148 results on '"Stephan F. van Eeden"'
Search Results
2. Systemic and Airway Epigenetic Disruptions Are Associated with Health Status in COPD
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Ana I. Hernandez Cordero, Xuan Li, Chen Xi Yang, Julia Yang, Julia L. MacIsaac, Kristy Dever, Michael S. Kobor, Stephen Milne, Stephan F. van Eeden, Tawimas Shaipanich, Stephen Lam, Janice M. Leung, and Don D. Sin
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epigenetics ,COPD ,blood ,airway ,SGRQ ,Biology (General) ,QH301-705.5 - Abstract
Epigenetic modifications are common in chronic obstructive pulmonary disease (COPD); however, their clinical relevance is largely unknown. We hypothesized that epigenetic disruptions are associated with symptoms and health status in COPD. We profiled the blood (n = 57) and airways (n = 62) of COPD patients for DNA methylation (n = 55 paired). The patients’ health status was assessed using the St. George’s Respiratory Questionnaire (SGRQ). We conducted differential methylation analyses and identified pathways characterized by epigenetic disruptions associated with SGRQ scores and its individual domains. 29,211 and 5044 differentially methylated positions (DMPs) were associated with total SGRQ scores in blood and airway samples, respectively. The activity, impact, and symptom domains were associated with 9161, 25,689 and 17,293 DMPs in blood, respectively; and 4674, 3730 and 5063 DMPs in airways, respectively. There was a substantial overlap of DMPs between airway and blood. DMPs were enriched for pathways related to common co-morbidities of COPD (e.g., ageing, cancer and neurological) in both tissues. Health status in COPD is associated with airway and systemic epigenetic changes especially in pathways related to co-morbidities of COPD. There are more blood DMPs than in the airways suggesting that blood epigenome is a promising source to discover biomarkers for clinical outcomes in COPD.
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- 2023
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3. Inhaled Corticosteroids Selectively Alter the Microbiome and Host Transcriptome in the Small Airways of Patients with Chronic Obstructive Pulmonary Disease
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William Yip, Xuan Li, Graeme J. Koelwyn, Stephen Milne, Fernando Sergio Leitao Filho, Chen Xi Yang, Ana I. Hernández Cordero, Julia Yang, Cheng Wei Tony Yang, Tawimas Shaipanich, Stephan F. van Eeden, Janice M. Leung, Stephen Lam, Kelly M. McNagny, and Don D. Sin
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COPD ,inhaled corticosteroids ,16S rRNA gene sequencing ,mRNA-sequencing ,transcriptomics ,bronchoscopy ,Biology (General) ,QH301-705.5 - Abstract
Background: Patients with chronic obstructive pulmonary disease (COPD) are commonly treated with inhaled corticosteroid/long-acting ß2-agonist combination therapy. While previous studies have investigated the host–microbiome interactions in COPD, the effects of specific steroid formulations on this complex cross-talk remain obscure. Methods: We collected and evaluated data from the Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota (DISARM), a randomized controlled trial. Bronchoscopy was performed on COPD patients before and after treatment with salmeterol/fluticasone, formoterol/budesonide or formoterol-only. Bronchial brush samples were processed for microbial 16S rRNA gene sequencing and host mRNA sequencing. Longitudinal changes in the microbiome at a community, phylum and genus level were correlated with changes in host gene expression using a Spearman’s rank correlation test. Findings: In COPD patients treated with salmeterol/fluticasone, the expression levels of 676 host genes were significantly correlated to changes in the alpha diversity of the small airways. At a genus level, the expression levels of 122 host genes were significantly related to changes in the relative abundance of Haemophilus. Gene enrichment analyses revealed the enrichment of pathways and biological processes related to innate and adaptive immunity and inflammation. None of these changes were evident in patients treated with formoterol/budesonide or formoterol alone. Interpretation: Changes in the microbiome following salmeterol/fluticasone treatment are related to alterations in the host transcriptome in the small airways of patients with COPD. These data may provide insights into why some COPD patients treated with inhaled corticosteroids may be at an increased risk for airway infection, including pneumonia. Funding: The Canadian Institute of Health Research, the British Columbia Lung Association, and an investigator-initiated grant from AstraZeneca.
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- 2022
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4. Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)
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Kentaro Akata, Kei Yamasaki, Fernando Sergio Leitao Filho, Chen Xi Yang, Hiroto Takiguchi, Basak Sahin, Beth A. Whalen, Cheng Wei Tony Yang, Janice M. Leung, Don D. Sin, and Stephan F. van Eeden
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macrophages ,phagocytosis ,COPD ,phenotype ,inflammation ,Biology (General) ,QH301-705.5 - Abstract
Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages’ phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I–III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression.
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- 2020
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5. Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease
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Kentaro Akata and Stephan F. van Eeden
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lung macrophages ,function ,copd ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune effector cells that identify, engulf, and destroy pathogens and process inhaled particles, including cigarette smoke and particulate matter (PM), the main environmental triggers for COPD. The number of LMs in lung tissues and airspaces is increased in COPD, suggesting a potential key role for LMs in initiating and perpetuating the chronic inflammatory response that underpins the progressive nature of COPD. The purpose of this brief review is to discuss the origins of LMs, their functional properties (chemotaxis, recruitment, mediator production, phagocytosis and apoptosis) and changes in these properties due to exposure to cigarette smoke, ambient particulate and pathogens, as well as their persistent altered functional properties in subjects with established COPD. We also explore the potential to therapeutically modulate and restore LMs functional properties, to improve impaired immune system, prevent the progression of lung tissue destruction, and improve both morbidity and mortality related to COPD.
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- 2020
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6. Lung Macrophage Phenotypes and Functional Responses: Role in the Pathogenesis of COPD
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Kei Yamasaki and Stephan F. van Eeden
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lung macrophage phenotypes ,chronic obstructive pulmonary disease ,phagocytic function of macrophage ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lung macrophages (LMs) are essential immune effector cells that are pivotal in both innate and adaptive immune responses to inhaled foreign matter. They either reside within the airways and lung tissues (from early life) or are derived from blood monocytes. Similar to macrophages in other organs and tissues, LMs have natural plasticity and can change phenotype and function depending largely on the microenvironment they reside in. Phenotype changes in lung tissue macrophages have been implicated in chronic inflammatory responses and disease progression of various chronic lung diseases, including Chronic Obstructive Pulmonary Disease (COPD). LMs have a wide variety of functional properties that include phagocytosis (inorganic particulate matter and organic particles, such as viruses/bacteria/fungi), the processing of phagocytosed material, and the production of signaling mediators. Functioning as janitors of the airways, they also play a key role in removing dead and dying cells, as well as cell debris (efferocytic functions). We herein review changes in LM phenotypes during chronic lung disease, focusing on COPD, as well as changes in their functional properties as a result of such shifts. Targeting molecular pathways involved in LM phenotypic shifts could potentially allow for future targeted therapeutic interventions in several diseases, such as COPD.
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- 2018
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7. Contribution of Lung Macrophages to the Inflammatory Responses Induced by Exposure to Air Pollutants
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Kunihiko Hiraiwa and Stephan F. van Eeden
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Pathology ,RB1-214 - Abstract
Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants.
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- 2013
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8. Effects of Inhaled Corticosteroid/Long-Acting β2-Agonist Combination on the Airway Microbiome of Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Clinical Trial (DISARM)
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Stephen Lam, Cheng Wei Tony Yang, Janice M. Leung, Fernando Sergio Leitao Filho, Seung Won Ra, Corey Nislow, Stephen Milne, Kentaro Akata, Yuji Cho, Julia Yang, Ji-Yong Moon, Tawimas Shaipanich, Hiroto Takiguchi, Hyun Kuk Kim, Don D. Sin, Xuan Li, Kei Yamasaki, and Stephan F. van Eeden
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,COPD ,medicine.diagnostic_test ,business.industry ,medicine.drug_class ,Pulmonary disease ,Inhaled corticosteroids ,Critical Care and Intensive Care Medicine ,medicine.disease ,Clinical trial ,Bronchoscopy ,Internal medicine ,Medicine ,Corticosteroid ,Microbiome ,Airway ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Rationale: Inhaled corticosteroids (ICS) are commonly prescribed with long-acting β2-agonists (LABA) in chronic obstructive pulmonary disease (COPD). To date, the effects of ICS therapy on the airw...
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- 2021
9. Common Respiratory Pathogens Other Than Haemophilus in Small Airways are Associated With Neutrophilic Inflammation and Poor Health Status in Stable COPD Patients
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Nawaf M. Alotaibi, Sheena Tam, Stephan F. van Eeden, Tawimas Shaipanich, Stephen Lam, Janice M. Leung, and Don D. Sin
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Pulmonary and Respiratory Medicine ,Brief Report - Abstract
This article does not contain an abstract.
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- 2022
10. Obstructive Sleep Apnea Severity, Body Mass Index, and Circulating Levels of Cellular Adhesion Molecules
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Nurit Fox, Ismail Laher, Bernardo U Peres, A J Hirsch Allen, Najib T. Ayas, Andrew J. Sandford, Fernanda R. Almeida, Tetyana Kendzerska, Rachel Jen, Stephan F. van Eeden, and Aditi Shah
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2. Zero hunger ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Cell adhesion molecule ,Polysomnogram ,medicine.disease ,Obesity ,Gastroenterology ,respiratory tract diseases ,3. Good health ,Obstructive sleep apnea ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Internal medicine ,Medicine ,Clinical significance ,030212 general & internal medicine ,business ,Cell adhesion ,Body mass index ,Morning - Abstract
To investigate the relationship between obstructive sleep apnea (OSA) severity, body mass index (BMI), and circulating levels of inflammatory adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin). A cross-sectional clinical cohort study on all consecutive adults referred to the University of British Columbia (UBC) Sleep Laboratory for a polysomnogram (PSG) for suspected OSA provided a morning blood sample. Samples were analyzed with multiplex immune assay (MilliporeSigma, CA) to assess the levels of adhesion molecules. 488 patients were studied; the majority were male (68%) with a mean age of 50 yrs, mean AHI of 23 events/hour, and mean BMI of 32 kg/m2. In multivariable linear regression models, all three adhesion molecules were significantly associated with BMI (E-selectin p
- Published
- 2020
11. Lung Macrophages: Pivotal Immune Effector Cells Orchestrating Acute and Chronic Lung Diseases
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Stephan F. van Eeden and Don D. Sin
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respiratory system - Abstract
Macrophages are key immune cells, where they play a pivotal role in host defense and tissue homeostasis. The lungs have two major subsets, alveolar macrophages (AMs) found in airspaces and interstitial macrophages (IMs) found in lung tissues. Lung macrophages (LM) are highly heterogeneous and have high levels of plasticity. A long-lasting population of LM with self-renewal ability populate the lung during embryogenesis and monocyte-derived macrophages recruited during infection, inflammation, or tissue repair, which are more short lived. AMs have been the main focus of research due in part to their abundance, accessibility, and ease of isolation compared with IMs. With advances in multichannel flow cytometry and single-cell sequencing, the importance of IMs has been recently appreciated. LM’s functions in the lungs include maintenance of homoeostasis, immune surveillance, removal of cellular debris, tissue repair, clearance of pathogens, and the resolution of inflammation. They also activate the adaptive immune response by functioning as antigen-presenting cells. LMs are pivotal in the pathogenesis of acute and chronic inflammatory lung conditions including lung cancer. This chapter will discuss the ontology, phenotypic heterogeneity, and functions of LM’s and how these characteristics orchestrate and impact common acute and chronic lung conditions.
