scholarly journals A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models

2017 ◽  
Vol 312 (2) ◽  
pp. L268-L276 ◽  
Author(s):  
Congxiao Gao ◽  
Reiko Fujinawa ◽  
Takayuki Yoshida ◽  
Manabu Ueno ◽  
Fumi Ota ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Keratan Sulfate ◽  
Airway Disease ◽  
Lavage Fluid ◽  
Small Airway ◽  
Chronic Obstructive ◽  
Murine Models ◽  
Obstructive Pulmonary Disease ◽  
Typical Component

Emphysema is a typical component of chronic obstructive pulmonary disease (COPD), a progressive and inflammatory airway disease. However, no effective treatment currently exists. Here, we show that keratan sulfate (KS), one of the major glycosaminoglycans produced in the small airway, decreased in lungs of cigarette smoke-exposed mice. To confirm the protective effect of KS in the small airway, a disaccharide repeating unit of KS designated L4 ([SO3−-6]Galβ1–4[SO3−-6]GlcNAc) was administered to two murine models: elastase-induced-emphysema and LPS-induced exacerbation of a cigarette smoke-induced emphysema. Histological and microcomputed tomography analyses revealed that, in the mouse elastase-induced emphysema model, administration of L4 attenuated alveolar destruction. Treatment with L4 significantly reduced neutrophil influx, as well as the levels of inflammatory cytokines, tissue-degrading enzymes (matrix metalloproteinases), and myeloperoxidase in bronchoalveolar lavage fluid, suggesting that L4 suppressed inflammation in the lung. L4 consistently blocked the chemotactic migration of neutrophils in vitro. Moreover, in the case of the exacerbation model, L4 inhibited inflammatory cell accumulation to the same extent as that of dexamethasone. Taken together, L4 represents one of the potential glycan-based drugs for the treatment of COPD through its inhibitory action against inflammation.

Role of the IL-33/ST2 axis in cigarette smoke-induced airways remodelling in chronic obstructive pulmonary disease

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-214712
Author(s):  
Qiong Huang ◽  
Chen Duo Li ◽  
Yi Ran Yang ◽  
Xiao Feng Qin ◽  
Jing Jing Wang ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Tissue Remodelling ◽  
Tissue Samples ◽  
Obstructive Pulmonary Disease ◽  
Interleukin 33 ◽  
Multiple Organs

BackgroundEfficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD.ObjectiveTo explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling.MethodsC57BL/6, BALB/c and IL-1RL1-/- mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls.ResultsWild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the IL-1RL1-/- mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD.ConclusionsExposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.

scholarly journals FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

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.

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

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2489 ◽  
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.

Chrysene accelerates the proceeding of chronic obstructive pulmonary disease with the aggravation of inflammation and apoptosis in cigarette smoke exposed mice

2020 ◽  
pp. 096032712097934
Author(s):  
Yuan Gao ◽  
Xinjia Zhou ◽  
Yan Zhou ◽  
Wei Zhang ◽  
Li Zhao
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Molecular Mechanisms ◽  
Smooth Muscle Actin ◽  
Lavage Fluid ◽  
Living Environment ◽  
Chronic Obstructive ◽  
High Morbidity ◽  
Obstructive Pulmonary Disease

Chrysene, one of the basic polycyclic aromatic hydrocarbons (PAHs), has been reported to make damages to human health and living environment. Chronic obstructive pulmonary disease (COPD) is a progressive disorder with high morbidity and mortality. To investigate the role of chrysene in the development of COPD, male C57BL/6 mice were exposed to the cigarette smoke (CS) followed with the administration of chrysene. Morphological analyses indicated that chrysene caused earlier and severer pathological changes in CS-exposed mice. Besides, CS-exposed mice with chrysene treatment showed obvious collagen deposition, elevated α-smooth muscle actin (α-SMA) expression and reduced E-cadherin abundance at earlier stage, which suggested the acceleration and aggravation of pulmonary fibrosis. Moreover, quantification of leukocytes and pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissues implied that chrysene significantly exacerbated the proceeding of inflammation in CS-exposed mice. Furthermore, significantly increased apoptotic rates, augmented expressions of apoptotic related proteins and highly expressed TRPV1 were determined in CS-exposed mice with chrysene treatment, which indicated the association between COPD pathogenesis and TRPV1 channel. In summary, our findings elucidate that chrysene accelerates the development of COPD in a murine model with new molecular mechanisms.

