Immune Cell Subtypes and Cytokines in Lung Tumor Microenvironment: Influence of COPD

Background: The immune microenvironment plays a role in tumorigenesis. Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for lung cancer (LC). We hypothesized that immune profile characterized by T regulatory (Treg), natural killer (NK), and plasma cells, as well as interleukin (IL)-10 and interferon-gamma, may differ within tumors of LC patients with/without COPD. Methods: Treg (anti-CD3 and anti-forkhead boxP3 antibodies), NK (anti-NCR1 antibody), IgG (anti-CD138-IgG antibody), IgA (anti-CD138-IgA antibody) using immunohistochemistry, and both IL-10 and interferon-gamma (ELISA) were quantified in tumor and non-tumor specimens (thoracotomy for lung tumor resection) from 33 LC–COPD patients and 20 LC-only patients. Results: Immune profile in tumor versus non-tumor specimens: Treg cell counts significantly increased in tumors of both LC and LC–COPD patients, while in tumors of the latter group, IgG-secreting plasma cells significantly decreased and IL-10 increased. No significant differences were seen in levels of NK cells, IgA-secreting cells, IgA/IgG, or interferon-gamma. Immune profile in tumors of LC–COPD versus LC: No significant differences were observed in tumors between LC–COPD and LC patients for any study marker. Conclusions: Immune cell subtypes and cytokines are differentially expressed in lung tumors, and the presence of COPD elicited a decline in IgG-secreting plasma cell levels but not in other cell types.

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Suppressor of Variegation 3-9 Homologue 1 Impairment and Neutrophil-skewed Systemic Inflammation Are Associated with Comorbidities in COPD

10.21203/rs.3.rs-45674/v2 ◽

2020 ◽

Author(s):

Tzu-Tao Chen ◽

Sheng-Ming Wu ◽

Kuan-Yuan Chen ◽

Chien-Hua Tseng ◽

Shu-Chuan Ho ◽

...

Keyword(s):

Blood Cell ◽

Clinical Outcomes ◽

Systemic Inflammation ◽

Mononuclear Cells ◽

Chronic Obstructive ◽

Th2 Response ◽

Neutrophilic Inflammation ◽

Cell Counts ◽

Blood Cell Counts ◽

Copd Patients

Abstract BACKGROUND: Systemic manifestations and comorbidities are characteristics of chronic obstructive pulmonary disease (COPD) and are probably due to systemic inflammation. The histone methyltransferase SUV39H1 controls the Th1/Th2 balance. We previously reported that reduced SUV39H1 expression contributed to abnormal inflammation in COPD.METHODS: To assess whether impaired SUV39H1 expression in COPD patients leads to neutrophilic inflammation, downstream responses to IL-8 and suppression of Th2 responses, the SUV39H1 levels in peripheral blood mononuclear cells (PBMCs) from 13 healthy subjects and 30 COPD patients were measured by immunoblotting. Clinical outcomes associated with SUV39H1-related inflammation were also studied. The relationships between SUV39H1 and neutrophil or eosinophil (Th2 response) counts and clinical outcomes were evaluated. In an extended COPD cohort (213 patients), association analyses of blood cell counts with comorbidities and exacerbations were performed.RESULTS: Low SUV39H1 expression was associated with high neutrophil counts and a trend towards low eosinophil counts. In the extended cohort, the high comorbidity group had higher neutrophil counts than the low comorbidity group but similar whole white blood cell counts. The eosinophil percentage and eosinophil/neutrophil ratio displayed contrasting results. The proportion of neutrophils was correlated with COPD comorbidities. Patients with 0-1 moderate to severe exacerbations in the past year had numbers of neutrophils and eosinophils similar to those of patients who experienced more than an exacerbation. Finally, patients with high comorbidities had lower SUV39H1 levels in their PBMCs than did those with low comorbidities.CONCLUSION: Blood neutrophil counts are associated with comorbidities in COPD patients. Impaired SUV39H1 expression in PBMCs from COPD patients are correlated with neutrophilic inflammation and comorbidities.

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Increased PARP Activity and DNA Damage in NSCLC Patients: The Influence of COPD

Cancers ◽

10.3390/cancers12113333 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3333

Author(s):

Jun Tang ◽

Víctor Curull ◽

Xuejie Wang ◽

Coral Ampurdanés ◽

Xavier Duran ◽

...