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- 2022
12. Immunmodulation bei chronisch-obstruktiver Lungenerkrankung: Aktuelle Konzepte und zukünftige Strategien
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J C Hogg and Stephan F. van Eeden
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Die chronisch-obstruktive Lungenerkrankung (chronic obstructive pulmonary disease, COPD) wird durch das langjährige aktive oder passive Einatmen schädlicher Partikel und Gase (vor allem, aber nicht nur, Zigarettenrauch) verursacht, wodurch es zu einer anhaltenden angeborenen und adaptiven Immunantwort in der Lunge kommt. Diese Immunantwort ist mit einer Störung der Gewebereparatur- und Remodelingprozesse verbunden und führt zu einer chronischen Entzündung mit übermäßiger Schleimproduktion in den zentralen Atemwegen und zu einer dauerhaften Zerstörung der kleinen Atemwege sowie der Gasaustausch-Oberfläche in der peripheren Lunge. Derzeit bestehen die Hauptziele der Behandlung bei COPD in einer Bronchodilatation zur Symptomkontrolle (durch inhalative kurz und lang wirksame β-Agonisten- und antimuskarinische Wirkstoffe) sowie in der Gabe unspezifischer breit wirksamer Entzündungshemmer (wie inhalative und orale Kortikosteroide, Phosphordiesterase-Hemmer und Makrolide). Diese bewirken eine symptomatische Linderung, haben jedoch, wenn überhaupt, nur einen sehr geringen Einfluss auf das Fortschreiten der Erkrankung oder die Mortalität. Mit zunehmendem Verständnis der Immunpathogenese der COPD wurden Immunmodulationstherapien verfügbar, die in der Lage sind, schädliche Immunmechanismen zu verändern oder zu stören, wodurch das unaufhaltsame Fortschreiten der Lungengewebezerstörung verlangsamt wird. In der vorliegenden kurzen Übersichtsarbeit sollen das aktuelle Wissen über die Immunpathogenese sowohl der Atemwegs- als auch der Parenchymschädigung sowie die gestörten Gewebereparaturprozesse erörtert werden, und es werden immunmodulierende Interventionen vorgeschlagen, die versuchen, die pathologischen Veränderungen zu stabilisieren oder in ihren Normalzustand zurückzuversetzen. Ziel der Immunmodulationstherapie ist es letztendlich, die mit der COPD verbundene Morbidität und Mortalität zu senken.
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- 2020
13. Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Influence of Social Factors in Determining Length of Hospital Stay and Readmission Rates
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Alyson WM Wong, Wen Q Gan, Jane Burns, Don D Sin, and Stephan F van Eeden
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Diseases of the respiratory system ,RC705-779 - Abstract
BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the leading reason for hospitalization in Canada and a significant financial burden on hospital resources. Identifying factors that influence the time a patient spends in the hospital and readmission rates will allow for better use of scarce hospital resources.
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- 2008
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14. Effects of Inhaled Corticosteroid/Long-Acting β
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Fernando Sergio, Leitao Filho, Hiroto, Takiguchi, Kentaro, Akata, Seung Won, Ra, Ji-Yong, Moon, Hyun Kuk, Kim, Yuji, Cho, Kei, Yamasaki, Stephen, Milne, Julia, Yang, Cheng Wei Tony, Yang, Xuan, Li, Corey, Nislow, Stephan F, van Eeden, Tawimas, Shaipanich, Stephen, Lam, Janice M, Leung, and Don D, Sin
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Adult ,Aged, 80 and over ,Male ,Microbiota ,Editorials ,Middle Aged ,Drug Combinations ,Pulmonary Disease, Chronic Obstructive ,Treatment Outcome ,Adrenal Cortex Hormones ,Administration, Inhalation ,Humans ,Female ,Receptors, Adrenergic, beta-2 ,Adrenergic beta-2 Receptor Agonists ,Aged - Published
- 2021
15. Oxidative Stress in Chronic Obstructive Pulmonary Disease: A Lung and Systemic Process
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Stephan F Van Eeden and Don D Sin
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Diseases of the respiratory system ,RC705-779 - Published
- 2013
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16. Altered Polarization and Impaired Phagocytic Activity of Lung Macrophages in People With Human Immunodeficiency Virus and Chronic Obstructive Pulmonary Disease
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Chen Xi Yang, Don D. Sin, Fernando Sergio Leitao Filho, Kei Yamasaki, Cheng Wei Tony Yang, Tawimas Shaipanich, Hiroto Takiguchi, Basak Sahin, Julia Yang, Kentaro Akata, Janice M. Leung, Stephan F. van Eeden, and Beth A. Whalen
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Phagocytosis ,Human immunodeficiency virus (HIV) ,Double negative ,medicine.disease_cause ,Pulmonary Disease, Chronic Obstructive ,Macrophages, Alveolar ,medicine ,Immunology and Allergy ,Humans ,Lung ,COPD ,CD40 ,biology ,business.industry ,Macrophages ,HIV ,medicine.disease ,Infectious Diseases ,Increased risk ,medicine.anatomical_structure ,Immunology ,biology.protein ,business ,CD163 - Abstract
Background People with human immunodeficiency virus (PWH) have an increased risk of developing chronic obstructive pulmonary disease (COPD). Methods We phenotyped lung macrophages in 4 subgroups—M1 (CD40+CD163−), M2 (CD40−CD163+), double positives (CD40+CD163+), and double negatives and (CD40−CD163−)—and we determined their phagocytic capacity in PWH with and without COPD. Results People with human immunodeficiency virus with COPD have more double-negative macrophages (84.1%) versus PWH without (54.3%) versus controls (23.9%) (P=.004) and reduced phagocytosis (P=.012). Double-negative macrophages had the worst phagocytic capacity (P Conclusions People with human immunodeficiency virus with COPD have an abundance of nonpolarized macrophages, which have poor phagocytic capacity and therefore predispose PWH to increased risk of disease progression.
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- 2021
17. Macrophages with reduced expressions of classical M1 and M2 surface markers in human bronchoalveolar lavage fluid exhibit pro-inflammatory gene signatures
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Cheng Wei Tony Yang, Beth A. Whalen, Julia Shun Wei Yang, Chen X. Yang, Don D. Sin, Kei Yamasaki, H. Takiguchi, Kelly M. McNagny, Fernando Sergio Leitao Filho, Kentaro Akata, Janice M. Leung, Chung Yan Cheung, Tawimas Shaipanich, Basak Sahin, Ryan Vander Werff, Stephen Milne, Ma'en Obeidat, and Stephan F. van Eeden
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Cell biology ,Science ,Immunology ,Antigens, Differentiation, Myelomonocytic ,Cellular homeostasis ,Diseases ,Receptors, Cell Surface ,Article ,Oxidative Phosphorylation ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,Antigens, CD ,Genetics ,medicine ,Homeostasis ,Humans ,Macrophage ,CD40 Antigens ,Inflammation ,COPD ,Multidisciplinary ,Lung ,CD40 ,medicine.diagnostic_test ,biology ,business.industry ,Macrophages ,medicine.disease ,respiratory tract diseases ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Antigens, Surface ,biology.protein ,Medicine ,business ,Bronchoalveolar Lavage Fluid ,CD163 - Abstract
The 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
- Published
- 2021
18. Relationship between resting heart rate and arterial stiffness in patients with chronic obstructive pulmonary disease: Implications for pulmonary rehabilitation
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W. Darlene Reid, Pat G. Camp, Andrew William Sheel, Stephan F. van Eeden, Ashley Kirkham, Carmen A. Sima, and Ori Benari
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Population ,Pulmonary disease ,Critical Care and Intensive Care Medicine ,medicine.disease ,RESTING HEART RATE ,Internal medicine ,medicine ,Cardiology ,Arterial stiffness ,Pulmonary rehabilitation ,In patient ,business ,education ,Pulse wave velocity - Abstract
RATIONALE: Pulse wave velocity (PWV), as a measure of arterial stiffness, has been shown to be associated with resting heart rate (RHR) in general population studies. Yet, the evidence on this rela...
- Published
- 2019
19. Airway Eosinophilia on Bronchoalveolar Lavage and the Risk of Exacerbations in COPD
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Chunman Germain Ho, Stephen Milne, Xuan Li, Chen Xi Yang, Fernando Sergio Leitao Filho, Chung Yan Cheung, Julia Shun Wei Yang, Ana I Hernández Cordero, Cheng Wei Tony Yang, Tawimas Shaipanich, Stephan F van Eeden, Janice M Leung, Stephen Lam, and Don D Sin
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biomarkers ,chronic obstructive pulmonary disease ,eosinophilia ,bronchoscopy ,Medicine (miscellaneous) ,respiratory system ,General Biochemistry, Genetics and Molecular Biology ,respiratory tract diseases - Abstract
The associations between airway eosinophilia, measured in sputum or peripheral blood, and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are inconsistent. We therefore aimed to determine the association between eosinophilia in bronchoalveolar lavage (BAL) fluid and AECOPD in a clinical cohort. We analyzed differential cell counts from baseline BAL fluid in participants in the DISARM clinical trial (Clinicaltrials.gov #NCT02833480) and classified participants by the presence or absence of BAL eosinophilia (>1% of total leukocytes). We determined the association between BAL eosinophilia and AECOPD over 1 year of follow-up using negative binomial regression and Cox proportional hazards test. N = 63 participants were randomized, and N = 57 had BAL differential cell counts available. Participants with BAL eosinophilia (N = 21) had a significantly increased rate of acute exacerbations (unadjusted incidence rate ratio (IRR) 2.0, p = 0.048; adjusted IRR 2.24, p = 0.04) and a trend toward greater probability of acute exacerbation (unadjusted hazard ratio (HR) 1.74, p = 0.13; adjusted HR 2.3, p = 0.1) in the year of follow-up compared to participants without BAL eosinophilia (N = 36). These associations were not observed for BAL neutrophilia (N = 41 participants), BAL lymphocytosis (N = 27 participants) or peripheral blood eosinophilia at various threshold definitions (2%, N = 37; 3%, N = 27; 4%, N = 16). BAL may therefore be a sensitive marker of eosinophilic inflammation in the distal lung and may be of benefit for risk stratification or biomarker-guided therapy in COPD.
