1
|
Li T, Tan X, Huang Y, Cui J, Chen F, Xiong Y. MicroRNA miR-627-5p restrains pulmonary artery smooth muscle cell dysfunction by targeting MAP 2 K4 and PI3K/AKT signaling. Genes Environ 2022; 44:23. [PMID: 36163195 PMCID: PMC9513949 DOI: 10.1186/s41021-022-00251-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/05/2022] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary vascular remodeling, which can be caused by abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Several microRNAs were demonstrated to regulate the PASMC dysfunction. Our study intends to evaluate whether miR-627-5p affects cigarette smoke extract (CSE)-induced aberrant biological behaviors of PASMCs. METHODS PASMCs was treated with CSE to create the in vitro cellular model of COPD. The viability and LDH release of PASMCs was detected by CCK-8 assay and LDH release assay. MiR-627-5p and MAP 2 K4 expression in CSE (2%)-treated PASMCs was detected by qRT-PCR. PASMC proliferation was observed under a microscope, and PASMC migration was assessed by Transwell migration assays. The binding of miR-627-5p on MAP 2 K4 was verified by dual-luciferase reporter assay. Protein levels of MAP2K4 and the PI3K/AKT signaling markers were examined by western blotting. RESULTS The viability of PASMCs treated with 2% CSE reached a peak. CSE dose-dependently downregulated miR-627-5p expression in PASMCs. MiR-627-5p overexpression attenuated the CSE-induced abnormal proliferation and migration of PASMCs. However, MAP2K4 overexpression antagonized the effects of miR-627-5p on PASMC dysfunction. Importantly, miR-627-5p inhibited CSE-stimulated activation of the PI3K/AKT pathway via downregulating MAP2K4. CONCLUSION MiR-627-5p improves CSE-induced abnormal proliferation and migration of PASMCs by inhibiting MAP2K4 expression and the PI3K/AKT pathway.
Collapse
Affiliation(s)
- Ting Li
- Department of Respiratory and Critical Care Medicine, Wuhan Fourth Hospital, Wuhan, Hubei, 430000, China
| | - Xiaoqin Tan
- Department of Respiratory and Critical Care Medicine, Wuhan Fourth Hospital, Wuhan, Hubei, 430000, China
| | - Yuexia Huang
- Department of Respiratory and Critical Care Medicine, Wuhan Fourth Hospital, Wuhan, Hubei, 430000, China
| | - Jun Cui
- Department of Respiratory and Critical Care Medicine, Wuhan Fourth Hospital, Wuhan, Hubei, 430000, China
| | - Fan Chen
- Department of Respiratory and Critical Care Medicine, Wuhan Fourth Hospital, Wuhan, Hubei, 430000, China
| | - Ying Xiong
- Department of Respiratory and Critical Care Medicine, Wuhan Fourth Hospital, Wuhan, Hubei, 430000, China.
- Wuhan Fourth Hospital, No. 473, Hanzheng Street, Qiaokou District, Wuhan, Hubei, China.
| |
Collapse
|
2
|
Abstract
Pulmonary hypertension (PH) because of chronic lung disease is categorized as Group 3 PH in the most recent classification system. Prevalence of these diseases is increasing over time, creating a growing need for effective therapeutic options. Recent approval of the first pulmonary arterial hypertension therapy for the treatment of Group 3 PH related to interstitial lung disease represents an encouraging advancement. This review focuses on molecular mechanisms contributing to pulmonary vasculopathy in chronic hypoxia, the pathology and epidemiology of Group 3 PH, the right ventricular dysfunction observed in this population and clinical trial data that inform the use of pulmonary vasodilators in Group 3 PH.
Collapse
Affiliation(s)
- Navneet Singh
- Division of Pulmonary, Critical Care and Sleep Medicine (N.S., C.E.V.), Brown University, Providence, RI
| | - Peter Dorfmüller
- Department of Pathology, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University, Germany (P.D.).,German Center for Lung Research (DZL), Giessen, Germany (P.D.)
| | - Oksana A Shlobin
- Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA (O.A.S.)
