scholarly journals Macrophages with reduced expressions of classical M1 and M2 surface markers in human bronchoalveolar lavage fluid exhibit pro-inflammatory gene signatures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroto Takiguchi ◽  
Chen X. Yang ◽  
Cheng Wei Tony Yang ◽  
Basak Sahin ◽  
Beth A. Whalen ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Lung Diseases ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Gene Signature ◽  
Chronic Obstructive ◽  
Surface Markers ◽  
Cellular Functions ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

AbstractThe classical M1/M2 polarity of macrophages may not be applicable to inflammatory lung diseases including chronic obstructive pulmonary disease (COPD) due to the complex microenvironment in lungs and the plasticity of macrophages. We examined macrophage sub-phenotypes in bronchoalveolar lavage (BAL) fluid in 25 participants with CD40 (a M1 marker) and CD163 (a M2 marker). Of these, we performed RNA-sequencing on each subtype in 10 patients using the Illumina NextSeq 500. Approximately 25% of the macrophages did not harbor classical M1 or M2 surface markers (double negative, DN), and these cells were significantly enriched in COPD patients compared with non-COPD patients (46.7% vs. 14.5%, p < 0.001). 1886 genes were differentially expressed in the DN subtype compared with  all other subtypes at a 10% false discovery rate. The 602 up-regulated genes included 15 mitochondrial genes and were enriched in 86 gene ontology (GO) biological processes including inflammatory responses. Modules associated with cellular functions including oxidative phosphorylation were significantly down-regulated in the DN subtype. Macrophages in the human BAL fluid, which were negative for both M1/M2 surface markers, harbored a gene signature that was pro-inflammatory and suggested dysfunction in cellular homeostasis. These macrophages may contribute to the pathogenesis and manifestations of inflammatory lung diseases such as COPD.

scholarly journals Bronchoalveolar Lavage Fluid from COPD Patients Reveals More Compounds Associated with Disease than Matched Plasma

Metabolites ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 157 ◽  
Author(s):  
Eitan Halper-Stromberg ◽  
Lucas Gillenwater ◽  
Charmion Cruickshank-Quinn ◽  
Wanda Kay O’Neal ◽  
Nichole Reisdorph ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Cell Metabolism ◽  
Lavage Fluid ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Exacerbations ◽  
False Discovery ◽  
Copd Patients ◽  
Clinical Covariates

Smoking causes chronic obstructive pulmonary disease (COPD). Though recent studies identified a COPD metabolomic signature in blood, no large studies examine the metabolome in bronchoalveolar lavage (BAL) fluid, a more direct representation of lung cell metabolism. We performed untargeted liquid chromatography–mass spectrometry (LC–MS) on BAL and matched plasma from 115 subjects from the SPIROMICS cohort. Regression was performed with COPD phenotypes as the outcome and metabolites as the predictor, adjusted for clinical covariates and false discovery rate. Weighted gene co-expression network analysis (WGCNA) grouped metabolites into modules which were then associated with phenotypes. K-means clustering grouped similar subjects. We detected 7939 and 10,561 compounds in BAL and paired plasma samples, respectively. FEV1/FVC (Forced Expiratory Volume in One Second/Forced Vital Capacity) ratio, emphysema, FEV1 % predicted, and COPD exacerbations associated with 1230, 792, eight, and one BAL compounds, respectively. Only two plasma compounds associated with a COPD phenotype (emphysema). Three BAL co-expression modules associated with FEV1/FVC and emphysema. K-means BAL metabolomic signature clustering identified two groups, one with more airway obstruction (34% of subjects, median FEV1/FVC 0.67), one with less (66% of subjects, median FEV1/FVC 0.77; p < 2 × 10−4). Associations between metabolites and COPD phenotypes are more robustly represented in BAL compared to plasma.