Keyword(s):

Dna Damage ◽

Lung Tumor ◽

Colorimetric Assay ◽

Thoracoscopic Surgery ◽

Lung Tumors ◽

Chronic Obstructive ◽

Activity Levels ◽

Copd Patients ◽

Parp Activity ◽

Parp 1

(1) Background: Lung cancer (LC) is a major leading cause of death worldwide. Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 are key players in cancer. We aimed to assess PARP-1 and PARP-2 expression and activity and DNA damage in tumors and non-tumor lungs from patients with/without chronic obstructive pulmonary disease (COPD). (2) Methods: Lung tumor and non-tumor specimens were obtained through video-assisted thoracoscopic surgery (VATS) in LC patients with/without underlying COPD (two groups of patients, n = 15/group). PARP-1 and PARP-2 expression (ELISA), PARP activity (PARP colorimetric assay kit) and DNA damage (immunohistochemistry) levels were identified in all samples. (3) Results: Both PARP-1 and PARP-2 expression levels were significantly lower in lung tumors (irrespective of COPD)compared to non-tumor specimens, while DNA damage and PARP activity levels significantly increased in lung tumors compared to non-tumor specimens only in LC-COPD patients. PARP-2 expression was positively correlated with smoking burden in LC-COPD patients. (4) Conclusions: In lung tumors of COPD patients, an overactivation of PARP enzyme was observed. A decline in PARP-1 and PARP-2 protein expression was seen in lung tumors irrespective of COPD. Other phenotypic features (airway obstruction) beyond cancer may account for the increase in PARP activity seen in the tumors of patients with underlying COPD.

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Antibody Responses to Respiratory Syncytial Virus: A Cross-Sectional Serosurveillance Study in the Dutch Population Focusing on Infants Younger Than 2 Years

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa483 ◽

2020 ◽

Author(s):

Guy Berbers ◽

Liesbeth Mollema ◽

Fiona van der Klis ◽

Gerco den Hartog ◽

Rutger Schepp

Keyword(s):

Respiratory Syncytial Virus ◽

Chronic Obstructive ◽

Igg Antibody ◽

Cross Sectional ◽

Mild Disease ◽

Copd Patients ◽

Increased Risk ◽

Iga Antibodies ◽

Rsv Infection ◽

Syncytial Virus

Abstract Background Respiratory syncytial virus (RSV) generally causes mild disease but can cause severe infections in (premature) infants and elderly adults. Here, we studied RSV-specific antibody concentrations throughout life with emphasis on infants and chronic obstructive pulmonary disease (COPD) patients. Methods Sera (N = 2655) from 2 nationwide cross-sectional studies in the Netherlands including individuals aged 0–90 years were analyzed for IgG and IgA antibodies to RSV prefusion F, postfusion F, N, Ga, and Gb proteins and for antibody avidity in 42 COPD patients. Results Maternal IgG concentrations declined to age 10–12 months. After the first year of life, approximately 40% of children lacked infection-induced IgA antibodies and may therefore be uninfected. All Dutch children showed serological evidence of RSV infection by age 3 years. Antibody concentrations reached a plateau by age 5–9 years and remains constant throughout life. COPD patients had similar levels and avidity of RSV-specific IgG antibodies compared with age-matched healthy controls. Conclusions RSV-IgG antibody patterns throughout life can be used to estimate the degree of immunity acquisition to RSV and to identify groups at increased risk of infection. Seroprevalence of IgA could be a proxy to determine RSV infection in children younger than 1 year.

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Beyond Uterine Natural Killer Cell Numbers in Unexplained Recurrent Pregnancy Loss: Combined Analysis of CD45, CD56, CD16, CD57, and CD138

Diagnostics ◽

10.3390/diagnostics10090650 ◽

2020 ◽

Vol 10 (9) ◽

pp. 650 ◽

Cited By ~ 1

Author(s):

Maia Chiokadze ◽

Christin Bär ◽

Jana Pastuschek ◽

Boris V. Dons’koi ◽

Kseniia G. Khazhylenko ◽

...

