scholarly journals Molecular and Cellular Mechanisms Responsible for Beneficial Effects of Mesenchymal Stem Cell-Derived Product “Exo-d-MAPPS” in Attenuation of Chronic Airway Inflammation

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Carl Randall Harrell ◽  
Dragica Miloradovic ◽  
Ruxana Sadikot ◽  
Crissy Fellabaum ◽  
Bojana Simovic Markovic ◽  
...  
Keyword(s):  
Animal Model ◽  
Airway Inflammation ◽  
Natural Killer ◽  
Inflammatory Cytokines ◽  
Therapeutic Agent ◽  
Alveolar Epithelial Cells ◽  
Chronic Obstructive ◽  
Cell Based Therapy ◽  
Copd Patients ◽  
Chronic Airway

Mesenchymal stem cells (MSCs), due to their potential for differentiation into alveolar epithelial cells and their immunosuppressive characteristics, are considered a new therapeutic agent in cell-based therapy of inflammatory lung disorders, including chronic obstructive pulmonary disease (COPD). Since most of the MSC-mediated beneficent effects were the consequence of their paracrine action, herewith, we investigated the effects of a newly designed MSC-derived product “Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)” in the attenuation of chronic airway inflammation by using an animal model of COPD (induced by chronic exposure to cigarette smoke (CS)) and clinical data obtained from Exo-d-MAPPS-treated COPD patients. Exo-d-MAPPS contains a high concentration of immunomodulatory factors which are capable of attenuating chronic airway inflammation, including soluble TNF receptors I and II, IL-1 receptor antagonist, and soluble receptor for advanced glycation end products. Accordingly, Exo-d-MAPPS significantly improved respiratory function, downregulated serum levels of inflammatory cytokines (TNF-α, IL-1β, IL-12, and IFN-γ), increased serum concentration of immunosuppressive IL-10, and attenuated chronic airway inflammation in CS-exposed mice. The cellular makeup of the lungs revealed that Exo-d-MAPPS treatment attenuated the production of inflammatory cytokines in lung-infiltrated macrophages, neutrophils, and natural killer and natural killer T cells and alleviated the antigen-presenting properties of lung-infiltrated macrophages and dendritic cells (DCs). Additionally, Exo-d-MAPPS promoted the expansion of immunosuppressive IL-10-producing alternatively activated macrophages, regulatory DCs, and CD4+FoxP3+T regulatory cells in inflamed lungs which resulted in the attenuation of chronic airway inflammation. In a similar manner, as it was observed in an animal model, Exo-d-MAPPS treatment significantly improved the pulmonary status and quality of life of COPD patients. Importantly, Exo-d-MAPPS was well tolerated since none of the 30 COPD patients reported any adverse effects after Exo-d-MAPPS administration. In summing up, we believe that Exo-d-MAPPS could be considered a potentially new therapeutic agent in the treatment of chronic inflammatory lung diseases whose efficacy should be further explored in large clinical trials.

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.

Effects of Repeated Stress on Distal Airway Inflammation, Remodeling and Mechanics in an Animal Model of Chronic Airway Inflammation

2012 ◽  
Vol 19 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Edna A. Leick ◽  
Fabiana G. Reis ◽  
Flávia Alves Honorio-Neves ◽  
Rafael Almeida-Reis ◽  
Carla M. Prado ◽  
...  
Keyword(s):  
Animal Model ◽  
Airway Inflammation ◽  
Repeated Stress ◽  
Distal Airway ◽  
Chronic Airway

scholarly journals Effect of Liuweibuqi Capsules in Pulmonary Alveolar Epithelial Cells and COPD Through JAK/STAT Pathway

2017 ◽  
Vol 43 (2) ◽  
pp. 743-756 ◽  
Author(s):  
Chengyang Wang ◽  
Huanzhang Ding ◽  
Xiao Tang ◽  
Zegeng Li ◽  
Lei Gan
Keyword(s):  
Lung Function ◽  
Cell Viability ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Interferon Γ ◽  
Normal Group ◽  
Alveolar Epithelial Cells ◽  
Chronic Obstructive ◽  
Model Control ◽  
Stat Pathway