| | - Corey E Ventetuolo
- Division of Pulmonary, Critical Care and Sleep Medicine (N.S., C.E.V.), Brown University, Providence, RI.,Department of Health Services, Policy and Practice (C.E.V.), Brown University, Providence, RI
| |
Collapse
|
3
|
Skurikhin E, Pershina O, Zhukova M, Widera D, Pan E, Pakhomova A, Krupin V, Ermakova N, Skurikhina V, Sandrikina L, Morozov S, Kubatiev A, Dygai A. Spiperone Stimulates Regeneration in Pulmonary Endothelium Damaged by Cigarette Smoke and Lipopolysaccharide. Int J Chron Obstruct Pulmon Dis 2022; 16:3575-3591. [PMID: 35002229 PMCID: PMC8722540 DOI: 10.2147/copd.s336410] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/06/2021] [Indexed: 12/30/2022] Open
Abstract
Background Endothelial dysfunction and destruction of the pulmonary microcirculation are important pathogenic factors in chronic obstructive pulmonary disease (COPD). In COPD, bronchial obstruction is associated with endothelial dysfunction. Thus, new pharmacological treatment options aimed at restoring the pulmonary endothelium represent a clinical need in COPD therapy. Notch1 has been shown to protect cells against apoptosis, inflammation, and oxidative stress caused by cigarette smoke extract (CSE). Therefore, drug which effect on Notch1 may be a potential therapeutic target for COPD in the future. Methods In this study, we assessed the potential of spiperone to mediate regeneration of pulmonary endothelium in model of pulmonary emphysema induced by a CSE and lipopolysaccharide (LPS) in female C57BL/6 mice. Results Spiperone increased the number of capillaries as well as the expression of the CD31 in the alveolar tissue compared to the controls. Moreover, application of spiperone prevented alveolar wall destruction (DI), and reduced the area of emphysema. Lastly, we demonstrated that spiperone positively influenced mobilization and migration of endothelial progenitor cells (EPC, CD45−CD34+CD31+), CD309+-endothelial cells, and angiogenesis precursors (CD45−CD117+CD309+) into the lung. Spiperone administration significantly reduced the number Notch1 positive CD309+-endothelial cells and Notch1+ EPCs. Conclusion Overall, our results suggest that spiperone mediates endothelial regeneration in an animal model of COPD. Thus, it could represent a novel therapeutic approach for treatment of emphysema associated with COPD.
Collapse
Affiliation(s)
- Evgenii Skurikhin
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Olga Pershina
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Mariia Zhukova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Darius Widera
- Stem Cell Biology and Regenerative Medicine Group, School of Pharmacy, University of Reading, Whiteknights Campus, Reading, RG6 6AP, UK
| | - Edgar Pan
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Angelina Pakhomova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Vyacheslav Krupin
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Natalia Ermakova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | | | - Lubov Sandrikina
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Sergey Morozov
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Aslan Kubatiev
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Alexander Dygai
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia.,Institute of General Pathology and Pathophysiology, Moscow, Russia
| |
Collapse
|
4
|
Skurikhin E, Pershina O, Zhukova M, Widera D, Ermakova N, Pan E, Pakhomova A, Morozov S, Kubatiev A, Dygai A. Potential of Stem Cells and CART as a Potential Polytherapy for Small Cell Lung Cancer. Front Cell Dev Biol 2021; 9:778020. [PMID: 34926461 PMCID: PMC8678572 DOI: 10.3389/fcell.2021.778020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022] Open
Abstract
Despite the increasing urgency of the problem of treating small cell lung cancer (SCLC), information on the causes of its development is fragmentary. There is no complete understanding of the features of antitumor immunity and the role of the microenvironment in the development of SCLC resistance. This impedes the development of new methods for the diagnosis and treatment of SCLC. Lung cancer and chronic obstructive pulmonary disease (COPD) have common pathogenetic factors. COPD is a risk factor for lung cancer including SCLC. Therefore, the search for effective approaches to prevention, diagnosis, and treatment of SCLC in patients with COPD is an urgent task. This review provides information on the etiology and pathogenesis of SCLC, analyses the effectiveness of current treatment options, and critically evaluates the potential of chimeric antigen receptor T cells therapy (CART therapy) in SCLC. Moreover, we discuss potential links between lung cancer and COPD and the role of endothelium in the development of COPD. Finally, we propose a new approach for increasing the efficacy of CART therapy in SCLC.