- Published
- 2022
20. Inhaled corticosteroids downregulate SARS-CoV-2-related genes in COPD: results from a randomised controlled trial
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Cheng Wei Tony Yang, Janice M. Leung, Don D. Sin, Tawimas Shaipanich, Chen Xi Yang, Stephen Milne, Ana I. Hernández Cordero, Fernando Sergio Leitao Filho, Xuan Li, Stephen Lam, and Stephan F. van Eeden
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,law.invention ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Immune system ,Randomized controlled trial ,Downregulation and upregulation ,law ,Adrenal Cortex Hormones ,Internal medicine ,Administration, Inhalation ,medicine ,Research Letter ,Humans ,030212 general & internal medicine ,Gene ,1102 Cardiorespiratory Medicine and Haematology ,11 Medical and Health Sciences ,COPD ,business.industry ,SARS-CoV-2 ,Bacterial pneumonia ,COVID-19 ,respiratory system ,medicine.disease ,respiratory tract diseases ,Coronavirus ,030228 respiratory system ,Airway ,business - Abstract
Observational studies show that chronic obstructive pulmonary disease (COPD) is associated with increased COVID-19 severity and mortality [1]. Inhaled corticosteroids (ICS), which are commonly used to treat COPD, have been associated with increased risk of bacterial pneumonia in COPD and impaired immune response to viruses. Whether this class of medication affects the airway expression of SARS-CoV-2 receptors and cofactors – changes which may modify COVID-19 susceptibility and outcomes – is currently unclear. We therefore examined the effects of ICS treatment on SARS-CoV-2-related gene expression in lower airway bronchial epithelial cells (BECs) in a randomised controlled trial of COPD patients. Acknowledgments: The authors would like to thank the generous fundraising and donation efforts by Irving Ding and Mrs. Chun Hong Tao to St. Paul's Foundation COVID-19 Response Fund. We are grateful to Mr Ryan Vander Werff and Ms Tara Stach at BRC-Seq for conducting the RNA sequencing; and Dr Chung Cheung and Ms Julia Yang for their assistance with laboratory specimens.
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- 2021
21. Obstructive Sleep Apnea Severity, Body Mass Index, and Circulating Levels of Cellular Adhesion Molecules
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Bernardo U, Peres, A J Hirsch, Allen, Tetyana, Kendzerska, Aditi, Shah, Nurit, Fox, Ismail, Laher, Fernanda, Almeida, Rachel, Jen, Andrew J, Sandford, Stephan F, van Eeden, and Najib T, Ayas
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Adult ,Male ,Sleep Apnea, Obstructive ,Polysomnography ,Vascular Cell Adhesion Molecule-1 ,Middle Aged ,Intercellular Adhesion Molecule-1 ,Severity of Illness Index ,Body Mass Index ,Cohort Studies ,Cross-Sectional Studies ,Linear Models ,Humans ,Female ,Obesity ,E-Selectin - Abstract
To investigate the relationship between obstructive sleep apnea (OSA) severity, body mass index (BMI), and circulating levels of inflammatory adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin).A cross-sectional clinical cohort study on all consecutive adults referred to the University of British Columbia (UBC) Sleep Laboratory for a polysomnogram (PSG) for suspected OSA provided a morning blood sample. Samples were analyzed with multiplex immune assay (MilliporeSigma, CA) to assess the levels of adhesion molecules.488 patients were studied; the majority were male (68%) with a mean age of 50 yrs, mean AHI of 23 events/hour, and mean BMI of 32 kg/mAlthough all three adhesion molecules were associated with BMI, only E-selectin was independently associated with OSA severity. Future studies are needed to determine the clinical significance of the relationship between E-selectin and OSA.
- Published
- 2020
22. Macrophages-the immune effector guardians of the lung: impact of corticosteroids on their functional responses
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Kentaro Akata and Stephan F. van Eeden
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0301 basic medicine ,Male ,Immunology & Inflammation ,Neutrophils ,Apoptosis ,Disease ,Dexamethasone ,corticosteroids ,Pathogenesis ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Adrenal Cortex Hormones ,Macrophage ,Lung ,Cells, Cultured ,COPD ,General Medicine ,Middle Aged ,Phenotype ,macrophages ,medicine.anatomical_structure ,Female ,Signal Transduction ,Iron ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,03 medical and health sciences ,Antigens, CD ,Commentaries ,Macrophages, Alveolar ,medicine ,Humans ,Aged ,Immune effector ,c-Mer Tyrosine Kinase ,business.industry ,Receptors, IgG ,medicine.disease ,Coculture Techniques ,respiratory tract diseases ,Pneumonia ,030104 developmental biology ,030228 respiratory system ,Gene Expression Regulation ,Case-Control Studies ,Immunology ,business - Abstract
The numbers of macrophages are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. COPD lung macrophages have reduced ability to phagocytose microbes and efferocytose apoptotic cells. Inhaled corticosteroids (ICSs) are widely used anti-inflammatory drugs in COPD; however, their role beyond suppression of cytokine release has not been explored in COPD macrophages. We have examined the effects of corticosteroids on COPD lung macrophage phenotype and function. Lung macrophages from controls and COPD patients were treated with corticosteroids; effects on gene and protein expression of CD163, CD164, CD206, MERTK, CD64, CD80 and CD86 were studied. We also examined the effect of corticosteroids on the function of CD163, MERTK and cluster of differentiation 64 (CD64). Corticosteroid increased CD163, CD164, CD206 and MERTK expression and reduced CD64, CD80 and CD86 expression. We also observed an increase in the uptake of the haemoglobin-haptoglobin complex (CD163) from 59 up to 81% and an increase in efferocytosis of apoptotic neutrophils (MERTK) from 15 up to 28% following corticosteroid treatment. We observed no effect on bacterial phagocytosis. Corticosteroids alter the phenotype and function of COPD lung macrophages. Our findings suggest mechanisms by which corticosteroids exert therapeutic benefit in COPD, reducing iron available for bacterial growth and enhancing efferocytosis.
- Published
- 2020
23. Myocardial Infarction Injury in Patients with Chronic Lung Disease Entering Pulmonary Rehabilitation: Frequency and Association with Heart Rate Parameters
- Author
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Benny Lau, Pat G. Camp, Stephan F. van Eeden, Andrew William Sheel, W. Darlene Reid, Carolyn Taylor, Carmen A. Sima, and Ashley Kirkham
- Subjects
Lung Diseases ,Male ,Chronotropic ,medicine.medical_specialty ,Outpatient Clinics, Hospital ,medicine.medical_treatment ,Myocardial Infarction ,Physical Therapy, Sports Therapy and Rehabilitation ,030204 cardiovascular system & hematology ,Rehabilitation Centers ,Electrocardiography ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Internal medicine ,Heart rate ,medicine ,Humans ,Outpatient clinic ,Pulmonary rehabilitation ,Myocardial infarction ,Aged ,Retrospective Studies ,Rehabilitation ,business.industry ,Retrospective cohort study ,Evidence-based medicine ,Middle Aged ,Prognosis ,medicine.disease ,030228 respiratory system ,Neurology ,Chronic Disease ,Exercise Test ,Cardiology ,Female ,Neurology (clinical) ,business ,Follow-Up Studies - Abstract
Myocardial infarction (MI) remains under-recognized in chronic lung disease (CLD) patients. Rehabilitation health professionals need accessible clinical measurements to identify the presence of prior MI in order to determine appropriate training prescription.To estimate prior MI in CLD patients entering a pulmonary rehabilitation program, as well as its association with heart rate parameters such as resting heart rate and chronotropic response index.Retrospective cohort design.Pulmonary rehabilitation outpatient clinic in a tertiary care university-affiliated hospital.Eighty-five CLD patients were studied.Electrocardiograms at rest and peak cardiopulmonary exercise testing, performed before pulmonary rehabilitation, were analyzed. Electrocardiographic evidence of prior MI, quantified by the Cardiac Infarction Injury Score (CIIS), was contrasted with reported myocardial events and then correlated with resting heart rate and chronotropic response index parameters.CIIS, resting heart rate, and chronotropic response index.Sixteen CLD patients (19%) demonstrated electrocardiographic evidence of prior MI, but less than half (8%) had a reported MI history (P.05). The Cohen's kappa test revealed poor level of agreement between CIIS and medical records (kappa = 0.165), indicating that prior MI diagnosis was under-reported in the medical records. Simple and multiple regression analyses showed that resting heart rate but not chronotropic response index was positively associated with CIIS in our population (RCLD patients entering pulmonary rehabilitation are at risk of unreported prior MI. Elevated resting heart rate appears to be an indicator of prior MI in CLD patients; therefore, careful adjustment of training intensity is recommended under these circumstances.III.
- Published
- 2018
24. Letter from Canada: A pandemic that has humbled us?
- Author
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Stephan F. van Eeden
- Subjects
Pulmonary and Respiratory Medicine ,Canada ,long‐term care facilities ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,COVID‐19 ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pandemic ,Letter from Asia‐Pacific and Beyond ,Medicine ,business ,Virology - Published
- 2021
25. Circulating levels of cell adhesion molecules and risk of cardiovascular events in obstructive sleep apnea
- Author
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Karin H. Humphries, Najib T. Ayas, Andrew J. Sandford, Carolyn Taylor, A J Hirsch Allen, Fernanda R. Almeida, Ismail Laher, Stephan F. van Eeden, Rachel Jen, Patrick Daniele, and Bernardo U Peres
- Subjects
Pulmonology ,Epidemiology ,Apnea ,Polysomnogram ,Myocardial Infarction ,Disease ,Cardiovascular Medicine ,030204 cardiovascular system & hematology ,Medical Conditions ,0302 clinical medicine ,Medicine and Health Sciences ,Myocardial infarction ,Immune Response ,Sleep Apnea, Obstructive ,Multidisciplinary ,Cell adhesion molecule ,Fasting ,Middle Aged ,Neurology ,Cardiovascular Diseases ,Cohort ,Medicine ,Research Article ,Adult ,medicine.medical_specialty ,Sleep Apnea ,Adhesion Molecules ,Science ,Immunology ,Cardiology ,Respiratory Disorders ,03 medical and health sciences ,Signs and Symptoms ,Diabetes mellitus ,Internal medicine ,Cell Adhesion ,medicine ,Humans ,Inflammation ,business.industry ,Biology and Life Sciences ,Cell Biology ,Plasma levels ,Molecular Development ,Cardiovascular Disease Risk ,medicine.disease ,respiratory tract diseases ,Obstructive sleep apnea ,030228 respiratory system ,Medical Risk Factors ,Clinical Medicine ,Sleep Disorders ,business ,Cell Adhesion Molecules ,Follow-Up Studies ,Developmental Biology - Abstract
Background Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the development of CVD. Research question Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA? Study design and methods Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases. Results 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m2. 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40–9.53, 2nd and 3rd tertiles vs. 1st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16–8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94–11.72, 2nd and 3rd tertiles vs. 1st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19–2.38), p-value for interaction = 0.07. Interpretation In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events.