Background/Aims: To evaluate the effect of Liuweibuqi capsules on chronic obstructive pulmonary disease (COPD) through the JAK/STAT pathway. Methods: Lung function was measured with a spirometer. Changes in lung histology were observed using H&E staining. Cigarette smoke extract combined with lipopolysaccharide (CSE+LPS) was used to establish the cellular COPD model. Cytokine levels were determined using ELISA, and changes in the JAK/STAT pathway were evaluated using western blotting. The CCK8 method and flow cytometry were used to measure cell viability and apoptosis, respectively. Results: Liuweibuqi capsules reduced the damage in the lung tissues and the loss of lung function in the COPD rats. Additionally, the levels of interleukin (IL)-1β, interferon γ (IFNγ), IL-6, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 were higher, whereas IL-10 was lower in the model control (MC) and CSE+LPS groups than in the normal group. The phosphorylation levels of JAK1, JAK2, STAT1, STAT3 and STAT5 were higher and the levels of SOCS1 and SOCS3 were lower in the MC group and CSE+LPS group compared with the normal group. After Liuweibuqi capsule treatment, the expression of inflammatory cytokines and elements of the JAK/STAT pathway were lower. In addition, over-expression of STAT3 blocked the effects of the Liuweibuqi capsules on the release of inflammatory cytokines, cell viability and apoptosis. Conclusion: Our findings suggested that Liuweibuqi capsule might effectively ameliorate the progression of COPD via the JAK/STAT pathway.

scholarly journals Clinical and inflammatory phenotyping by breathomics in chronic airway diseases irrespective of the diagnostic label

2018 ◽  
Vol 51 (1) ◽  
pp. 1701817 ◽  
Author(s):  
Rianne de Vries ◽  
Yennece W.F. Dagelet ◽  
Pien Spoor ◽  
Erik Snoey ◽  
Patrick M.C. Jak ◽  
...  
Keyword(s):  
Principal Component ◽  
Chronic Obstructive ◽  
Exhaled Breath ◽  
Dependent Manner ◽  
Cross Sectional ◽  
Exacerbation Rate ◽  
Copd Patients ◽  
Validation Set ◽  
Inflammatory Phenotypes ◽  
Chronic Airway

Asthma and chronic obstructive pulmonary disease (COPD) are complex and overlapping diseases that include inflammatory phenotypes. Novel anti-eosinophilic/anti-neutrophilic strategies demand rapid inflammatory phenotyping, which might be accessible from exhaled breath.Our objective was to capture clinical/inflammatory phenotypes in patients with chronic airway disease using an electronic nose (eNose) in a training and validation set.This was a multicentre cross-sectional study in which exhaled breath from asthma and COPD patients (n=435; training n=321 and validation n=114) was analysed using eNose technology. Data analysis involved signal processing and statistics based on principal component analysis followed by unsupervised cluster analysis and supervised linear regression.Clustering based on eNose resulted in five significant combined asthma and COPD clusters that differed regarding ethnicity (p=0.01), systemic eosinophilia (p=0.02) and neutrophilia (p=0.03), body mass index (p=0.04), exhaled nitric oxide fraction (p<0.01), atopy (p<0.01) and exacerbation rate (p<0.01). Significant regression models were found for the prediction of eosinophilic (R2=0.581) and neutrophilic (R2=0.409) blood counts based on eNose. Similar clusters and regression results were obtained in the validation set.Phenotyping a combined sample of asthma and COPD patients using eNose provides validated clusters that are not determined by diagnosis, but rather by clinical/inflammatory characteristics. eNose identified systemic neutrophilia and/or eosinophilia in a dose-dependent manner.

scholarly journals Suppression of Rcn3 in the alveolar epithelial cells may have beneficial effect against COPD

2020 ◽  
Author(s):  
Qianyu Zhang ◽  
Tong Wang ◽  
Jiawei Jin ◽  
Xiaoqian Shi ◽  
Zhenru Ma ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Secretory Pathway ◽  
Alveolar Epithelial Cell ◽  
Critical Role ◽  
Airflow Obstruction ◽  
Alveolar Epithelial Cells ◽  
Conditional Knockout ◽  
Chronic Obstructive ◽  
Alveolar Epithelial ◽  
Copd Patients

