Author(s):

M. D. Evans ◽

W. A. Pryor

Keyword(s):

Cigarette Smoke ◽

Proteinase Inhibitor ◽

Inflammatory Cells ◽

Lavage Fluid ◽

Lung Lavage ◽

Tissue Destruction ◽

Phagocytic Cells ◽

Lung Fluid

The proteinase-antiproteinase theory for the pathogenesis of emphysema proposes that the connective tissue destruction associated with emphysema arises from excessive proteinase activity in the lower respiratory tract. For this reason, the relative activities of neutrophil elastase and alpha 1-proteinase inhibitor (alpha 1-PI) are considered important. Most emphysema is observed in smokers; therefore, alpha 1-PI has been studied as a target for smoke-induced damage. Damage to alpha 1-PI in lung fluid could occur by several mechanisms involving species delivered to the lung by cigarette smoke and/or stimulated inflammatory cells. Oxidative damage to alpha 1-PI has received particular attention, since both cigarette smoke and inflammatory cells are rich sources of oxidants. In this article we review almost two decades of research on mechanistic studies of damage to alpha 1-PI by cigarette smoke and phagocytic cells in vitro, studies emphasizing the importance of elastinolytic activity in the pathogenesis of emphysema in vivo and studies of human lung lavage fluid to detect defects in alpha 1-PI at the molecular and functional levels.

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Galgeun-tang Attenuates Cigarette Smoke and Lipopolysaccharide Induced Pulmonary Inflammation via IκBα/NF-κB Signaling

Molecules ◽

10.3390/molecules23102489 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2489 ◽

Cited By ~ 6

Author(s):

Na-Rae Shin ◽

Chul Kim ◽

Chang-Seob Seo ◽

Je-Won Ko ◽

Young-Kwon Cho ◽

...

Keyword(s):

Cigarette Smoke ◽

Inflammatory Cell ◽

Pulmonary Inflammation ◽

Water Extract ◽

Lavage Fluid ◽

Chronic Obstructive ◽

Necrosis Factor Alpha ◽

Obstructive Pulmonary Disease ◽

Cell Counts ◽

Oxide Synthase

Galgeun-tang water extract (GGWE) is used to treat various diseases such as the common cold, eczema and asthma in China and Korea. In this study, we investigated the anti-inflammatory effect of GGWE using a cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced induced pulmonary inflammation mouse model. The mice were exposed to CS for a total of seven days (eight cigarettes per day for 1 h) and LPS was administered intranasally to mice on day 4. GGWE was administered by oral gavage at doses of 50 mg/kg or 100 mg/kg 1 h before exposure to CS. GGWE decreased inflammatory cell counts, and expression of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid (BALF) from mice exposed to CS and LPS. GGWE reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as the phosphorylation of inhibitor of kappa-B subunit alpha (IκBα) and nuclear factor kappa-B (NF-κB) in CS- and LPS-exposed mice. Histological examinations revealed that GGWE suppressed inflammatory cell infiltration into lung tissue compared to untreated CS- and LPS-exposed mice. In conclusion, GGWE effectively suppressed CS- and LPS-induced pulmonary inflammation. Our results indicate that GGWE may be used as a protective drug to control pulmonary inflammation diseases such as chronic obstructive pulmonary disease.

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Erythromycin Suppresses the Cigarette Smoke Extract-Exposed Dendritic Cell-Mediated Polarization of CD4+ T Cells into Th17 Cells

Journal of Immunology Research ◽

10.1155/2020/1387952 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Jifeng Liu ◽

Xiaoning Zhong ◽

Zhiyi He ◽

Jianquan Zhang ◽

Jing Bai ◽

...

Keyword(s):

T Cells ◽

Cigarette Smoke ◽

Th17 Cells ◽

Mixed Lymphocyte Reaction ◽

Mononuclear Cells ◽

Cigarette Smoke Extract ◽

Exposed Group ◽

Control Group ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease

Cigarette smoke is a major effector of chronic obstructive pulmonary disease (COPD), and Th17 cells and dendritic cells (DCs) involve in the pathogenesis of COPD. Previous studies have demonstrated the anti-inflammatory effects of macrolides. However, the effects of macrolides on the cigarette smoke extract- (CSE-) induced immune response are unclear. Accordingly, in this study, we evaluated the effects of erythromycin (EM) on CSE-exposed DCs polarizing naïve CD4+ T cells into Th17 cells. DCs were generated from bone marrow-derived mononuclear cells isolated from male BALB/c mice and divided into five groups: control DC group, CSE-exposed DC group, CD40-antibody-blocked CSE-exposed DC group, and EM-treated CSE-exposed DC group. The function of polarizing CD4+ T cells into Th17 cells induced by all four groups of DCs was assayed based on the mixed lymphocyte reaction (MLR) of naïve CD4+ T cells. CD40 expression in DCs in the CSE-exposed group increased significantly compared with that in the control group (P<0.05). The Th17 cells in the CSE-exposed DC/MLR group increased significantly compared with those in the control DC/MLR group (P<0.05). Moreover, Th17 cells in the CD40-blocked CSE-exposed DC/MLR group and EM-treated CSE-exposed DC/MLR group were reduced compared with those in the CSE-exposed DC/MLR group (P<0.05). Thus, these findings suggested that EM suppressed the CSE-exposed DC-mediated polarization of CD4+ T cells into Th17 cells and that this effect may be mediated through inhibition of the CD40/CD40L pathway.

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