- Published
- 2021
26. Air Pollution and Systemic Inflammation in Patients With Suspected OSA Living in an Urban Residential Area
- Author
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Nurit Fox, Christopher Carlsten, A J Hirsch Allen, Najib T. Ayas, Stephan F. van Eeden, Tetyana Kendzerska, Michael Brauer, Cheryl R. Laratta, and Bernardo U Peres
- Subjects
Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Polysomnogram ,Polysomnography ,Critical Care and Intensive Care Medicine ,Systemic inflammation ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,Air Pollution ,medicine ,Humans ,030212 general & internal medicine ,Morning ,Aged ,Inflammation ,Sleep Apnea, Obstructive ,medicine.diagnostic_test ,business.industry ,Interleukin-6 ,Urban Health ,Middle Aged ,medicine.disease ,Interleukin-10 ,Obstructive sleep apnea ,030228 respiratory system ,Apnea–hypopnea index ,Quartile ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Air pollution and OSA are independently associated with systemic inflammation, but it is unknown if these exposures interact to influence systemic inflammation. Research Question The study objective was to determine the relative importance of these factors and their combined potential to influence systemic inflammation in patients under assessment for sleep ailments. Study Design and Methods A total of 315 patients contributed data, including a questionnaire, polysomnogram, and morning serum IL-6 and IL-10 concentrations. For each patient, residential annual average air pollution exposure (nitrogen dioxide [NO2], black carbon [BC], and particulate matter with an aerodynamic diameter ≤ 2.5 μm [PM2.5]) was estimated with a land use regression model. Linear regression modeling was used adjusting for age, sex, apnea-hypopnea index, BMI, smoking, socioeconomic status, and comorbidities. Results In adjusted models, quartile 4 PM2.5 exposure (compared with quartiles 1-3) was associated with increased IL-6 and IL-10 concentrations (estimated adjusted, 7.1 pg/mL [95% CI, 2.5-11.7; P Interpretation Long-term residential PM2.5 exposure was associated with increased IL-6 and IL-10 concentrations in patients evaluated for suspected OSA. BC exposure was also associated with increased IL-6 but only in the subgroup of patients with moderate to severe OSA. These data suggest the potential for joint effects of moderate to severe OSA and air pollution on systemic inflammation.
- Published
- 2019
27. Immune-Modulation in Chronic Obstructive Pulmonary Disease: Current Concepts and Future Strategies
- Author
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James C. Hogg and Stephan F. van Eeden
- Subjects
Pulmonary and Respiratory Medicine ,COPD ,Lung ,Inhalation ,business.industry ,Inflammation ,medicine.disease ,Acquired immune system ,Symptomatic relief ,Pathogenesis ,Immunomodulation ,Pulmonary Disease, Chronic Obstructive ,medicine.anatomical_structure ,Immune system ,Immunology ,Medicine ,Humans ,medicine.symptom ,business - Abstract
Chronic obstructive pulmonary disease (COPD) is caused by the chronic inhalation of toxic particles and gases that are primarily but not exclusively derived from cigarette smoke that may be either actively or passively inhaled, which initiates a persistent innate and adaptive immune response in the lung. This immune response is associated with an aberrant tissue repair and remodeling process that results in varying degrees of chronic inflammation with excess production of mucus in the central airways and permanent destruction of the smaller conducting airways and gas exchanging surface in the peripheral lung. Currently, the primary aims of treatment in COPD are bronchodilation (inhaled short- and long-acting β-agonist and antimuscarinic therapies), to control symptoms and nonspecific broad-acting anti-inflammatory agents (inhaled and oral corticosteroids, phosphor-di-esterase inhibitors, and macrolides). That provide symptomatic relief but have little or no impact on either disease progression or mortality. As our understanding of the immune pathogenesis of the COPD improves, available immune modulation therapies have the potential to alter or interfere with damaging immune pathways, thereby slowing relentless progression of lung tissue destruction. The purpose of this brief review is to discuss our current understanding of the immune pathogenesis of both the airways and parenchymal injury as well as the dysfunctional tissue repair process to propose immune modulating interventions in an attempt to stabilize or return these pathological changes to their normal state. The ultimate goal of the immune modulation therapy is to improve both morbidity and mortality associated with COPD.
- Published
- 2019
28. Adhesion molecule gene variants and plasma protein levels in patients with suspected obstructive sleep apnea
- Author
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Loubna Akhabir, Simon C. Warby, Amanda Ha, Aabida Saferali, Nurit Fox, Stephan F. van Eeden, A J Hirsch Allen, David A. Ngan, Andrew J. Sandford, and Najib T. Ayas
- Subjects
0301 basic medicine ,Male ,Heredity ,Pulmonology ,Genotyping Techniques ,Apnea ,Physiology ,Epidemiology ,Disease ,030204 cardiovascular system & hematology ,030105 genetics & heredity ,Cardiovascular Medicine ,Gastroenterology ,0302 clinical medicine ,Blood plasma ,Medicine and Health Sciences ,Sleep Apnea, Obstructive ,Multidisciplinary ,Cell adhesion molecule ,Sleep apnea ,Blood Proteins ,Middle Aged ,Intercellular Adhesion Molecule-1 ,3. Good health ,Body Fluids ,Genetic Mapping ,Blood ,Neurology ,Cardiovascular Diseases ,Medicine ,Regression Analysis ,Female ,Anatomy ,E-Selectin ,Research Article ,Adult ,medicine.medical_specialty ,Genotyping ,Sleep Apnea ,Science ,Polysomnography ,Vascular Cell Adhesion Molecule-1 ,Variant Genotypes ,Research and Analysis Methods ,Blood Plasma ,Ethnic Epidemiology ,03 medical and health sciences ,ABO blood group system ,Internal medicine ,medicine ,Genetics ,Humans ,Allele ,Molecular Biology Techniques ,Molecular Biology ,business.industry ,Biology and Life Sciences ,Human Genetics ,medicine.disease ,Obstructive sleep apnea ,Multivariate Analysis ,business ,Sleep Disorders ,Blood Groups - Abstract
Study objectivesUntreated obstructive sleep apnea (OSA) patients have an increased risk of cardiovascular disease (CVD). Adhesion molecules, including soluble E-selectin (sE-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1), are associated with incident CVD. We hypothesized that specific genetic variants will be associated with plasma levels of adhesion molecules in suspected OSA patients. We also hypothesized that there may be an interaction between these variants and OSA.MethodsWe measured levels of sE-selectin, sICAM-1 and sVCAM-1 in 491 patients with suspected OSA and genotyped them for 20 polymorphisms.ResultsThe most significant association was between the ABO rs579459 polymorphism and sE-selectin levels (P = 7×10-21), with the major allele T associated with higher levels. The direction of effect and proportion of the variance in sE-selectin levels accounted for by rs579459 (16%) was consistent with estimates from non-OSA cohorts. In a multivariate regression analysis, addition of rs579459 improved the model performance in predicting sE-selectin levels. Three polymorphisms were nominally associated with sICAM-1 levels but none with sVCAM-1 levels. The combination of severe OSA and two rs579459 T alleles identified a group of patients with high sE-selectin levels; however, the increase in sE-selectin levels associated with severe OSA was greater in patients without two T alleles (P = 0.05 test for interaction).ConclusionsThese genetic polymorphisms may help to identify patients at greatest risk of incident CVD and may help in developing a more precision-based approach to OSA care.
- Published
- 2019
29. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease: factors predicting readmission
- Author
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Stephan F. van Eeden, Don D. Sin, Simon L. Adamson, Lisa Leung, and Wiebke Bartels
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Pulmonary disease ,International Journal of Chronic Obstructive Pulmonary Disease ,Patient Readmission ,readmissions ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,cardiovascular disease ,Forced Expiratory Volume ,Internal medicine ,substance abuse ,medicine ,COPD ,Humans ,In patient ,030212 general & internal medicine ,Poisson regression ,Original Research ,Aged ,Retrospective Studies ,British Columbia ,business.industry ,Retrospective cohort study ,General Medicine ,Emergency department ,Middle Aged ,medicine.disease ,Readmission rate ,mental illness ,Substance abuse ,030228 respiratory system ,Disease Progression ,symbols ,Regression Analysis ,Female ,Triage ,Emergency Service, Hospital ,business - Abstract
Wiebke Bartels, Simon Adamson, Lisa Leung, Don D Sin, Stephan F van Eeden Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, BC, Canada Rationale: Readmissions are common following acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and are partially responsible for increased morbidity and mortality in COPD. Numerous factors have been shown to predict readmission of patients previously admitted to hospital for AECOPD; however, factors related to readmission in patients who are triaged in emergency departments (EDs) and sent directly home are poorly understood. We postulate that patients seen in the ED for AECOPD and directly sent home have a high readmission rate, and we suspect that inadequate management and follow-up contribute to this high readmission rate. Methods: We conducted a 1-year retrospective study of all patients seen in the ED for AECOPD at an inner-city tertiary care hospital; 30- and 90-day readmission rates for COPD and all-cause admissions to the ED and hospital were determined. Patients discharged directly home from the ED were compared with those admitted to hospital for management. Patient, treatment, and system variables that could potentially impact readmission were documented. Multivariate Poisson regression models were used to determine which factors predicted readmissions. Results: The readmission rates in the ED group (n=240) were significantly higher than that in the hospitalized group (n=271): 1) the 90-day ED readmissions (1.29 vs 0.51, p
- Published
- 2018
30. Lung Macrophage Phenotypes and Functional Responses: Role in the Pathogenesis of COPD
- Author
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Stephan F. van Eeden and Kei Yamasaki
- Subjects
0301 basic medicine ,Inflammation ,Review ,Biology ,Adaptive Immunity ,Catalysis ,Monocytes ,chronic obstructive pulmonary disease ,lcsh:Chemistry ,Inorganic Chemistry ,Pathogenesis ,lung macrophage phenotypes ,phagocytic function of macrophage ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,Immune system ,Phagocytosis ,Macrophages, Alveolar ,medicine ,Macrophage ,Humans ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Lung ,Spectroscopy ,COPD ,Organic Chemistry ,Smoking ,General Medicine ,medicine.disease ,Acquired immune system ,Phenotype ,Immunity, Innate ,3. Good health ,Computer Science Applications ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,Immunology ,medicine.symptom - Abstract
Lung macrophages (LMs) are essential immune effector cells that are pivotal in both innate and adaptive immune responses to inhaled foreign matter. They either reside within the airways and lung tissues (from early life) or are derived from blood monocytes. Similar to macrophages in other organs and tissues, LMs have natural plasticity and can change phenotype and function depending largely on the microenvironment they reside in. Phenotype changes in lung tissue macrophages have been implicated in chronic inflammatory responses and disease progression of various chronic lung diseases, including Chronic Obstructive Pulmonary Disease (COPD). LMs have a wide variety of functional properties that include phagocytosis (inorganic particulate matter and organic particles, such as viruses/bacteria/fungi), the processing of phagocytosed material, and the production of signaling mediators. Functioning as janitors of the airways, they also play a key role in removing dead and dying cells, as well as cell debris (efferocytic functions). We herein review changes in LM phenotypes during chronic lung disease, focusing on COPD, as well as changes in their functional properties as a result of such shifts. Targeting molecular pathways involved in LM phenotypic shifts could potentially allow for future targeted therapeutic interventions in several diseases, such as COPD.