Abstract Background: Chronic obstructive pulmonary disease (COPD) is a highly prevalent lung disease worldwide and imposes increasing disease burdens globally. COPD is characterized by irreversible airflow obstruction. Emphysema is one of the primary pathological features causing the irreversible decline of pulmonary function, while the precise mechanisms behind emphysema remain unclear. Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum (ER) lumen protein localized in the secretory pathway of living cells. We have reported that Rcn3 in type II alveolar epithelial cell (AECIIs) plays a critical role in perinatal lung development and bleomycin-induced lung injury-repair. Since is associated with alveolar epithelial disruption, Rcn3 might be involved in the development of emphysema during COPD. Materials and Methods : We examined Rcn3 expression in lung specimens from patients (44 COPD patients and 26 non-COPD control patients) undergoing lung lobectomy or pneumonectomy. Mouse models of COPD and emphysema were established by cigarette smoke (CS) exposure and intratracheal installation of pancreatic porcine elastase (PPE), respectively. Rcn3 expression was detected in the lung tissues from these mice. Furthermore, conditional knockout (CKO) mice with Rcn3 deletion specific to AECIIs, were used to explore the role of Rcn3 in PPE-induced emphysema progression. Rcn3 protein expression in lung tissues were evaluated by Western blot and immunohistochemistry. Rcn3 mRNA expression in lung tissues was detected by qPCR.Results : Compared with non-COPD patients, Rcn3 expression was significantly increased in the lung specimens from COPD patients. Rcn3 expression was also significantly up-regulated in the lung tissues from COPD mice and emphysematous mice. Moreover, selective ablation of Rcn3 in AEC IIs significantly alleviated severity of the mouse emphysema in response to intratracheal installation of PPE.Conclusions: Our data, for the first time, indicated that Rcn3 in AECIIs might play a role in modulating the progression of emphysema, and thus be involved in the development of COPD. Suppression of Rcn3 expression in AECIIs may have a beneficial effect on COPD.This work was supported by National Natural Science Foundation of China (No. 81641004).

scholarly journals The Strong Correlation Between ADAM33 Expression and Airway Inflammation in Chronic Obstructive Pulmonary Disease and Candidate for Biomarker and Treatment of COPD

2021 ◽  
Author(s):  
Muhammad Fachri ◽  
Mochammad Hatta ◽  
Muhammad Nasrum Massi ◽  
Arif Santoso ◽  
Tri Ariguntar Wikanningtyas ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Airway Inflammation ◽  
Pulmonary Disease ◽  
Univariate Analysis ◽  
Bivariate Analysis ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Potential Biomarker

Abstract Airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is an amplified response of the normal immune system that occurs as a result of chronic irritation by toxic substances, such as cigarette smoke. This leads to the characteristic pathological changes in the inflammatory cells of COPD patients. ADAM33 has been reported to be involved in the pathogenesis of COPD in East Asia by affecting airway inflammation and other immune responses. The aim of this study was to determine the potential role of ADAM33 (mRNA and soluble levels) as a biomarker of inflammation in COPD patients. This is a case-control study using consecutive sampling. The COPD case and control (non-COPD) groups comprised 37 and 29 patients, respectively. We used univariate analysis to assess differences in the parameters between the groups and bivariate analysis to non-parametrically compare these parameters between the two groups. We observed significantly higher mRNA levels of ADAM33 in the COPD patients (10.39 ± 1.76) as compared to that in the non-COPD individuals (6.93 ± 0.39; p < 0.001). The levels of soluble ADAM33 were also significantly higher in the COPD patients (2.188 ± 1.142 ng/ml) compared to the non-COPD individuals (0.487 ± 0.105 ng/ml; p < 0.001). The mRNA and soluble ADAM33 levels were significantly higher in COPD patients compared to those in the parameter-matched non-COPD individuals. Thus, ADAM33 is a potential biomarker and treatment for inflammation in COPD patients.