Collapse
Affiliation(s)
- Evgenii Skurikhin
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Olga Pershina
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Mariia Zhukova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Darius Widera
- Stem Cell Biology and Regenerative Medicine Group, School of Pharmacy, University of Reading, Reading, United Kingdom
| | - Natalia Ermakova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Edgar Pan
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Angelina Pakhomova
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
| | - Sergey Morozov
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Aslan Kubatiev
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Alexander Dygai
- Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, Tomsk, Russia
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| |
Collapse
|
5
|
He Z, Peng H, Gao M, Liang G, Zeng M, Zhang X. p300/Sp1-Mediated High Expression of p16 Promotes Endothelial Progenitor Cell Senescence Leading to the Occurrence of Chronic Obstructive Pulmonary Disease. Mediators Inflamm 2021; 2021:5599364. [PMID: 34456628 PMCID: PMC8397552 DOI: 10.1155/2021/5599364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 07/19/2021] [Accepted: 08/02/2021] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE Chronic obstructive pulmonary disease (COPD) is a common chronic disease and develops rapidly into a grave public health problem worldwide. However, what exactly causes the occurrence of COPD remains largely unclear. Here, we are trying to explore whether the high expression of p16 mediated by p300/Sp1 can cause chronic obstructive pulmonary disease through promoting the senescence of endothelial progenitor cells (EPCs). METHODS Peripheral blood EPCs were isolated from nonsmoking non-COPD, smoking non-COPD, and smoking COPD patients. The expressions of p16, p300, and senescence-related genes were detected by RT-PCR and Western Blot. Then, we knocked down or overexpressed Sp1 and p300 and used the ChIP assay to detect the histone H4 acetylation level in the promoter region of p16, CCK8 to detect cell proliferation, flow cytometry to detect the cell cycle, and β-galactosidase staining to count the proportion of senescent cells. RESULTS The high expression of p16 was found in peripheral blood EPCs of COPD patients; the cigarette smoke extract (CSE) led to the increase of p16. The high expression of p16 in EPCs promoted cell cycle arrest and apoptosis. The CSE-mediated high expression of p16 promoted cell senescence. The expression of p300 was increased in peripheral blood EPCs of COPD patients. Moreover, p300/Sp1 enhanced the histone H4 acetylation level in the promoter region of p16, thereby mediating the senescence of EPCs. And knockdown of p300/Sp1 could rescue CSE-mediated cell senescence. CONCLUSION p300/Sp1 enhanced the histone H4 acetylation level in the p16 promoter region to mediate the senescence of EPCs.
Collapse
Affiliation(s)
- Zhihui He
- Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China
| | - Huaihuai Peng
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011 Hunan, China
| | - Min Gao
- Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China
| | - Guibin Liang
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011 Hunan, China
| | - Menghao Zeng
- Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China
| | - Xuefeng Zhang
- Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China
| |
Collapse
|
6
|
Pistenmaa CL, Nardelli P, Ash SY, Come CE, Diaz AA, Rahaghi FN, Barr RG, Young KA, Kinney GL, Simmons JP, Wade RC, Wells JM, Hokanson JE, Washko GR, San José Estépar R. Pulmonary Arterial Pruning and Longitudinal Change in Percent Emphysema and Lung Function: The Genetic Epidemiology of COPD Study. Chest 2021; 160:470-480. [PMID: 33607083 PMCID: PMC8411454 DOI: 10.1016/j.chest.2021.01.084] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/28/2020] [Accepted: 01/23/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Pulmonary endothelial damage has been shown to precede the development of emphysema in animals, and vascular changes in humans have been observed in COPD and emphysema. RESEARCH QUESTION Is intraparenchymal vascular pruning associated with longitudinal progression of emphysema on CT imaging or decline in lung function over 5 years? STUDY DESIGN AND METHODS The Genetic Epidemiology of COPD Study enrolled ever smokers with and without COPD from 2008 through 2011. The percentage of emphysema-like lung, or "percent emphysema," was assessed at baseline and after 5 years on noncontrast CT imaging as the percentage of lung voxels < -950 Hounsfield units. An automated CT imaging-based tool assessed and classified intrapulmonary arteries and veins. Spirometry measures are postbronchodilator. Pulmonary arterial pruning was defined as a lower ratio of small artery volume (< 5 mm2 cross-sectional area) to total lung artery volume. Mixed linear models included demographics, anthropomorphics, smoking, and COPD, with emphysema models also adjusting for CT imaging scanner and lung function models adjusting for clinical center and baseline percent emphysema. RESULTS At baseline, the 4,227 participants were 60 ± 9 years of age, 50% were women, 28% were Black, 47% were current smokers, and 41% had COPD. Median percent emphysema was 2.1 (interquartile range, 0.6-6.3) and