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 PPARγas a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yongchun Shen ◽  
Lei Chen ◽  
Tao Wang ◽  
Fuqiang Wen
Keyword(s):  
Transcription Factor ◽  
Inflammatory Diseases ◽  
Chronic Obstructive ◽  
Peroxisome Proliferator ◽  
Mucus Hypersecretion ◽  
Mucin Production ◽  
Airway Mucus ◽  
Chronic Airway

Airway mucus hypersecretion (AMH) is a key pathophysiological feature of chronic airway inflammatory diseases such as bronchial asthma, cystic fibrosis, and chronic obstructive pulmonary disease. AMH contributes to the pathogenesis of chronic airway inflammatory diseases, and it is associated with reduced lung function and high rates of hospitalization and mortality. It has been suggested that AMH should be a target in the treatment of chronic airway inflammatory diseases. Recent evidence suggests that a key regulator of airway inflammation, hyperresponsiveness, and remodeling is peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor that regulates adipocyte differentiation and lipid metabolism. PPARγis expressed in structural, immune, and inflammatory cells in the lung. PPARγis involved in mucin production, and PPARγagonists can inhibit mucin synthesis bothin vitroandin vivo. These findings suggest that PPARγis a novel target in the treatment of AMH and that further work on this transcription factor may lead to new therapies for chronic airway inflammatory diseases.

scholarly journals Pneumocystis murina Infection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

2008 ◽  
Vol 76 (8) ◽  
pp. 3481-3490 ◽  
Author(s):  
Paul J. Christensen ◽  
Angela M. Preston ◽  
Tony Ling ◽  
Ming Du ◽  
W. Bradley Fields ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Respiratory Pathogens ◽  
Obstructive Pulmonary Disease ◽  
Immunocompetent Mice

ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.

Nrf2 Improves Airway Goblet Cell Metaplasia in Chronic Obstructive Pulmonary Disease (COPD) and Its Mechanism

2022 ◽  
Vol 12 (4) ◽  
pp. 739-746
Author(s):  
Zhihong Qiu ◽  
Li Yan ◽  
Juan Xu ◽  
Xiaojun Qian
Keyword(s):  
Protein Expression ◽  
Goblet Cell ◽  
Inflammatory Cells ◽  
Cell Number ◽  
Chronic Obstructive ◽  
Model Group ◽  
Down Regulation ◽  
Obstructive Pulmonary Disease ◽  
Pas Staining

Objective: The aim of our research was to evaluate Nrf2 in COPD treatment and relative mechanism by vivo study. Materials: The mice were divided into Normal, Model and CCL16 groups. Measuring Pathology and goblet cell number by HE or AB/PAS staining; Evaluating apoptosis cell number by TUNEL assay; using flow separation to analysis inflammatory cells in difference groups; MAPK and NF-κB(p65) protein expression were evaluated by IHC assay in tissues; Total protein concentration of MUC5AC, Nrf2, Bax and Bcl-2 were evaluated by WB assay. Results: Compared with Normal group, the pathology was deteriorate and goblet cell number were significantly up-regulation in Model group, apoptosis goblet cell number were significantly depressed (P < 0.001), lympbocyte rate and hypertrophic rate were significantly down-regulation and Eosinophils rate, Macrophage rate and Neutrophils rate were significantly up-regulation (P < 0.001, respectively) in Model group. By IHC assay, MAPK and NF-κB(p65) proteins expression significantly increased (P < 0.001, respectively) in Model group; by WB assay, MUC5AC and Bcl-2 protein expression were significantly up-regulation and Nrf2 and Bax proteins expression were significantly down-regulation (P < 0.001, respectively) in Model group. Nrf2 supplement, the COPD were significantly improved with relative inflammatory cells rates significantly improving and relative proteins improving. Conclusion: Nrf2 could improve COPD by inducing goblet cell apoptosis increasing via regulation MAPK/NF-κB(p65) pathway in vivo study.

scholarly journals A Window on the Lung: Molecular Imaging as a Tool to Dissect Pathophysiologic Mechanisms of Acute Lung Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Guido Musch
Keyword(s):  
Inflammatory Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
In Vivo Measurement ◽  
Ventilator Induced Lung Injury ◽  
Positron Emission ◽  
Lung Strain ◽  
Ventilation And Perfusion ◽  
Pathophysiologic Mechanisms

In recent years, imaging has given a fundamental contribution to our understanding of the pathophysiology of acute lung diseases. Several methods have been developed based on computed tomography (CT), positron emission tomography (PET), and magnetic resonance (MR) imaging that allow regional, in vivo measurement of variables such as lung strain, alveolar size, metabolic activity of inflammatory cells, ventilation, and perfusion. Because several of these methods are noninvasive, they can be successfully translated from animal models to patients. The aim of this paper is to review the advances in knowledge that have been accrued with these imaging modalities on the pathophysiology of acute respiratory distress syndrome (ARDS), ventilator-induced lung injury (VILI), asthma and chronic obstructive pulmonary disease (COPD).