- Published
- 2018
31. The impacts of traffic-related and woodsmoke particulate matter on measures of cardiovascular health: a HEPA filter intervention study
- Author
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Stephan F. van Eeden, Michael Brauer, Christopher Carlsten, Barbara Karlen, Majid Kajbafzadeh, and Ryan W. Allen
- Subjects
Adult ,Male ,Air pollution ,medicine.disease_cause ,Systemic inflammation ,Article ,Young Adult ,HEPA ,Smoke ,Environmental health ,medicine ,Humans ,Aged ,Vehicle Emissions ,Inflammation ,Inhalation exposure ,Air Pollutants ,Inhalation Exposure ,Cross-Over Studies ,British Columbia ,biology ,Interleukin-6 ,business.industry ,C-reactive protein ,Public Health, Environmental and Occupational Health ,Endothelial Cells ,Middle Aged ,Particulates ,Wood ,Intervention studies ,Motor Vehicles ,C-Reactive Protein ,Cardiovascular Diseases ,Air Pollution, Indoor ,biology.protein ,Female ,Particulate Matter ,medicine.symptom ,business ,Biomarkers ,Filtration - Abstract
Background Combustion-generated fine particulate matter (PM 2.5 ) is associated with cardiovascular morbidity. Both traffic-related air pollution and residential wood combustion may be important, but few studies have compared their impacts. Objectives To assess and compare effects of traffic-related and woodsmoke PM 2.5 on endothelial function and systemic inflammation (C reactive protein, interleukin-6 and band cells) among healthy adults in Vancouver, British Columbia, Canada, using high efficiency particulate air (HEPA) filtration to introduce indoor PM 2.5 exposure gradients. Methods We recruited 83 healthy adults from 44 homes in traffic-impacted or woodsmoke-impacted areas to participate in this randomised, single-blind cross-over intervention study. PM 2.5 concentrations were measured during two consecutive 7-day periods, one with filtration and the other with ‘placebo filtration’. Endothelial function and biomarkers of systematic inflammation were measured at the end of each 7-day period. Results HEPA filtration was associated with a 40% decrease in indoor PM 2.5 concentrations. There was no relationship between PM 2.5 exposure and endothelial function. There was evidence of an association between indoor PM 2.5 and C reactive protein among those in traffic-impacted locations (42.1% increase in C reactive protein per IQR increase in indoor PM 2.5 , 95% CI 1.2% to 99.5%), but not among those in woodsmoke-impacted locations. There were no associations with interleukin-6 or band cells. Conclusions Evidence of an association between C reactive protein and indoor PM 2.5 among healthy adults in traffic-impacted areas is consistent with the hypothesis that traffic-related particles, even at relatively low concentrations, play an important role in the cardiovascular effects of the urban PM mixture. Trial registration number http://www.clinicaltrials.gov (NCT01570062).
- Published
- 2015
32. Impact of a COPD comprehensive case management program on hospital length of stay and readmission rates
- Author
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Jeremy Road, Abdulmajeed Alshabanat, Don D. Sin, Michael Otterstatter, Carmen Rempel, Stephan F. van Eeden, Jane Burns, and JM FitzGerald
- Subjects
Male ,medicine.medical_specialty ,Poor prognosis ,Time Factors ,Length of hospitalization ,International Journal of Chronic Obstructive Pulmonary Disease ,Patient Readmission ,Social burden ,Patient Care Planning ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Quality of life (healthcare) ,Health care ,medicine ,COPD ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Original Research ,Aged ,Retrospective Studies ,Aged, 80 and over ,CCP ,British Columbia ,business.industry ,readmission ,Delivery of Health Care, Integrated ,General Medicine ,Length of Stay ,Middle Aged ,Case management ,medicine.disease ,respiratory tract diseases ,Treatment Outcome ,030228 respiratory system ,admission ,Emergency medicine ,Female ,Health Services Research ,business ,Program Evaluation - Abstract
Abdulmajeed Alshabanat,1 Michael C Otterstatter,2,3 Don D Sin,4,5 Jeremy Road,5,6 Carmen Rempel,6 Jane Burns,6 Stephan F van Eeden,4,5 JM FitzGerald5–7 On behalf of the COPD Transition Team Program 1Department of Experimental Medicine, University of British Columbia, 2British Columbia Centre for Disease Control, 3School of Population and Public Health, 4Department of Medicine, Centre for Heart Lung Innovation, St Paul’s Hospital, 5Division of Respirology, Department of Medicine, 6Department of Medicine, Faculty of Medicine, Institute for Heart and Lung Health, University of British Columbia, 7Centre for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Institute, Vancouver, BC, Canada Background: COPD accounts for the highest rate of hospital admissions among major chronic diseases. COPD hospitalizations are associated with impaired quality of life, high health care utilization, and poor prognosis and result in an economic and a social burden that is both substantial and increasing.Aim: The aim of this study is to determine the efficacy of a comprehensive case management program (CCMP) in reducing length of stay (LOS) and risk of hospital admissions and readmissions in patients with COPD.Materials and methodology: We retrospectively compared outcomes across five large hospitals in Vancouver, BC, Canada, following the implementation of a systems approach to the management of COPD patients who were identified in the hospital and followed up in the community for 90days. We compared numbers, rates, and intervals of readmission and LOS during 2years of active program delivery compared to 1year prior to program implementation.Results: A total of 1,564 patients with a clinical diagnosis of COPD were identified from 2,719 hospital admissions during the 3years of study. The disease management program reduced COPD-related hospitalizations by 30% and hospitalizations for all causes by 13.6%. Similarly, the rate of readmission for all causes showed a significant decline, with hazard ratios (HRs) of 0.55 (year 1) and 0.51 (year 2) of intervention (P
- Published
- 2017
33. Systemic and vascular effects of circulating diesel exhaust particulate matter
- Author
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Ni Bai and Stephan F. van Eeden
- Subjects
Pathology ,medicine.medical_specialty ,Diesel exhaust ,Health, Toxicology and Mutagenesis ,Aorta, Thoracic ,Pharmacology ,Toxicology ,Proinflammatory cytokine ,Leukocyte Count ,Mice ,medicine.artery ,medicine ,Animals ,Peripheral blood cell ,Lung ,Phenylephrine ,Vehicle Emissions ,Air Pollutants ,Aorta ,Chemistry ,Myocardium ,Diesel Exhaust Particulate ,Mice, Inbred C57BL ,Liver ,Cytokines ,Particulate Matter ,Sodium nitroprusside ,Spleen ,Granulocytes ,medicine.drug ,Myograph - Abstract
Numerous studies have found an association between transiently increased particulate matter air pollution and acute adverse cardiovascular health effects; however, the mechanisms underlying these effects are not clear. Translocation of ultra-fine ambient particulate matter has been proposed to play a key role in these acute side effects. This study was designed to determine the contribution of circulating (translocated) diesel exhaust particles (DEPs) to the systemic and vascular effects.C57 mice (10-week) received intravenous DEPs via tail vein injection. Following 1-h post-injection, inflammatory cytokines (IL-1β, IL-6 and TNF-α), peripheral blood cell counts, band cell counts, aortic endothelial function and vascular constriction were assessed. Thoracic aortae were isolated, and endothelial function was examined by measuring acetylcholine (ACh) and sodium nitroprusside (SNP)-stimulated vascular relaxation using a wire myograph. In addition, phenylephrine (PE)-stimulated vasoconstriction was also measured. The amount of DEPs deposited and trapped in tissues (the spleen, liver, lungs and heart) were quantified.Acute systemic DEP exposure caused a significant increase in TNF-α, peripheral neutrophil and band cell counts. ACh and SNP-induced relaxation were not affected by acute systemic DEP exposure, neither was PE-stimulated constriction. There was a significantly increased DEP deposition in the spleen as well as in the liver. No significantly increased DEPs were detected in the lung and heart.Here we show that circulating DEPs induce a systemic response characterized by increased TNF-α, peripheral granulocytes, but does not impact endothelial function. Our study also suggests that circulating particles are rapidly removed from the circulation and predominantly sequestered in the spleen and liver.
- Published
- 2013
34. Contribution of Lung Macrophages to the Inflammatory Responses Induced by Exposure to Air Pollutants
- Author
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Stephan F. van Eeden and Kunihiko Hiraiwa
- Subjects
Immunology ,Large population ,Apoptosis ,Review Article ,Biology ,Proinflammatory cytokine ,Ozone ,Phagocytosis ,Air pollutants ,Bone Marrow ,Air Pollution ,Macrophages, Alveolar ,lcsh:Pathology ,medicine ,Animals ,Humans ,Particle Size ,Lung ,Inflammation ,Air Pollutants ,Inhalation ,Acute-phase protein ,Cell Biology ,Particulates ,Phenotype ,medicine.anatomical_structure ,Cytokines ,Bone marrow ,lcsh:RB1-214 - Abstract
Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants.
- Published
- 2013
35. Vascular Risk in Chronic Obstructive Pulmonary Disease: Role of Inflammation and Other Mediators
- Author
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Don D. Sin, S. F. Paul Man, and Stephan F. van Eeden
- Subjects
COPD ,medicine.medical_specialty ,Lung ,Respiratory tract infections ,business.industry ,Pulmonary disease ,Inflammation ,Disease ,Vascular risk ,medicine.disease ,Tobacco smoke ,respiratory tract diseases ,medicine.anatomical_structure ,Internal medicine ,medicine ,Physical therapy ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition that affects 3 million adult Canadians aged 40 years or older. Most patients have mild to moderate disease and as such have only modest symptoms of cough and breathlessness. However, many will go on to experience ischemic heart disease and stroke and die of cardiovascular complications rather than from their lung disease. Indeed, nearly 50% of all hospitalizations and 25% of all deaths in patients with mild to moderate COPD are cardiovascular system related. Experimental and epidemiologic data from the past 20 years provide compelling evidence that chronic lung inflammation (related to COPD or exposure to irritants such as tobacco smoke or air pollution) contributes to atherosclerotic plaque progression and that acute inflammatory stimulus such as acute respiratory tract infections or acute exacerbations of COPD induce plaque rupture, leading to cardiovascular events. In this paper, we provide an overview of the epidemiologic and experimental data linking COPD with cardiovascular disease and highlight the clinical implications of this linkage for clinicians who evaluate and manage patients with COPD, cardiovascular diseases, or both.
- Published
- 2012
36. The Relationship between Lung Inflammation and Cardiovascular Disease
- Author
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Jonathon Leipsic, S. F. Paul Man, Don D. Sin, and Stephan F. van Eeden
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,COPD ,Lung ,business.industry ,Inflammation ,Disease ,Critical Care and Intensive Care Medicine ,medicine.disease ,medicine.anatomical_structure ,Internal medicine ,Epidemiology ,Immunology ,medicine ,Cardiology ,Cigarette smoke ,Animal studies ,medicine.symptom ,Risk factor ,business - Abstract
Acute and chronic lung inflammation is an underrecognized risk factor for cardiovascular disease. Yet, there are compelling epidemiological data to indicate that airway exposures to cigarette smoke, air pollution particles, and viral and bacterial pathogens are strongly related to acute ischemic events. Over the past 10 years, there have been important human and animal studies that have provided experimental evidence to support a causal link. In this article, we review the epidemiological data for the relationship between lung inflammation and cardiovascular disease and provide plausible mechanistic pathways by which acute and chronic inflammation contributes to the development of acute cardiovascular syndromes.