progressed 0.24 percentage points/y (95% CI, 0.22-0.26 percentage points/y) over 5.6 years. Mean FEV1 to FVC ratio was 68.5 ± 14.2% and declined 0.26%/y (95% CI, -0.30 to -0.23%/y). Greater pulmonary arterial pruning was associated with more rapid progression of percent emphysema (0.11 percentage points/y per 1-SD increase in arterial pruning; 95% CI, 0.09-0.16 percentage points/y), including after adjusting for baseline percent emphysema and FEV1. Arterial pruning also was associated with a faster decline in FEV1 to FVC ratio (-0.04%/y per 1-SD increase in arterial pruning; 95% CI, -0.008 to -0.001%/y). INTERPRETATION Pulmonary arterial pruning was associated with faster progression of percent emphysema and more rapid decline in FEV1 to FVC ratio over 5 years in ever smokers, suggesting that pulmonary vascular differences may be relevant in disease progression. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
Collapse
Affiliation(s)
| | - P Nardelli
- Department of Radiology, Brigham and Women's Hospital, Boston, MA
| | - S Y Ash
- Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - C E Come
- Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - A A Diaz
- Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - F N Rahaghi
- Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - R G Barr
- Departments of Medicine and Epidemiology, Columbia University, New York, NY
| | - K A Young
- Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO
| | - G L Kinney
- Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO
| | - J P Simmons
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - R C Wade
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - J M Wells
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - J E Hokanson
- Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO
| | - G R Washko
- Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | | |
Collapse
|
7
|
Karnati S, Seimetz M, Kleefeldt F, Sonawane A, Madhusudhan T, Bachhuka A, Kosanovic D, Weissmann N, Krüger K, Ergün S. Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target. Front Cardiovasc Med 2021; 8:649512. [PMID: 33912600 PMCID: PMC8072123 DOI: 10.3389/fcvm.2021.649512] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cells via aberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD.
Collapse
Affiliation(s)
- Srikanth Karnati
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Michael Seimetz
- Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Florian Kleefeldt
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Avinash Sonawane
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - Thati Madhusudhan
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
| | - Akash Bachhuka
- UniSA Science, Technology, Engineering and Mathematics, University of South Australia, Mawson Lakes Campus, Adelaide, SA, Australia
| | - Djuro Kosanovic
- Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.,Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Norbert Weissmann
- Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Karsten Krüger
- Department of Exercise Physiology and Sports Therapy, University of Giessen, Giessen, Germany
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| |
Collapse
|
8
|
Systemic Inflammation, Vascular Function, and Endothelial Progenitor Cells after an Exercise Training Intervention in COPD. Am J Med 2021; 134:e171-e180. [PMID: 32781050 DOI: 10.1016/j.amjmed.2020.07.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Exercise training is a cornerstone of the treatment of chronic obstructive pulmonary disease (COPD) in all disease stages. Data about the training effects with supplemental oxygen in nonhypoxemic patients remains inconclusive. In this study we set out to investigate the training and oxygen effects on inflammatory markers, vascular function, and endothelial progenitor cells in this population of increased cardiovascular risk. METHODS In this prospective, randomized, double-blind, crossover study, 29 patients with nonhypoxemic COPD performed combined endurance and strength training 3 times a week while breathing medical air or supplemental oxygen for the first 6-week period, and were then reallocated to the opposite gas for the following 6 weeks. Exercise capacity, inflammatory biomarkers, endothelial function (peripheral arterial tone analysis), and endothelial progenitor cells were assessed. Data were also analyzed for a subgroup with endothelial dysfunction (reactive hyperemia index <1.67). RESULTS Following 12 weeks of exercise training, patients demonstrated a significant improvement of peak work rate and an associated decrease of blood fibrinogen and leptin. Eosinophils were found significantly reduced after exercise training in patients with endothelial dysfunction. In this subgroup, peripheral arterial tone analysis revealed a significant improvement of reactive hyperemia index. Generally, late endothelial progenitor cells were found significantly reduced after the exercise training intervention. Supplemental oxygen during training positively influenced the effect on exercise capacity without impact on inflammation and endothelial function. CONCLUSIONS This is the first randomized controlled trial in patients with COPD to show beneficial effects of exercise training not only on exercise capacity, but also on systemic/eosinophilic inflammation and endothelial dysfunction.