Club Cell Secretion Protein 16 (CC16) Improve Chronic Obstructive Pulmonary Disease In Vivo Study

2022 ◽  
Vol 12 (2) ◽  
pp. 279-286
Author(s):  
Zhihong Qiu ◽  
Li Yan ◽  
Juan Xu ◽  
Xiaojun Qian
Keyword(s):  
Protein Expression ◽  
Goblet Cell ◽  
Inflammatory Cells ◽  
Cell Number ◽  
Chronic Obstructive ◽  
Model Group ◽  
Cell Secretion ◽  
Down Regulation ◽  
Club Cell

Purpose: The purpose of this study was to evaluate CC16 in COPD treatment and relative mechanism by vivo study. Materials and methods: The mice were divided into Normal, Model and CC16 groups. Measuring Pathology and goblet cell number by HE or AB/PAS staining; Evaluating apoptosis cell number by TUNEL assay; using flow separation to analysis inflammatory cells in difference groups; MAPK and NF-κB(p65) protein expression were evaluated by IHC assay in tissues; Total protein concentration of MUC5AC, CC16, Bax and Bcl-2 were evaluated by Western Blot (WB) assay. Results: Compared with Normal group, the pathology was deteriorate and goblet cell number were significantly up-regulation in Model group, apoptosis goblet cell number were significantly depressed (P < 0.001), lympbocyte rate and hypertrophic rate were significantly down-regulation and Eosinophils rate, Macrophage rate and Neutrophils rate were significantly up-regulation (P < 0.001, respectively) in Model group. By IHC assay, MAPK and NF-κB(p65) proteins expression were significantly increased (P < 0.001, respectively) in Model group; by WB assay, MUC5AC and Bcl-2 protein expression were significantly up-regulation and CC16 and Bax proteins expression were significantly down-regulation (P < 0.001, respectively) in Model group. CC16 supplement, the COPD were significantly improved with relative inflammatory cells rates significantly improving and relative proteins improving. Conclusion: CC16 could improve COPD by inducing goblet cell apoptosis increasing via regulation MAPK/NF-κB(p65) pathway In Vivo study.

scholarly journals The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia

2016 ◽  
Vol 310 (1) ◽  
pp. L59-L70 ◽  
Author(s):  
Mark J. Turner ◽  
Elizabeth Matthes ◽  
Arnaud Billet ◽  
Amy J. Ferguson ◽  
David Y. Thomas ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Therapeutic Option ◽  
Beat Frequency ◽  
Primary Cultures ◽  
Bronchial Epithelial Cells ◽  
Chronic Obstructive ◽  
Intracellular Camp ◽  
Bronchial Epithelial

Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/ F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.

Systemic deficiency of glutathione in cystic fibrosis

1993 ◽  
Vol 75 (6) ◽  
pp. 2419-2424 ◽  
Author(s):  
J. H. Roum ◽  
R. Buhl ◽  
N. G. McElvaney ◽  
Z. Borok ◽  
R. G. Crystal
Keyword(s):  
Cystic Fibrosis ◽  
Reduced Glutathione ◽  
Chronic Obstructive Lung Disease ◽  
Inflammatory Cells ◽  
Normal Subjects ◽  
Chronic Obstructive ◽  
Lung Pathology ◽  
Epithelial Surface ◽  
Glutathione Deficiency ◽  
Respiratory Epithelial

Cystic fibrosis (CF), a disorder characterized by mutations of the CF transmembrane regulator gene, is characterized in the lung by chronic inflammation, leading to progressive damage to the airway epithelium, bronchiectasis, and chronic obstructive lung disease. One process contributing to the airway derangement is the chronic burden of oxidants released by inflammatory cells on the respiratory epithelial surface. With this background, we hypothesized that glutathione in respiratory epithelial lining fluid (ELF) in CF patients might be oxidized and/or diminished in amount compared with that in normal subjects. Recovery of ELF by bronchoalveolar lavage from young adults with CF (n = 21) and normal subjects (n = 25) demonstrated marked neutrophil-dominated inflammation in ELF in CF patients. As predicted, ELF in CF patients was characterized by a deficiency of glutathione (P < 0.001), but this was secondary to a reduction in reduced glutathione (P < 0.001), inasmuch as there were no differences in ELF levels of oxidized glutathione (P > 0.2). Unexpectedly, there was also a marked deficiency of reduced glutathione in plasma (P < 0.02); i.e., the glutathione "deficiency" observed in ELF in CF patients is not limited to the site of the inflammation but is systemic. Although the etiology of this generalized deficiency of extracellular glutathione is unknown, it is important in considering options for treating the concomitant and devastating lung pathology in this disorder.