- Published
- 2012
37. Assemblée annuelle commune / Gemeinsame Jahresversammlung
- Author
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Stephan F. van Eeden, Antoine Khalil, Gustavo Juan, Joran Holtman, Rui-e Feng, Teresa Peiró, Don D. Sin, Hong-rui Liu, Javier Milara, Winfried Randerath, Charles Mayaud, Charlotte Ringsted, Wouter D. van Dijk, Druck Reinhardt Druck Basel, Muriel Fartoukh, Gerhard Schultze-Werninghaus, Grigoris Stratakos, Lars Konge, Markus P. Radsak, Konrad E. Bloch, Joke Grootens, Reinier Akkermans, Arnoldus J. R. van Gestel, Jacques Cadranel, Ana Montes-Worboys, Thomas Brack, Sebastian Teschler, Christian von Buchwald, Marie-France Carette, Rasih Yazkan, Chris van Weel, Babak Khoshnood, Helmut Teschler, Gene L. Colice, Christian Taube, Roland Buhl, Adela Serrano, Tjard Schermer, Jörg Steier, Annabelle Stoclin, Yvonne F. Heijdra, Francisco Rodriguez-Panadero, İbrahim Metin Çiriş, Antoine Parrot, Irmgard Borg, Malcolm Kohler, Quan-cai Cui, Gernot Rohde, Pierre-Yves Ancel, Erich W. Russi, Julio Cortijo, Satz Mengensatzproduktion, Klaus Richter Larsen, Henrik Arendrup, Chun-kai Yu, Jacques W.M. Lenders, and Paul Frost Clementsen
- Subjects
Pulmonary and Respiratory Medicine ,business.industry ,Medicine ,business ,Humanities - Published
- 2012
38. Patterns of Retention of Particulate Matter in Lung Tissues of Patients With COPD
- Author
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James C. Hogg, Sean H. Ling, W. Mark Elliott, John E. McDonough, Stephan F. van Eeden, Shizu Hayashi, and John V. Gosselink
- Subjects
Pulmonary and Respiratory Medicine ,COPD ,Pathology ,medicine.medical_specialty ,Lung ,medicine.diagnostic_test ,business.industry ,Case-control study ,respiratory system ,Critical Care and Intensive Care Medicine ,medicine.disease ,Obstructive lung disease ,respiratory tract diseases ,medicine.anatomical_structure ,Parenchyma ,Severity of illness ,Biopsy ,medicine ,Immunohistochemistry ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Particulate matter (PM) is present in lung tissues of smokers and urban dwellers. This study was designed to quantify the burden of PM in different lung tissues of subjects with COPD and determine its relationship to disease severity. Methods Surgical lung tissue samples from nonsmokers (control subjects) were compared with those from smokers with normal spirometry and subjects in the four other categories of the GOLD (Global Initiative for Obstructive Lung Disease) classification of COPD severity using quantitative histologic techniques. Results PM was present in the lung parenchyma, blood vessel walls, airways, lymphoid follicles, and alveolar macrophages. The total burden of PM (volume fraction [Vv]) in all tissues of the lung was higher in smokers than nonsmokers (P Conclusions We conclude that retained PM is widely distributed in lung tissues of subjects with COPD and that cigarette smoke exposure and airflow obstruction are associated with retention of PM in lung tissues. We attribute the downward trend in PM burden in severe COPD to either less deposition and retention or selective removal of PM containing tissues by emphysematous destruction.
- Published
- 2011
39. Intrinsic Phenotypic Differences of Asthmatic Epithelium and Its Inflammatory Responses to Respiratory Syncytial Virus and Air Pollution
- Author
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Richard G. Hegele, Furquan Shaheen, Stephan F. van Eeden, George R. Jackson, Tillie-Louise Hackett, Patrick Hayden, Gurpreet K. Singhera, Darryl A. Knight, Tony R. Bai, and Delbert R. Dorscheid
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Clinical Biochemistry ,Apoptosis ,Respiratory Mucosa ,Mucin 5AC ,Granulocyte ,p38 Mitogen-Activated Protein Kinases ,Proinflammatory cytokine ,Young Adult ,Air Pollution ,medicine ,Humans ,Macrophage ,Phosphorylation ,Respiratory system ,Child ,Molecular Biology ,Cells, Cultured ,Plaque-forming unit ,business.industry ,NF-kappa B ,Cell Biology ,respiratory system ,Cadherins ,Asthma ,Epithelium ,Respiratory Syncytial Viruses ,respiratory tract diseases ,Ki-67 Antigen ,medicine.anatomical_structure ,Child, Preschool ,Immunology ,Cytokines ,Keratin-5 ,Respiratory epithelium ,Female ,Particulate Matter ,business ,Ex vivo - Abstract
A substantial proportion of healthcare cost associated with asthma is attributable to exacerbations of the disease. Within the airway, the epithelium forms the mucosal immune barrier, the first structural cell defense against common environmental insults such as respiratory syncytial virus (RSV) and particulate matter. We sought to characterize the phenotype of differentiated asthmatic-derived airway epithelial cultures and their intrinsic inflammatory responses to environmental challenges. Air-liquid interface (ALI) cultures were generated from asthmatic (n = 6) and nonasthmatic (n = 6) airway epithelial cells. Airway tissue and ALI cultures were analyzed by immunohistochemistry for cytokeratin-5, E-cadherin, Ki67, Muc5AC, NF-κB, the activation of p38, and apoptosis. ALI cultures were exposed to RSV (4 × 10(6) plaque forming unit/ml), particulate matter collected by Environmental Health Canada (EHC-93, 100 μg/ml), or mechanically wounded for 24, 48, and 96 hours and basolateral supernatants analyzed for inflammatory cytokines, using Luminex and ELISA. The airway epithelium in airway sections of patients with asthma as well as in vitro ALI cultures demonstrated a less differentiated epithelium, characterized by elevated numbers of basal cells marked by the expression of cytokeratin-5, increased phosphorylation of p38 mitogen-activated protein kinase, and less adherens junction protein E-cadherin. Transepithelial resistance was not different between asthmatic and nonasthmatic cultures. In response to infection with RSV, exposure to EHC-93, or mechanical wounding, asthmatic ALI cultures released greater concentrations of IL-6, IL-8, and granulocyte macrophage colony-stimulating factor, compared with nonasthmatic cultures (P < 0.05). This parallel ex vivo and in vitro study of the asthmatic epithelium demonstrates an intrinsically altered phenotype and aberrant inflammatory response to common environmental challenges, compared with nonasthmatic epithelium.
- Published
- 2011
40. Endotoxin-induced cardiovascular dysfunction in mice: effect of simvastatin
- Author
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Masashi Tsuruta, Xi Wang, Jihyoun Eom, Don D. Sin, Koichi Suda, Tammy Mui, Ni Bai, Stephan F. van Eeden, Jen Erh Jaw, Yuexin Li, Sheena Tam, Chris Or, David A. Ngan, and S. Paul Man
- Subjects
Lipopolysaccharides ,Male ,Nitroprusside ,Simvastatin ,medicine.medical_specialty ,Endothelium ,Lipopolysaccharide ,Physiology ,Vasodilator Agents ,Acute Lung Injury ,Lung injury ,Systemic inflammation ,Gastroenterology ,Permeability ,Veins ,Mice ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Endothelial dysfunction ,Lung ,Aorta ,Inflammation ,Interleukin-6 ,business.industry ,Cell Differentiation ,Heart ,medicine.disease ,Acetylcholine ,Mice, Inbred C57BL ,Vasodilation ,Pneumonia ,medicine.anatomical_structure ,chemistry ,Cardiovascular Diseases ,Anesthesia ,Endothelium, Vascular ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid ,medicine.drug - Abstract
Lung infections are associated with acute lung injury (ALI), systemic inflammation, and vascular events. Clinical studies suggest that statins improve health outcomes of patients with pneumonia and ALI. The mechanisms by which this occurs are unknown. The aim of this study was to determine whether statins attenuate systemic inflammation and cardiovascular dysfunction related to ALI in mice. Simvastatin (SS; 20 mg/kg) or vehicle solution was instilled intraperitoneally into mice 24 h before and again just prior to intratracheal LPS instillation (1 μg/g). These mice were then anesthetized with 2.0% isoflurane and underwent a short surgical procedure to instill LPS. Four hours later, IL-6 levels in bronchoalveolar lavage fluid and in arterial and venous serum were measured. Cardiac function was evaluated using 2-D echocardiography, and endothelial function was determined using wire myography on aortic sections. LPS induced a significant increase in serum IL-6 levels. SS reduced venous ( P = 0.040) but not arterial concentrations of IL-6 ( P = 0.112). SS improved the maximal vasodilatory response of the aorta to ACh ( P = 0.004) but not to sodium nitroprusside ( P = 1.000). SS also improved cardiac output ( P = 0.023). Vasodilatory response to ACh was impaired when aorta from untreated mice was incubated with ex vivo IL-6 ( P = 0.004), whereas in the aorta from mice pretreated with SS, the vasodilatory response did not change with IL-6 incubation ( P = 0.387). SS significantly improved LPS-induced cardiovascular dysfunction possibly by reducing systemic expression of IL-6 and its downstream signaling pathways. These findings may explain how statins improve health outcomes in patients with ALI.