Keyword(s):

Natural Killer ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Plasma Cells ◽

Immune Cell ◽

Killer Cell ◽

Cell Counts ◽

Unk Cells ◽

Uterine Natural Killer

Changes in the number and cytotoxic potential of uterine Natural Killer (uNK) cells have been associated with reduced fertility. To provide a better characterization of immunophenotypes in the endometrium of women with uRPL (unexplained recurrent pregnancy loss), we examined the applicability of a set of five immune cell markers. The concentration (cells/mm2) of CD45+ leukocytes, CD56+ uNK cells, and CD138+ plasma cells as well as of CD16+ and CD57+ cells, which indicate high cytotoxic uNK cells, were assessed by immunohistochemistry in endometrial biopsies from 61 uRPL patients and 10 controls. Control fertile endometria presented 90–300 CD56+ uNK cells/mm2. uRPL cases were classified in subgroups of low (uRPL-CD56low < 90 cells/mm2), normal (uRPL-CD56normal 90–300 cells/mm2), and high uNK cell counts (uRPL-CD56high > 300 cells/mm2). Some cases from the uRPL-CD56low and uRPL-CD56normal subgroups showed elevated proportions of cytotoxic CD16+ and CD57+ cells in relation to CD56+ cells. In the uRPL-CD56high subgroup, the CD57/CD56 ratio was reduced in most samples and the CD16/CD56 ratio was unaltered. Analysis of CD138 excluded the influence of chronic endometritis on these observations. Our results reinforce a link between uRPL and a dysfunctional endometrial environment associated with distinct immune cell profiles.

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RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation

European Respiratory Journal ◽

10.1183/13993003.00188-2017 ◽

2017 ◽

Vol 50 (4) ◽

pp. 1700188 ◽

Cited By ~ 21

Author(s):

Catherine E. Charron ◽

Paul Russell ◽

Kazuhiro Ito ◽

Simon Lea ◽

Yasuo Kizawa ◽

...

Keyword(s):

Cigarette Smoke ◽

Kinase Inhibitor ◽

Forced Expiratory Volume ◽

Mitogen Activated Protein Kinase ◽

Poly I:C ◽

Chronic Obstructive ◽

Cell Counts ◽

Copd Patients ◽

Anti Inflammatory

Novel anti-inflammatory approaches targeting chronically activated kinase pathways in chronic obstructive pulmonary disease (COPD) are needed. We evaluated RV568, a p38 mitogen-activated protein kinase-α and -γ and SRC family kinase inhibitor, in cellular and in vivo models relevant to COPD and examined its safety and efficacy in COPD patients.The anti-inflammatory activities of RV568 were tested in primary cultured monocytes, macrophages and bronchial epithelial cells and in vivo in lipopolysaccharide and cigarette smoke-exposed murine models. RV568 was evaluated in a 14-day trial in COPD patients.RV568 showed potent anti-inflammatory effects in monocytes and macrophages, which were often greater than those of corticosteroids or the p38 inhibitor Birb796. RV568 combined with corticosteroid had anti-inflammatory effects suggestive of a synergistic interaction in poly I:C-stimulated BEAS-2B cells and in the cigarette smoke model. In COPD patients, inhaled RV568 (50 µg and 100 µg) improved pre-bronchodilator forced expiratory volume in 1 s (69 mL and 48 mL respectively) and significantly reduced sputum malondialdehyde (p<0.05) compared to placebo, although there were no changes in sputum cell counts. Adverse events during RV568 and placebo treatment were similar.RV568 shows potent anti-inflammatory effects on cell and animal models relevant to COPD. RV568 was well-tolerated and demonstrated a modest clinical benefit in a 14-day COPD clinical trial.

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B Cells and Tertiary Lymphoid Structures Influence Survival in Lung Cancer Patients with Resectable Tumors

Cancers ◽

10.3390/cancers12092644 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2644

Author(s):

Jun Tang ◽

Daniel Ramis-Cabrer ◽

Víctor Curull ◽

Xuejie Wang ◽

Mercé Mateu-Jiménez ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

B Cells ◽

Survival Rates ◽

Chronic Obstructive ◽

Immune Profile ◽

Immune Biomarkers ◽

Copd Patients ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients’ 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC.

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Chronic obstructive pulmonary condition (COPD) is a prevalent, preventable, and curable illness with persistent respiratory symptoms and airflow limitation

10.31219/osf.io/vkdut ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Signaling Pathways ◽