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 Induction and regulation of murine emphysema by elastin peptides

2016 ◽  
Vol 310 (1) ◽  
pp. L8-L23 ◽  
Author(s):  
Mehdi Sellami ◽  
Aïda Meghraoui-Kheddar ◽  
Christine Terryn ◽  
Caroline Fichel ◽  
Nicole Bouland ◽  
...  
Keyword(s):  
Biological Activities ◽  
Inflammatory Cells ◽  
Binding Activity ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Docking Simulations ◽  
Copd Patients ◽  
Cell Accumulation

Emphysema is the major component of chronic obstructive pulmonary disease (COPD). During emphysema, elastin breakdown in the lung tissue originates from the release of large amounts of elastase by inflammatory cells. Elevated levels of elastin-derived peptides (EP) reflect massive pulmonary elastin breakdown in COPD patients. Only the EP containing the GXXPG conformational motif with a type VIII β-turn are elastin receptor ligands inducing biological activities. In addition, the COOH-terminal glycine residue of the GXXPG motif seems a prerequisite to the biological activity. In this study, we endotracheally instilled C57BL/6J mice with GXXPG EP and/or COOH-terminal glycine deleted-EP whose sequences were designed by molecular dynamics and docking simulations. We investigated their effect on all criteria associated with the progression of murine emphysema. Bronchoalveolar lavages were recovered to analyze cell profiles by flow cytometry and lungs were prepared to allow morphological and histological analysis by immunostaining and confocal microscopy. We observed that exposure of mice to EP elicited hallmark features of emphysema with inflammatory cell accumulation associated with increased matrix metalloproteinases and desmosine expression and of remodeling of parenchymal tissue. We also identified an inactive COOH-terminal glycine deleted-EP that retains its binding-activity to EBP and that is able to inhibit the in vitro and in vivo activities of emphysema-inducing EP. This study demonstrates that EP are key actors in the development of emphysema and that they represent pharmacological targets for an alternative treatment of emphysema based on the identification of EP analogous antagonists by molecular modeling studies.

Abstract 210: Biosynthesis of D-series Resolvin by Isolated Vascular Cells and Tissues

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Sevan R Komshian ◽  
Anuran Chatterjee ◽  
Bian Wu ◽  
Giorgio Mottola ◽  
Mian Chen ◽  
...  
Keyword(s):  
Vascular Tissue ◽  
De Novo ◽  
Culture Media ◽  
Primary Cultures ◽  
Rabbit Aorta ◽  
Inflammatory Cells ◽  
Local Source ◽  
Vascular Cells ◽  
Resolvin D1

Introduction: Resolvin-D1 (RvD1) and other specialized pro-resolving lipid mediators (SPM) are synthesized in-vivo from docosahexaenoic acid (DHA) through transcellular pathways involving leukocytes. We investigated if vascular tissues, in the absence of inflammatory cells, can contribute to the local production of SPM. Methods: Primary cultures of human saphenous vein endothelial (EC) and smooth muscle (SMC) cells were supplemented with DHA in cell culture media (10% serum) for 4h-24h. Freshly harvested rabbit aorta was incubated intact or following gentle EC denudation in medium with or without DHA for 48h. RvD1 levels were quantified by ELISA, and lipoxygenase (LO) expression by western blotting. Results: In the absence of DHA supplementation, EC and SMC produced undetectable levels of RvD1. DHA treatment produced a dose and time-dependent increase in RvD1 production by EC and SMC (10.1 ±1.0 pg, 7.4 ±0.2 pg respectively; 1000nM DHA; 24h; Fig A, B). 5-LO expression was demonstrated in both cell types, however DHA induced increased 5-LO expression in EC (Fig C) but not in SMC. DHA-treated intact rabbit aorta segments produced 0.24±0.05 pg RvD1/mg tissue versus 0.13±0.01 pg RvD1/mg tissue in media alone. Moreover, EC-denuded aortas produced significantly less RvD1 (Fig D). Conclusions: Human vascular cells and rabbit vascular tissue can biosynthesize RvD1 de novo from its precursor DHA, signifying a potentially important local source of SPM in the vasculature.

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