- Published
- 2011
41. Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice
- Author
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Michael E. Rosenfeld, Cornelis van Breemen, Terrance J. Kavanagh, Takashi Kido, Ni Bai, Stephan F. van Eeden, and Joel D. Kaufman
- Subjects
CD36 Antigens ,Male ,Apolipoprotein E ,Benzylamines ,medicine.medical_specialty ,Pathology ,Amidines ,Nitric Oxide Synthase Type II ,Aorta, Thoracic ,Toxicology ,complex mixtures ,Article ,Gene Expression Regulation, Enzymologic ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Apolipoproteins E ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Enzyme Inhibitors ,Phenylephrine ,Vehicle Emissions ,Mice, Knockout ,Pharmacology ,biology ,Myocardium ,NF-kappa B ,Atherosclerosis ,NFKB1 ,Up-Regulation ,Nitric oxide synthase ,Endocrinology ,chemistry ,Vasoconstriction ,Knockout mouse ,biology.protein ,Tyrosine ,Particulate Matter ,medicine.symptom ,Myograph ,medicine.drug - Abstract
Traffic related particulate matter air pollution is a risk factor for cardiovascular events; however, the biological mechanisms are unclear. We hypothesize that diesel exhaust (DE) inhalation induces up-regulation of inducible nitric oxide synthase (iNOS), which is known to contribute to vascular dysfunction, progression of atherosclerosis and ultimately cardiovascular morbidity and mortality. Methods: ApoE knockout mice (30-week) were exposed to DE (at 200 {mu}g/m{sup 3} of particulate matter) or filtered-air (control) for 7 weeks (6 h/day, 5 days/week). iNOS expression in the blood vessels and heart was evaluated by immunohistochemistry and western blotting analysis. To examine iNOS activity, thoracic aortae were mounted in a wire myograph, and vasoconstriction stimulated by phenylephrine (PE) was measured with and without the presence of the specific inhibitor for iNOS (1400 W). NF-{kappa}B (p65) activity was examined by ELISA. The mRNA expression of iNOS and NF-{kappa}B (p65) was determined by real-time PCR. Results: DE exposure significantly enhanced iNOS expression in the thoracic aorta (4-fold) and heart (1.5 fold). DE exposure significantly attenuated PE-stimulated vasoconstriction by {approx} 20%, which was partly reversed by 1400 W. The mRNA expression of iNOS and NF-{kappa}B was significantly augmented after DE exposure. NF-{kappa}B activity was enhanced 2-fold after DE inhalation, andmore » the augmented NF-{kappa}B activity was positively correlated with iNOS expression (R{sup 2} = 0.5998). Conclusions: We show that exposure to DE increases iNOS expression and activity possibly via NF-{kappa}B-mediated pathway. We suspect that DE exposure-caused up-regulation of iNOS contributes to vascular dysfunction and atherogenesis, which could ultimately lead to urban air pollution-associated cardiovascular morbidity and mortality. - Highlights: > Exposed ApoE knockout mice (30-week) to diesel exhaust (DE) for 7 weeks. > Examine iNOS expression and activity in the blood vessels and heart. > DE exposure enhanced iNOS protein and mRNA expression in the aorta and heart. > iNOS activity was also increased after DE exposure. > This up-regulation of iNOS may contribute to vascular dysfunction and atherogenesis.« less
- Published
- 2011
42. Diesel exhaust inhalation induces heat shock protein 70 expressionin vivo
- Author
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Takashi Kido, Hiroshi Mukae, Ni Bai, Michael E. Rosenfeld, Hisashi Suzuki, Anna Meredith, Stephan F. van Eeden, and Kazuhiro Yatera
- Subjects
Male ,Apolipoprotein E ,medicine.medical_specialty ,Pathology ,Endothelium ,Health, Toxicology and Mutagenesis ,Aorta, Thoracic ,Enzyme-Linked Immunosorbent Assay ,Toxicology ,Pathogenesis ,Mice ,Apolipoproteins E ,Internal medicine ,Heat shock protein ,medicine ,Animals ,HSP70 Heat-Shock Proteins ,Aorta, Abdominal ,Lung ,Vehicle Emissions ,Inhalation exposure ,Air Pollutants ,Inhalation Exposure ,Inhalation ,business.industry ,Immunohistochemistry ,Hsp70 ,Endocrinology ,medicine.anatomical_structure ,Cardiovascular Diseases ,Vasoconstriction ,Endothelium, Vascular ,business - Abstract
Exposure to urban air pollution is an independent risk factor for increased cardiovascular diseases. Heat shock protein 70 (HSP70) has been implicated in the pathogenesis of vascular dysfunction and cardiovascular diseases. This study has been designed to determine whether inhalation of urban air induces HSP70 expression in the lung and blood as well as the association of HSP70 and air pollution-induced vascular dysfunction. Apolipoprotein E (Apo-E) deficient mice were exposed to diesel exhaust (DE) either acutely (3 days, 200 or 400 µg/m(3) for 6 h/day) or chronically (7 weeks, 200 or 400 µg/m(3) for 6 h/day). HSP70 was measured in the lung using immunohistochemistry, and in the plasma by ELISA. Abdominal aorta rings were used to determine vascular functional responses. Chronic DE-exposure increased the fraction of HSP70 positive alveolar macrophages (AM) that was related to the fraction of particle-laden AM in the lung (r(2) = 0.48, p 0.01). Chronic DE-exposure increased plasma HSP70 levels and reduced blood vessel responses to phenylephrine (PE). The fraction of particle-laden HSP70 positive AM was associated with abnormal vasoconstriction responses to PE induced by DE-exposure (r(2) = 0.12, p = 0.02). Our results show that chronic inhalation of DE increases HSP70 expression in the lung and systemic circulation, and we postulate that HSP70 possibly contributes to air pollution induced vascular dysfunction and cardiovascular diseases.
- Published
- 2011
43. Effects of 10 days of modest intermittent hypoxia on circulating measures of inflammation in healthy humans
- Author
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Alan T. Mulgrew, Najib T. Ayas, Andrew William Sheel, Jordan S. Querido, Rupi Cheema, and Stephan F. van Eeden
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Inflammation ,Autonomic Nervous System ,Systemic inflammation ,Hypoxemia ,Young Adult ,chemistry.chemical_compound ,Reference Values ,Internal medicine ,medicine ,Humans ,Hypoxia ,Sleep Apnea, Obstructive ,business.industry ,Intermittent hypoxia ,Hypoxia (medical) ,medicine.disease ,Oxygen ,Obstructive sleep apnea ,Vascular endothelial growth factor ,Cytokine ,Endocrinology ,Otorhinolaryngology ,chemistry ,Neurology (clinical) ,Inflammation Mediators ,medicine.symptom ,business - Abstract
Obstructive sleep apnea (OSA) is a common disease which is associated with elevated inflammatory markers and adhesion molecules, possibly due to nightly intermittent hypoxia (IH). The purpose of this study was to test the hypothesis that IH would increase systemic inflammatory markers in healthy human males. Healthy, young male subjects (n = 9; 24 ± 2 years) were exposed to a single daily isocapnic hypoxia exposure (oxyhemoglobin saturation = 80%, 1 h/day) for 10 consecutive days. Serum granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1β, interleukin-6, interleukin-8, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1 were measured before and following the 10 days of IH using Luminex. Nine subjects completed the study (24 ± 2 years; 24 ± 2 kg/m2). The mean oxyhemoglobin saturation was 80.8 ± 1.6% during the hypoxia exposures. There was no significant change in any of the markers of inflammation (paired t test, P > 0.2 all cytokines). These findings suggest that (1) a more substantial or a different pattern of hypoxemia might be necessary to activate systemic inflammation, (2) the system may need to be primed before hypoxic exposure, or (3) increases in inflammatory markers in patients with OSA may be more related to other factors such as obesity or nocturnal arousal.
- Published
- 2011
44. Particulate Matter Induces Translocation of IL-6 from the Lung to the Systemic Circulation
- Author
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Hiroshi Mukae, Eiji Tamagawa, Ni Bai, Huei Hsin C. Yang, Yuexin Li, Don D. Sin, Takashi Kido, Stephan F. van Eeden, Gary Chiang, Koichi Suda, and Kazuhiro Yatera
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Clinical Biochemistry ,Biological Transport, Active ,Systemic inflammation ,Mice ,Internal medicine ,medicine.artery ,medicine ,Animals ,Aorta, Abdominal ,Lung ,Molecular Biology ,Phenylephrine ,Inflammation ,Mice, Knockout ,Aorta ,medicine.diagnostic_test ,Interleukin-6 ,business.industry ,Abdominal aorta ,Cell Biology ,Venous blood ,Mice, Inbred C57BL ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Endocrinology ,Cardiovascular Diseases ,Arterial blood ,Particulate Matter ,Inflammation Mediators ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid ,medicine.drug - Abstract
The biological mechanisms responsible for an association between elevated concentrations of ambient particulate matter (PM) and increased cardiovascular morbidity and mortality remain unclear. Our laboratory showed that exposure to PM induces systemic inflammation that contributes to vascular dysfunction. This study was designed to determine whether the lung is a major source of systemic inflammatory mediators, using IL-6 as a surrogate marker. We also sought to determine the impact on vascular dysfunction after exposure to PM of less than 10 μm in diameter (PM(10)). C57BL/6 mice were intratracheally exposed to a single instillation of PM(10) (10 or 200 μg) or saline. Four hours or 24 hours after exposure, venous and arterial blood samples were simultaneously collected from the right atrium and descending aorta. Concentrations of IL-6 were measured in bronchoalveolar lavage fluid (BALF) and serum samples. Vascular functional responses to acetylcholine (ACh) and phenylephrine were measured in the abdominal aorta. Concentrations of IL-6 in BALF samples were increased at 4 and 24 hours after exposure to PM(10). At baseline, concentrations of IL-6 in venous blood were higher than those in arterial blood. Exposure to PM(10) reversed this arteriovenous gradient, 4 hours after exposure. The relaxation responses of the abdominal aorta to ACh decreased 4 hours after exposure to 200 μg PM(10). In IL-6 knockout mice, the instillation of recombinant IL-6 increased IL-6 concentrations in the blood, and exposure to PM(10) did not cause vascular dysfunction. These results support our hypothesis that exposure to PM(10) increases pulmonary inflammatory mediators that translocate to the circulation, contributing to systemic inflammation, with downstream effects such as vascular dysfunction.
- Published
- 2011
45. Endotoxin-induced translocation of interleukin-6 from lungs to the systemic circulation
- Author
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Eiji Tamagawa, Stephan F. van Eeden, Koichi Suda, Don D. Sin, S. F. Paul Man, Yuan Wei, Li Xing, Yuexin Li, and Tammy Mui
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Immunology ,Anti-Inflammatory Agents ,Systemic inflammation ,Microbiology ,Dexamethasone ,Mice ,Internal medicine ,medicine.artery ,Intubation, Intratracheal ,medicine ,Animals ,Interleukin 6 ,Lung ,Molecular Biology ,Aorta ,biology ,Interleukin-6 ,business.industry ,Interleukin ,Pneumonia ,Cell Biology ,Venous blood ,Endotoxins ,Mice, Inbred C57BL ,Disease Models, Animal ,Infectious Diseases ,medicine.anatomical_structure ,Endocrinology ,Blood Circulation ,biology.protein ,Arterial blood ,medicine.symptom ,business ,Bronchoalveolar Lavage Fluid ,medicine.drug - Abstract
It is widely postulated that systemic inflammation related to lung infections is largely caused by cytokine translocation from the lungs into the systemic circulation but there is a paucity of animal models to evaluate this hypothesis. In this proof-of-concept study, we developed a murine model to determine whether interleukin (IL)-6, a primary inflammatory cytokine, translocates following airway exposure to endotoxin. We collected central venous blood from the right atrium and arterial blood from the aorta simultaneously at 4 h and 24 h following intratracheal exposure to endotoxin (25 mg) and measured IL-6 in the serum and broncho-alveolar lavage (BAL) fluid (n = 33 mice). We repeated the experiment following 3 d of treatment with dexamethasone (n = 31 mice). Without stimulation, there was no significant arteriovenous gradient (3 pg/ml with interquartile range [IQR] of 3—5 pg/ml in arterial versus 18 pg/ml with IQR of 8—24 pg/ml in venous serum; P = 0.86). A significant arteriovenous difference was observed by 4 h post-exposure to endotoxin (2813 pg/ml with IQR of 1578—4316 pg/ml in arterial versus 1282 pg/ml with IQR of 778—2699 pg/ml in venous serum; P50.0001). The rise in the BAL IL-6 levels correlated with the increases in the arterial serum levels (P50.0001). Administration of intraperitoneal dexamethasone for 3 d attenuated the increased arteriovenous gradient. This murine model facilitates the estimation of cytokine translocation across the lungs and evaluation of compounds to modulate this gradient.