Respiratory Symptoms ◽

Immune Cell ◽

Airway Remodeling ◽

Tobacco Smoke Exposure ◽

Airflow Limitation ◽

Chronic Obstructive ◽

Alveolar Wall ◽

Small Airways ◽

Copd Patients

Global Initiative for Chronic Obstructive Lung Disease (GOLD) research on chronic obstructive pulmonary condition (COPD) characterizes it as a prevalent, preventable, and curable illness with persistent respiratory symptoms and airflow limitation. airway blockage resulting in dyspnoea and air trapping when exercising airflow restriction can be attributed to smoking, ambient tobacco smoke exposure, and the patient's TB history COPD airflow restriction is largely caused by airway tightness, chronic bronchitis, or emphysema. Repeated inhalation of hazardous particles induces chronic inflammatory immune cell infiltration, tissue repair, and airway remodeling, resulting in a 4-to 40-fold increase in airway resistance and bronchiolar constriction. 20% of small airways are bronchi, with the rest being either bronchioles or alveolar ductal gaps. Flow restriction includes alveolar wall disintegration and alveolar support. The modifications worsen the rapid FEV1 fall and contribute to the airway obstruction seen in COPD. COPD, small airway disease (SAD), has been extensively studied. Inflammation, fibrosis, and destruction of bronchioles are all indications of this illness. mixed pulmonary fibrosis and emphysema (CPFE). In fact, fibrosis appears to be involved in the obstruction of small airways.RAGE participates in several intracellular processes by binding to several ligands. RAGE ligand interactions trigger downstream signaling pathways that have been associated with COPD and other disorders. Thus, inhibitors of RAGE and its signaling pathways also have been found to play a function in other disorders, which suggests that they might be used to treat COPD. There are currently no established biomarkers to diagnose COPD. COPD patients are shown to have altered RAGE and some of its ligands. Despite a lack of agreement on how smoking affects sRAGE levels, greater study is needed to discover whether or not this biomarker is stable. It was discovered that among the North Han Chinese,-429T > C is associated with COPD. COPD vulnerability is furthermore associated with the genetics of RAGE. To get a better diagnosis, population-based studies are needed. Finally, RAGE, AGE-RAGE, and sRAGE all impact COPD, and RAGE may be employed as a biomarker for diagnosis and management of COPD patients if more study supports this hypothesis.

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Suppressor of Variegation 3-9 Homologue 1 Impairment and Neutrophil-Skewed Systemic Inflammation Are Associated with Comorbidities in COPD

10.21203/rs.3.rs-45674/v1 ◽

2020 ◽

Author(s):

Tzu-Tao Chen ◽

Sheng-Ming Wu ◽

Kuan-Yuan Chen ◽

Chien-Hua Tseng ◽

Shu-Chuan Ho ◽

...

Keyword(s):

Blood Cell ◽

Clinical Outcomes ◽

Systemic Inflammation ◽

Mononuclear Cells ◽

Chronic Obstructive ◽

Th2 Response ◽

Neutrophilic Inflammation ◽

Cell Counts ◽

Blood Cell Counts ◽

Copd Patients

Abstract BACKGROUND: Systemic manifestations and comorbidities are characteristics of chronic obstructive pulmonary disease (COPD) and are probably due to systemic inflammation. The histone methyltransferase SUV39H1 controls the Th1/Th2 balance. We previously reported that reduced SUV39H1 expression contributed to abnormal inflammation in COPD.METHODS: To assess whether impaired SUV39H1 expression in COPD patients leads to neutrophilic inflammation, downstream responses to IL-8 and suppression of Th2 responses, the SUV39H1 levels in peripheral blood mononuclear cells (PBMCs) from 10 healthy subjects and 14 COPD patients were measured by immunoblotting. Clinical outcomes associated with SUV39H1-related inflammation were also studied. The relationships between SUV39H1 and neutrophil or eosinophil (Th2 response) counts and clinical outcomes were evaluated. In an extended COPD cohort (213 patients), association analyses of blood cell counts with comorbidities and exacerbations were performed.RESULTS: Low SUV39H1 expression was associated with high neutrophil counts and a trend towards low eosinophil counts. In the extended cohort, the high comorbidity group had higher neutrophil counts than the low comorbidity group but similar whole white blood cell counts. The eosinophil percentage and eosinophil/neutrophil ratio displayed contrasting results. The proportion of neutrophils was correlated with COPD comorbidities. Patients with 0-1 moderate to severe exacerbations in the past year had numbers of neutrophils and eosinophils similar to those of patients who experienced more than an exacerbation. Finally, patients with high comorbidities had lower SUV39H1 levels in their PBMCs than did those with low comorbidities.CONCLUSION: Blood neutrophil counts are associated with comorbidities in COPD patients. Impaired SUV39H1 expression in PBMCs from COPD patients are correlated with neutrophilic inflammation and comorbidities.