scholarly journals Increased IgA production by B-cells in COPDvialung epithelial interleukin-6 and TACI pathways

2014 ◽  
Vol 45 (4) ◽  
pp. 980-993 ◽  
Author(s):  
Maha Zohra Ladjemi ◽  
Marylène Lecocq ◽  
Birgit Weynand ◽  
Holly Bowen ◽  
Hannah J. Gould ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cigarette Smoke ◽  
Lung Tissue ◽  
Plasma Cells ◽  
Bronchial Epithelium ◽  
Chronic Obstructive ◽  
Promoting Effect ◽  
Obstructive Pulmonary Disease

Despite their relevance to mucosal defense, production of IgA and the function of lung B-cells remain unknown in chronic obstructive pulmonary disease (COPD).We assessed IgA synthesis in the lungs of COPD (n=28) and control (n=21) patients, and regulation of B-cells co-cultured within vitro-reconstituted airway epithelium.In COPD lung tissue, synthesis of IgA1 was increased, which led to its accumulation in subepithelial areas.In vitro, the COPD bronchial epithelium imprinted normal human B-cells for increased production of IgA (mainly IgA1) and maturation into CD38+plasma cells. These effects were associated with upregulation of TACI (transmembrane activator and CAML interactor) and were observed under resting conditions, while being partly inhibited upon stimulation with cigarette smoke extract. Interleukin (IL)-6 and BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) were upregulated in the COPD epithelium and lung tissue, respectively; the IgA-promoting effect of the COPD bronchial epithelium was inhibited by targeting IL-6 and, to a lower extent, by blocking TACI.These data show that in COPD, the bronchial epithelium imprints B-cells with signals promoting maturation into IgA-producing plasma cells through the action of two epithelial/B-cell axes, namely the IL-6/IL-6 receptor and BAFF-APRIL/TACI pathways, while cigarette smoke partly counteracts this IgA-promoting effect.

scholarly journals Lung microbiota associations with clinical features of COPD in the SPIROMICS cohort

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kristopher Opron ◽  
Lesa A. Begley ◽  
John R. Erb-Downward ◽  
Christine Freeman ◽  
Siddharth Madapoosi ◽  
...  
Keyword(s):  
Clinical Features ◽  
Flow Rate ◽  
Functional Impairment ◽  
Symptom Burden ◽  
Airway Disease ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Disease Heterogeneity ◽  
Obstructive Pulmonary Disease ◽  
Expiratory Flow

AbstractChronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25–75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.

scholarly journals Extracellular Vesicles from Airway Secretions: New Insights in Lung Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 583
Author(s):  
Laura Pastor ◽  
Elisabeth Vera ◽  
Jose M. Marin ◽  
David Sanz-Rubio
Keyword(s):  
Extracellular Vesicles ◽  
Lung Diseases ◽  
Biomarker Discovery ◽  
Cell Communication ◽  
Membrane Vesicles ◽  
Lavage Fluid ◽  
In Vitro Models ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

Lung diseases (LD) are one of the most common causes of death worldwide. Although it is known that chronic airway inflammation and excessive tissue repair are processes associated with LD such as asthma, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF), their specific pathways remain unclear. Extracellular vesicles (EVs) are heterogeneous nanoscale membrane vesicles with an important role in cell-to-cell communication. EVs are present in general biofluids as plasma or urine but also in secretions of the airway as bronchoalveolar lavage fluid (BALF), induced sputum (IS), nasal lavage (NL) or pharyngeal lavage. Alterations of airway EV cargo could be crucial for understanding LD. Airway EVs have shown a role in the pathogenesis of some LD such as eosinophil increase in asthma, the promotion of lung cancer in vitro models in COPD and as biomarkers to distinguishing IPF in patients with diffuse lung diseases. In addition, they also have a promising future as therapeutics for LD. In this review, we focus on the importance of airway secretions in LD, the pivotal role of EVs from those secretions on their pathophysiology and their potential for biomarker discovery.