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 The effect of induced sputum and bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease on neutrophil migration in vitro

Medicina ◽  
2010 ◽  
Vol 46 (5) ◽  
pp. 315 ◽  
Author(s):  
Agnė Babušytė ◽  
Jolanta Jeroch ◽  
Rimantas Stakauskas ◽  
Kristina Stravinskaitė ◽  
Kęstutis Malakauskas ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Neutrophil Migration ◽  
Lavage Fluid ◽  
Interleukin 8 ◽  
Induced Sputum ◽  
Chronic Obstructive ◽  
Healthy Individuals ◽  
Copd Patients

Objective. The aim of study was to investigate a chemotactic effect of induced sputum and bronchoalveolar lavage fluid on blood neutrophils in patients with chronic obstructive pulmonary disease (COPD) and healthy individuals. Material and methods. Forty-three smokers with COPD, 19 ex-smokers with COPD, 13 healthy smokers, and 17 healthy nonsmokers were recruited to the study. Neutrophils were isolated from peripheral blood of study individuals. For the same experimental conditions, pooled induced sputum and bronchoalveolar lavage fluid of 20 COPD patients were used. Neutrophil chemotaxis in vitro was performed in cell-transmigration chamber. Substances tested for chemoattraction (interleukin-8, induced sputum, bronchoalveolar lavage fluid directly or in addition to interleukin-8) were added to lower wells. Upper wells were filled with 2.5×106/mL of neutrophil culture and incubated for 2 hours. Migration was analyzed by flow cytometry. Results. Interleukin-8 (10–100 ng/mL) induced a dose-dependant neutrophil migration in all the groups. Only 100 ng/L of interleukin-8 induced more intensive chemotaxis of neutrophils from COPD smokers as compared to ex-smokers (P<0.05). Such difference between healthy individuals was obtained using 30 ng/mL of interleukin-8 (P<0.05). Induced sputum/interleukin-8 (10–100 ng/mL), as well as induced sputum directly, induced neutrophil migration (P<0.05). Chemotaxis of neutrophils isolated from COPD patients and healthy nonsmokers did not depend on additional interleukin-8 concentration. Bronchoalveolar lavage fluid/interleukin-8 (30–100 ng/mL) induced more intensive migration of neutrophils from COPD patients than bronchoalveolar lavage fluid (P<0.05) alone. Conclusions. Migration of neutrophils isolated from patients with COPD was more intensive compared to healthy individuals. Induced sputum and bronchoalveolar lavage fluid directly and with addition of interleukin-8 stimulated chemotaxis, and it was higher in neutrophils from COPD patients. Migration of neutrophils did not depend on smoking status.

scholarly journals Cigarette smoke and CFTR: implications in the pathogenesis of COPD

2013 ◽  
Vol 305 (8) ◽  
pp. L530-L541 ◽  
Author(s):  
Andras Rab ◽  
Steven M. Rowe ◽  
S. Vamsee Raju ◽  
Zsuzsa Bebok ◽  
Sadis Matalon ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cigarette Smoke ◽  
Inflammatory Responses ◽  
Common Mechanism ◽  
Chronic Obstructive ◽  
Respiratory Disorder ◽  
Chronic Infections ◽  
Gene Encoding ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder consisting of chronic bronchitis and/or emphysema. COPD patients suffer from chronic infections and display exaggerated inflammatory responses and a progressive decline in respiratory function. The respiratory symptoms of COPD are similar to those seen in cystic fibrosis (CF), although the molecular basis of the two disorders differs. CF is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene encoding a chloride and bicarbonate channel (CFTR), leading to CFTR dysfunction. The majority of COPD cases result from chronic oxidative insults such as cigarette smoke. Interestingly, environmental stresses including cigarette smoke, hypoxia, and chronic inflammation have also been implicated in reduced CFTR function, and this suggests a common mechanism that may contribute to both the CF and COPD. Therefore, improving CFTR function may offer an excellent opportunity for the development of a common treatment for CF and COPD. In this article, we review what is known about the CF respiratory phenotype and discuss how diminished CFTR expression-associated ion transport defects may contribute to some of the pathological changes seen in COPD.

scholarly journals Upregulation of Leukocyte Immunoglobulin-Like Receptor B4 on Interstitial Macrophages in COPD; Their Possible Protective Role Against Emphysema Formation

2021 ◽  
Author(s):  
Ayumi Mitsune ◽  
Mitsuhiro Yamada ◽  
Naoya Fujino ◽  
Tadahisa Numakura ◽  
Tomohiro Ichikawa ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Feedback System ◽  
Surface Expression ◽  
Protective Role ◽  
Chronic Obstructive ◽  
Wild Type ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Deficient Mice

Abstract Background: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD.Methods: We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice.Results: The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model.Conclusions: LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.

scholarly journals Different source of sample strains corresponds to different characteristics of patients with non-tuberculous mycobacterium.