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Alveolar macrophage transcriptomic profiling in COPD shows major lipid metabolism changes

ERJ Open Research ◽

10.1183/23120541.00915-2020 ◽

2021 ◽

pp. 00915-2020

Author(s):

Wataru Fujii ◽

Theodore S. Kapellos ◽

Kevin Baßler ◽

Kristian Händler ◽

Lisa Holsten ◽

...

Keyword(s):

Lipid Metabolism ◽

Immune Cells ◽

Fatty Acid Biosynthesis ◽

Immune Cell ◽

Cholesterol Metabolism ◽

Chronic Obstructive ◽

Dependent Manner ◽

Transcriptional Reprogramming ◽

Copd Patients ◽

Lipid Species

BackgroundImmune cells play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Albeit established changes in distribution and cellular functions of major immune cells, such as alveolar macrophages (AMs) and neutrophils, their transcriptional reprogramming and contribution to the pathophysiology of COPD are still not fully understood.Aim and methodsTo determine changes in transcriptional reprogramming and lipid metabolism in the major immune cell type within the bronchoalveolar lavage fluid, we analysed whole transcriptomes and lipidomes of sorted CD45+Lin−HLA-DR+CD66b−Autofluorescencehi AMs from control and COPD patients.ResultsWe observed global transcriptional reprogramming featuring a spectrum of activation states, including pro- and anti-inflammatory signatures. We further detected significant changes between COPD patients and controls in genes involved in lipid metabolism, such as fatty acid biosynthesis in GOLD2 patients. Based on these findings, assessment of a total of 202 lipid species in sorted AMs revealed changes of cholesteryl esters, monoacylglycerols and phospholipids in a disease grade-dependent manner.ConclusionsTranscriptome and lipidome profiling of COPD AMs revealed GOLD grade-dependent changes, such as in cholesterol metabolism and interferon alpha and gamma responses.

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Oral and Oropharyngeal Sensory Function in Adults With Chronic Obstructive Pulmonary Disease

American Journal of Speech-Language Pathology ◽

10.1044/2019_ajslp-19-00095 ◽

2020 ◽

Vol 29 (2) ◽

pp. 864-872

Author(s):

Fernanda Borowsky da Rosa ◽

Adriane Schmidt Pasqualoto ◽

Catriona M. Steele ◽

Renata Mancopes

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Oral Cavity ◽

Pulmonary Disease ◽

Thermal Sensation ◽

Sensory Function ◽

Control Group ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Age Related ◽

Copd Patients

Introduction The oral cavity and pharynx have a rich sensory system composed of specialized receptors. The integrity of oropharyngeal sensation is thought to be fundamental for safe and efficient swallowing. Chronic obstructive pulmonary disease (COPD) patients are at risk for oropharyngeal sensory impairment due to frequent use of inhaled medications and comorbidities including gastroesophageal reflux disease. Objective This study aimed to describe and compare oral and oropharyngeal sensory function measured using noninstrumental clinical methods in adults with COPD and healthy controls. Method Participants included 27 adults (18 men, nine women) with a diagnosis of COPD and a mean age of 66.56 years ( SD = 8.68). The control group comprised 11 healthy adults (five men, six women) with a mean age of 60.09 years ( SD = 11.57). Spirometry measures confirmed reduced functional expiratory volumes (% predicted) in the COPD patients compared to the control participants. All participants completed a case history interview and underwent clinical evaluation of oral and oropharyngeal sensation by a speech-language pathologist. The sensory evaluation explored the detection of tactile and temperature stimuli delivered by cotton swab to six locations in the oral cavity and two in the oropharynx as well as identification of the taste of stimuli administered in 5-ml boluses to the mouth. Analyses explored the frequencies of accurate responses regarding stimulus location, temperature and taste between groups, and between age groups (“≤ 65 years” and “> 65 years”) within the COPD cohort. Results We found significantly higher frequencies of reported use of inhaled medications ( p < .001) and xerostomia ( p = .003) in the COPD cohort. Oral cavity thermal sensation ( p = .009) was reduced in the COPD participants, and a significant age-related decline in gustatory sensation was found in the COPD group ( p = .018). Conclusion This study found that most of the measures of oral and oropharyngeal sensation remained intact in the COPD group. Oral thermal sensation was impaired in individuals with COPD, and reduced gustatory sensation was observed in the older COPD participants. Possible links between these results and the use of inhaled medication by individuals with COPD are discussed.

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