The Regulation Of Inflammatory Cytokines In Chronic Airway Inflammation

2010 ◽  
Author(s):  
Weihua Wang ◽  
Wei le ◽  
Gabriel Tsao ◽  
Do-Yean Cho ◽  
Peter H. Hwang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Cytokines ◽  
Chronic Airway

scholarly journals Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD

2016 ◽  
Vol 311 (5) ◽  
pp. L881-L892 ◽  
Author(s):  
Simon D. Pouwels ◽  
Laura Hesse ◽  
Alen Faiz ◽  
Jaap Lubbers ◽  
Priya K. Bodha ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Cigarette Smoke ◽  
Gene Set Enrichment Analysis ◽  
Gene Profiling ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Copd Patients ◽  
Galectin 3

Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD). We investigated whether CS-induced damage-associated molecular pattern (DAMP) release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings, were collected from young and old individuals, susceptible and nonsusceptible for the development of COPD, before and after smoking, and used for gene profiling and airway epithelial cell (AEC) culture. AECs were exposed to CS extract (CSE) or specific DAMPs. BALB/cByJ and DBA/2J mice were intranasally exposed to LL-37 and mitochondrial (mt)DAMPs. Functional gene-set enrichment analysis showed that CS significantly increases the airway epithelial gene expression of DAMPs and DAMP receptors in COPD patients. In cultured AECs, we observed that CSE induces necrosis and DAMP release, with specifically higher galectin-3 release from COPD-derived compared with control-derived cells. Galectin-3, LL-37, and mtDAMPs increased CXCL8 secretion in AECs. LL-37 and mtDAMPs induced neutrophilic airway inflammation, exclusively in mice susceptible for CS-induced airway inflammation. Collectively, we show that in airway epithelium from COPD patients, the CS-induced expression of DAMPs and DAMP receptors in vivo and the release of galectin-3 in vitro is exaggerated. Furthermore, our studies indicate that a predisposition to release DAMPs and subsequent induction of inflammation may contribute to the development of COPD.

scholarly journals Comparison of the Serological Responses to Moraxella catarrhalis Immunoglobulin D-Binding Outer Membrane Protein and the Ubiquitous Surface Proteins A1 and A2

2006 ◽  
Vol 74 (11) ◽  
pp. 6377-6386 ◽  
Author(s):  
Thuan Tong Tan ◽  
Jens Jørgen Christensen ◽  
Morten Hanefeld Dziegiel ◽  
Arne Forsgren ◽  
Kristian Riesbeck
Keyword(s):  
Young Children ◽  
Moraxella Catarrhalis ◽  
Healthy Adults ◽  
Alveolar Epithelial Cells ◽  
Surface Proteins ◽  
Functional Domains ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Immunoglobulin D

ABSTRACT Moraxella catarrhalis immunoglobulin D-binding protein (MID) is a complex antigen with unique immunoglobulin D (IgD)-binding, adhesion, and hemagglutination properties. Previous studies have shown that antibodies raised against MID764-913 in rabbits inhibited M. catarrhalis adhesion to human alveolar epithelial cells, and immunization with MID764-913 resulted in an increased pulmonary clearance in a murine model. Strong immune responses against MID have also consistently been shown in humans. Here, the MID-specified IgG responses were compared to those of ubiquitous surface proteins A1 and A2 (UspA1/A2) using a series of recombinant fragments that spanned all three proteins. Sera were obtained from young children, aged 6 months to 1 year (n = 8) and 2 to 3 years (n = 15), and healthy adults (n = 16). Acute- and convalescent-phase sera from chronic obstructive pulmonary disease (COPD) patients with M. catarrhalis infective exacerbations (n = 23) were also analyzed. Young children, who are at risk of M. catarrhalis infection, had low levels of anti-MID and anti-UspA1/A2 antibodies. Healthy adults and the majority of COPD patients (16/23) had high levels of antibodies directed against, among others, the adhesive domain of MID and the fibronectin- and C3-binding domains of UspA1/A2. Among eight COPD patients in whom a rise in antibody levels could be detected, these functional domains were also the main regions targeted by the antibodies. In addition, human IgG directed against MID was bactericidal and anti-MID antibodies were additive to antibodies targeting UspA1/A2. Hence, the functional domains in these three antigens may have significant potential in a future vaccine against M. catarrhalis.

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