- Published
- 2009
46. Particulate matter air pollution exposure: role in the development and exacerbation of chronic obstructive pulmonary disease
- Author
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Sean H. Ling and Stephan F. van Eeden
- Subjects
medicine.medical_specialty ,Exacerbation ,air pollution ,Air pollution ,Pulmonary disease ,Review ,medicine.disease_cause ,Risk Assessment ,chronic obstructive pulmonary disease ,Pulmonary Disease, Chronic Obstructive ,Risk Factors ,Macrophages, Alveolar ,medicine ,Humans ,Particle Size ,Intensive care medicine ,Adverse effect ,Lung ,particulate matter ,lcsh:RC705-779 ,COPD ,Inhalation Exposure ,business.industry ,General Medicine ,Pneumonia ,lcsh:Diseases of the respiratory system ,Particulates ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Immunology ,Disease Progression ,alveolar macrophage ,Inflammation Mediators ,business ,Respiratory tract - Abstract
Sean H Ling, Stephan F van EedenJames Hogg iCAPTURE Centre for Pulmonary and Cardiovascular Research and Heart and Lung Institute, University of British Columbia, Vancouver, British Columbia, CanadaAbstract: Due to the rapid urbanization of the world population, a better understanding of the detrimental effects of exposure to urban air pollution on chronic lung disease is necessary. Strong epidemiological evidence suggests that exposure to particulate matter (PM) air pollution causes exacerbations of pre-existing lung conditions, such as, chronic obstructive pulmonary disease (COPD) resulting in increased morbidity and mortality. However, little is known whether a chronic, low-grade exposure to ambient PM can cause the development and progression of COPD. The deposition of PM in the respiratory tract depends predominantly on the size of the particles, with larger particles deposited in the upper and larger airways and smaller particles penetrating deep into the alveolar spaces. Ineffective clearance of this PM from the airways could cause particle retention in lung tissues, resulting in a chronic, low-grade inflammatory response that may be pathogenetically important in both the exacerbation, as well as, the progression of lung disease. This review focuses on the adverse effects of exposure to ambient PM air pollution on the exacerbation, progression, and development of COPD.Keywords: chronic obstructive pulmonary disease, particulate matter, air pollution, alveolar macrophage
- Published
- 2009
47. Particulate matter air pollution exposure promotes recruitment of monocytes into atherosclerotic plaques
- Author
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Kazuhiro Yatera, Hisashi Suzuki, Renaud Vincent, Joanne Hsieh, Stephan F. van Eeden, Chih-Horng Shih, James C. Hogg, Ali Reza Behzad, and Erin M. Tranfield
- Subjects
Antimetabolites ,Physiology ,Air pollution exposure ,Air pollution ,medicine.disease_cause ,Monocytes ,Leukocyte Count ,Physiology (medical) ,Animals ,Medicine ,Aorta ,Air Pollutants ,business.industry ,Particulates ,Atherosclerosis ,Flow Cytometry ,Particulate air pollution ,Immunohistochemistry ,Microscopy, Electron ,Bromodeoxyuridine ,Immunology ,Female ,Particulate Matter ,Endothelium, Vascular ,Rabbits ,Cardiology and Cardiovascular Medicine ,business ,Cell Adhesion Molecules ,Half-Life - Abstract
Epidemiologic studies have shown an association between exposure to ambient particulate air pollution 10) and increased cardiovascular morbidity and mortality. We previously showed that PM10 exposure causes progression of atherosclerosis in coronary arteries. We postulate that the recruitment of monocytes from the circulation into atherosclerotic lesions is a key step in this PM10-induced acceleration of atherosclerosis. The study objective was to quantify the recruitment of circulating monocytes into vessel walls and the progression of atherosclerotic plaques induced by exposure to PM10. Female Watanabe heritable hyperlipidemic rabbits, which naturally develop systemic atherosclerosis, were exposed to PM10 (EHC-93) or vehicle by intratracheal instillation twice a week for 4 wk. Monocytes, labeled with 5-bromo-2′-deoxyuridine (BrdU) in donors, were transfused to recipient rabbits as whole blood, and the recruitment of BrdU-labeled cells into vessel walls and plaques in recipients was measured by quantitative histological methodology. Exposure to PM10 caused progression of atherosclerotic lesions in thoracic and abdominal aorta. It also decreased circulating monocyte counts, decreased circulating monocytes expressing high levels of CD31 (platelet endothelial cell adhesion molecule-1) and CD49d (very late antigen-4 α-chain), and increased expression of CD54 (ICAM-1) and CD106 (VCAM-1) in plaques. Exposure to PM10 increased the number of BrdU-labeled monocytes adherent to endothelium over plaques and increased the migration of BrdU-labeled monocytes into plaques and smooth muscle underneath plaques. We conclude that exposure to ambient air pollution particles promotes the recruitment of circulating monocytes into atherosclerotic plaques and speculate that this is a critically important step in the PM10-induced progression of atherosclerosis.
- Published
- 2008
48. Calcium dependent and independent cytokine synthesis by air pollution particle-exposed human bronchial epithelial cells
- Author
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Yuji Ishimatsu, Noriho Sakamoto, John V. Gosselink, Stephan F. van Eeden, Shizu Hayashi, James C. Hogg, Hiroshi Mukae, and Hiroshi Ishii
- Subjects
medicine.medical_treatment ,Calcium pump ,Interleukin-1beta ,chemistry.chemical_element ,Bronchi ,Enzyme-Linked Immunosorbent Assay ,Inflammation ,Calcium ,Toxicology ,Leukemia Inhibitory Factor ,Polymerase Chain Reaction ,Calcium in biology ,Cytosol ,medicine ,Humans ,Particle Size ,Cells, Cultured ,Aged ,Fluorescent Dyes ,Aged, 80 and over ,Pharmacology ,Air Pollutants ,Dose-Response Relationship, Drug ,Interleukin-8 ,Granulocyte-Macrophage Colony-Stimulating Factor ,Epithelial Cells ,Middle Aged ,Molecular biology ,In vitro ,Epithelium ,Cytokine ,medicine.anatomical_structure ,chemistry ,Immunology ,Cytokines ,Inflammation Mediators ,medicine.symptom ,Fura-2 ,Intracellular - Abstract
Exposure to ambient air pollution particles with a diameter of10 microm (PM(10)) has been associated with increased cardiopulmonary morbidity and mortality. We have shown that human bronchial epithelial cells (HBECs) exposed to PM(10) produce pro-inflammatory mediators that contribute to a local and systemic inflammatory response. Changes in intracellular calcium concentrations ([Ca(2+)](i)) have been demonstrated to regulate several functions of the airway epithelium including the production of pro-inflammatory mediators. The aim of the present study was to determine the nature and mechanism of calcium responses induced by PM(10) in HBECs and its relationship to cytokine synthesis.Primary HBECs were exposed to urban air pollution particles (EHC-93) and [Ca(2+)](i) responses were measured using the fluoroprobe (Fura-2). Cytokine levels were measured at mRNA and protein levels using real-time PCR and ELISA.PM(10) increased [Ca(2+)](i) in a dose-dependent manner. This calcium response was reduced by blocking the influx of calcium into cells (i.e. calcium-free medium, NiCl(2), LaCl(3)). PM(10) also decreased the activity of calcium pumps. PM(10) increased the production of IL-1beta, IL-8, GM-CSF and LIF. Preincubation with intracellular calcium chelator (BAPTA-AM) attenuated IL-1beta and IL-8 production, but not GM-CSF and LIF production.We conclude that exposure to PM(10) induces an increase in cytosolic calcium and cytokine production in bronchial epithelial cells. Our results also suggest that PM(10) induces the production of pro-inflammatory mediators via either intracellular calcium-dependent (IL-1beta, IL-8) or -independent (GM-CSF, LIF) pathways.
- Published
- 2007
49. CCL23/myeloid progenitor inhibitory factor-1 inhibits production and release of polymorphonuclear leukocytes and monocytes from the bone marrow
- Author
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James C. Hogg, Chih-Horng Shih, Stephan F. van Eeden, and Yukinobu Goto
- Subjects
Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Neutrophils ,Bone Marrow Cells ,Monocytes ,Mice ,chemistry.chemical_compound ,In vivo ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Progenitor cell ,Molecular Biology ,business.industry ,Monocyte ,Cell Biology ,Hematology ,Recombinant Proteins ,Endocrinology ,medicine.anatomical_structure ,Bromodeoxyuridine ,chemistry ,Leukopoiesis ,Chemokines, CC ,Blood Circulation ,Immunology ,Female ,Rabbits ,Bone marrow ,business ,CCL23 - Abstract
CCL23/Myeloid progenitor inhibitory factor-1 is a human CC chemokine with potent in vitro suppressor effects on both human and murine myeloid progenitor cells. This study concerns in vivo inhibitory effect of CCL23 on production of polymorphonuclear leukocytes (PMNs) and monocytes in the bone marrow and their release into the circulation.5'-Bromo-2'-deoxyuridine (BrdU; 100 mg/kg) was used to label dividing PMNs and monocytes in the bone marrow, and BrdU-labeled cells were followed for 10 days in the circulation and identified using immunocytochemistry. Rabbits were given CCL23 (100 mug/kg, n = 5) or saline (control: n = 5) intravenously daily for 3 days before labeling with BrdU. Turnover of PMNs and monocytes in the bone marrow and their transit times through the bone marrow were calculated.CCL23 treatment tended to prolong transit time of PMN (98.4 +/- 4.3 hours vs 111.2 +/- 3.8 hours, control vs CCL23, p = 0.06) through the bone marrow and decreased the size of the bone marrow mitotic pool of PMN (p0.01). CCL23 treatment also prolonged the transit time of monocyte (43.4 +/- 3.1 hours vs 54.2 +/- 1.3 hours, control vs CCL23, p0.05) through the bone marrow and decreased turnover and pool size of monocytes in the bone marrow (p0.05).We conclude that CCL23 suppresses PMN and monocyte progenitors, decreases the pool size and slows their turnover in the bone marrow.
- Published
- 2005
50. Flow cytometric method for enumeration and characterization of newly released polymorphonuclear leukocytes from the bone marrow using 5′-bromo-2′-deoxyuridine
- Author
-
Stephan F. van Eeden, James C. Hogg, Beth A. Whalen, Chih-Horng Shih, and Yukinobu Goto
- Subjects
Pathology ,medicine.medical_specialty ,Antimetabolites ,Neutrophils ,Physiology ,Neutrophile ,Bone Marrow Cells ,Inflammation ,Transit time ,Biology ,Flow cytometry ,Leukocyte Count ,chemistry.chemical_compound ,medicine ,Animals ,Fluorescent Dyes ,Polymorphonuclear leukocyte ,medicine.diagnostic_test ,Cell Biology ,Flow Cytometry ,Deoxyuridine ,medicine.anatomical_structure ,Bromodeoxyuridine ,chemistry ,Female ,Rabbits ,Bone marrow ,medicine.symptom ,Fluorescein-5-isothiocyanate - Abstract
Inflammation accelerates polymorphonuclear leukocyte (PMN) release from the bone marrow, and these PMNs are implicated in inappropriate tissue injury. We have previously developed a method using 5′-bromo-2′-deoxyuridine (BrdU) to study PMN kinetics using an immunocytochemical grading system of PMN on cytospin slides. The aim of this study was to develop a flow cytometric method to quantify the number of positively stained PMN and grade the intensity of staining for the transit time calculation of PMN through the marrow. Dividing myeloid progenitors in the marrow of rabbits were labeled with a pulse dosage of intravenous BrdU. BrdU-labeled PMN (PMNBrdU) were detected in the circulation using a FITC-conjugated anti-BrdU monoclonal antibody. The PMNBrdUwere assigned to five groups according to their FITC intensity, and the transit times of PMN at different stages of development in the marrow were calculated. Results were compared using parallel immunocytochemical analysis of the same samples. In control animals, PMNBrdUin the circulation peaked at 72 h after BrdU labeling with 36.0% of PMN labeled. In normal rabbits, the transit times of PMN through the mitotic pool (49.5 ± 4.2 h) and maturation pool (65.5 ± 3.1 h) correlated well with immunocytochemical analysis and previously published values. Using this method, we demonstrated that exposure to air pollution particles accelerates the release of PMNBrdUfrom the marrow. We conclude that a flow cytometric approach for identifying BrdU-labeled leukocytes provides an objective and accurate method for studying leukocyte kinetics and behavior.
- Published
- 2005
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