2020 ◽  
Author(s):  
Xinling Pan ◽  
Jin Zhao ◽  
Xiaoling Jin ◽  
Songjun Ji
Keyword(s):  
Lavage Fluid ◽  
Smoking History ◽  
Lower Percentage ◽  
Chronic Obstructive ◽  
Symptom Duration ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Different Characteristics ◽  
Different Sources ◽  
Positive Results

Abstract Background: The non-tuberculous mycobacteria (NTM) strains are important in the diagnosis of pulmonary diseases. However, the different source of the sample may correspond to different characteristics of both NTM disease and infected patients and these aspects have not been investigated. Methods: Samples isolated from different sources in inpatients with NTM strains were comprehensively analyzed in this study, including basic information, laboratory examination and coexisting diseases.Results: A total of 242 inpatients with NTM strains were considered in this study. Sputum (n=129) and bronchoalveolar lavage fluid (BALF, n=50) were the most common samples among patients with NTM strains from whom a sample was collected from a single source (n=179). The patients with NTM-positive BALF differed in age, gender, acid fast assay, the percentage of presence of chronic obstructive pulmonary disease (COPD) and bronchiectasis, and symptom duration compared to the patients with NTM-positive sputum. The patients with COPD were older and mainly male, with longer symptom duration, with higher rates of smoking history and prostatic hyperplasia than those without COPD. Patients with bronchiectasis were mainly females, with a lower percentage of them with a tuberculosis history and smoking history compared to patients without bronchiectasis. Excluding the patients with COPD and bronchiectasis, patients with NTM-positive sputum were older, with positive results in acid-fast assay and T. spot assay compared to patients with NTM-positive BALF. Conclusions: The different specimen source in NTM patients was associated with different patients’ characteristics, and its choice could be influenced by presence of COPD and bronchiectasis. Patients with COPD and bronchiectasis differed in gender and smoking history, thus, these aspects should be comprehensively analyzed during the investigation of patients with pulmonary NTM infection.

scholarly journals New Pharmacological Tools to Target Leukocyte Trafficking in Lung Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Kylie B. R. Belchamber ◽  
Michael J. Hughes ◽  
Daniella A. Spittle ◽  
Eloise M. Walker ◽  
Elizabeth Sapey
Keyword(s):  
Lung Disease ◽  
Immune Cells ◽  
Lung Diseases ◽  
Immune Cell ◽  
Current Evidence ◽  
Chronic Obstructive ◽  
Cellular Functions ◽  
Obstructive Pulmonary Disease ◽  
Microbial Invasion ◽  
Infection And Inflammation

Infection and inflammation of the lung results in the recruitment of non-resident immune cells, including neutrophils, eosinophils and monocytes. This swift response should ensure clearance of the threat and resolution of stimuli which drive inflammation. However, once the threat is subdued this influx of immune cells should be followed by clearance of recruited cells through apoptosis and subsequent efferocytosis, expectoration or retrograde migration back into the circulation. This cycle of cell recruitment, containment of threat and then clearance of immune cells and repair is held in exquisite balance to limit host damage. Advanced age is often associated with detrimental changes to the balance described above. Cellular functions are altered including a reduced ability to traffic accurately towards inflammation, a reduced ability to clear pathogens and sustained inflammation. These changes, seen with age, are heightened in lung disease, and most chronic and acute lung diseases are associated with an exaggerated influx of immune cells, such as neutrophils, to the airways as well as considerable inflammation. Indeed, across many lung diseases, pathogenesis and progression has been associated with the sustained presence of trafficking cells, with examples including chronic diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis and acute infections such as Pneumonia and Pneumonitis. In these instances, there is evidence that dysfunctional and sustained recruitment of cells to the airways not only increases host damage but impairs the hosts ability to effectively respond to microbial invasion. Targeting leukocyte migration in these instances, to normalise cellular responses, has therapeutic promise. In this review we discuss the current evidence to support the trafficking cell as an immunotherapeutic target in lung disease, and which potential mechanisms or pathways have shown promise in early drug trials, with a focus on the neutrophil, as the quintessential trafficking immune cell.

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