scholarly journals Loading of Beclomethasone in Liposomes and Hyalurosomes Improved with Mucin as Effective Approach to Counteract the Oxidative Stress Generated by Cigarette Smoke Extract

Nanomaterials ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 850
Author(s):  
Maria Letizia Manca ◽  
Maria Ferraro ◽  
Elisabetta Pace ◽  
Serena Di Vincenzo ◽  
Donatella Valenti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cigarette Smoke ◽  
Room Temperature ◽  
Cigarette Smoke Extract ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Bronchial Epithelial ◽  
Promising Tool ◽  
Next Generation Impactor

In this work beclomethasone dipropionate was loaded into liposomes and hyalurosomes modified with mucin to improve the ability of the payload to counteract the oxidative stress and involved damages caused by cigarette smoke in the airway. The vesicles were prepared by dispersing all components in the appropriate vehicle and sonicating them, thus avoiding the use of organic solvents. Unilamellar and bilamellar vesicles small in size (~117 nm), homogeneously dispersed (polydispersity index lower than 0.22) and negatively charged (~−11 mV), were obtained. Moreover, these vesicle dispersions were stable for five months at room temperature (~25 °C). In vitro studies performed using the Next Generation Impactor confirmed the suitability of the formulations to be nebulized as they were capable of reaching the last stages of the impactor that mimic the deeper airways, thus improving the deposition of beclomethasone in the target site. Further, biocompatibility studies performed by using 16HBE bronchial epithelial cells confirmed the high biocompatibility and safety of all the vesicles. Among the tested formulations, only mucin-hyalurosomes were capable of effectively counteracting the production of reactive oxygen species (ROS) induced by cigarette smoke extract, suggesting that this formulation may represent a promising tool to reduce the damaging effects of cigarette smoke in the lung tissues, thus reducing the pathogenesis of cigarette smoke-associated diseases such as chronic obstructive pulmonary disease, emphysema, and cancer.

scholarly journals Keratan sulfate-based glycomimetics using Langerin as a target for COPD: lessons from studies on Fut8 and core fucose

2021 ◽  
Author(s):  
Yuki Ohkawa ◽  
Yoichiro Harada ◽  
Naoyuki Taniguchi
Keyword(s):  
Posttranslational Modification ◽  
Therapeutic Strategy ◽  
Keratan Sulfate ◽  
Therapeutic Strategies ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Cooperative Action ◽  
The Core ◽  
Area Of Interest

Glycosylation represents one of the most abundant posttranslational modification of proteins. Glycosylation products are diverse and are regulated by the cooperative action of various glycosyltransferases, glycosidases, substrates thereof: nucleoside sugars and their transporters, and chaperons. In this article, we focus on a glycosyltransferase, α1,6-fucosyltransferase (Fut8) and its product, the core fucose structure on N-glycans, and summarize the potential protective functions of this structure against emphysema and chronic obstructive pulmonary disease (COPD). Studies of FUT8 and its enzymatic product, core fucose, are becoming an emerging area of interest in various fields of research including inflammation, cancer and therapeutics. This article discusses what we can learn from studies of Fut8 and core fucose by using knockout mice or in vitro studies that were conducted by our group as well as other groups. We also include a discussion of the potential protective functions of the keratan sulfate (KS) disaccharide, namely L4, against emphysema and COPD as a glycomimetic. Glycomimetics using glycan analogs is one of the more promising therapeutics that compensate for the usual therapeutic strategy that involves targeting the genome and the proteome. These typical glycans using KS derivatives as glycomimetics, will likely become a clue to the development of novel and effective therapeutic strategies.

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