Collapse
|
9
|
Liu Y, Huang X, Chen D, Chen F, Mo C, Guo Y, Xie C, Liu G, Zeng H, Sun Y, Yang Z. The detrimental qualitative and quantitative alterations of circulating endothelial progenitor cells in patients with bronchiectasis. Respir Med 2021; 176:106270. [PMID: 33302144 DOI: 10.1016/j.rmed.2020.106270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/01/2022]
Abstract
BACKGROUND Bronchiectasis is an independent risk factor for cardiovascular disease(CVD)and cardiac dysfunction. Endothelial progenitor cells (EPCs) play a crucial role in maintaining endothelial function, and is inversely correlated with cardiovascular risk factors or cardiac dysfunction. However, the relationship between EPCs and bronchiectasis is unknown. METHODS Twenty-nine patients with stable bronchiectasis and 15 healthy controls were recruited. Fasting venous blood were collected for determining circulating EPC number and activity as well as systemic inflammatory cytokines. RESULTS The number and migratory or proliferative activity of circulating EPCs in bronchiectasis patients were significantly reduced (p < 0.001). In high E-FACED group, the number of circulating EPCs evaluated by cell culture assay and EPC proliferation were decreased (p < 0.05). Similarly, the number and function of circulating EPCs were both reduced in low forced expiratory volume in 1 s (FEV1) or high mMRC group (p < 0.05). There was a significant correlation between circulating EPCs and bronchiectasis disease severity, according to the E-FACED score (p < 0.05), particularly to FEV1 (p < 0.05) and mMRC dyspnea score (p < 0.05). The count and activity of EPCs inversely correlated with hsCRP levels and IL-6 levels (p < 0.01). CONCLUSIONS Deficiencies in the number and function of circulating EPCs are present in patients with bronchiectasis. The changes are related to disease severity and may be partly attributed to systemic inflammation. The current findings may provide novel surrogate evaluation biomarkers and potential therapeutic target for bronchiectasis.
Collapse
Affiliation(s)
- Yangli Liu
- Division of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, PR China
| | - Xinyan Huang
- Division of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, PR China
| | - Dubo Chen
- Laboratory Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, PR China
| | - Fengjia Chen
- Division of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, PR China
| | - Chengqiang Mo
- Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, PR China
| | - Yubiao Guo
- Division of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, PR China
| | - Canmao Xie
- Division of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Province Guangdong, PR China
| | - Gexiu Liu
- Institute of Hematology, School of Basic Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Haitao Zeng
- Center for Reproductive Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, PR China
| | - Yunwei Sun
- Guangzhou Development District Hospital, Guangzhou, 510730, Province Guangdong, PR China.
| | - Zhen Yang
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, PR China; NHC Key Laboratory on Assisted Circulation, Sun Yat-Sen University, Guangzhou, 510080, PR China.
| |
Collapse
|
10
|
Skurikhin EG, Krupin VA, Pershina OV, Pan ES, Pakhomova AV, Sandrikina LA, Ermakova NN, Vaizova OE, Zhukova MA, Dygai AM. Blockade of Dopamine D2 Receptors as a Novel Approach to Stimulation of Notch1 + Endothelial Progenitor Cells and Angiogenesis in C57BL/6 Mice with Pulmonary Emphysema Induced by Proteases and Deficiency of α1-Antitrypsin. Bull Exp Biol Med 2020; 168:718-723. [PMID: 32328949 DOI: 10.1007/s10517-020-04787-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Indexed: 11/24/2022]
Abstract
We studied the effects of spiperone, a selective blocker of dopamine D2 receptors, on the model of pulmonary emphysema provoked by administration of elastase and D-galactosamine hydrochloride to female C57BL/6 mice and characterized by activation of proteases in the lungs and systemic deficiency of its inhibitor α1-antitrypsin. In this model, spiperone prevented the development of inflammatory reaction and reduced the area of emphysematous expanded alveolar tissue. The expression of angiogenic marker CD31 in the lungs increased under these conditions. Regeneration of the damaged microvascular bed under the action of spiperone resulted from recruiting of Notch1+ endothelial progenitor cells (CD45-CD31+CD34+) into the lungs and blockade of the inhibitory effect of dopamine on phosphorylation of VEGF-2 receptors in endothelial cells of different maturity. In addition, spiperone produced a protective effect on hepatocytes and restored the production and secretion of α1-antitrypsin by these cells.
Collapse
Affiliation(s)
- E G Skurikhin
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia.
| | - V A Krupin
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia
| | - O V Pershina
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia
| | - E S Pan
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia
| | - A V Pakhomova
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia
| | - L A Sandrikina
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia
| | - N N Ermakova
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia
| | - O E Vaizova
- Department of Pharmacology, Siberian State Medical University, Ministry of Health of the Russian Federation, Tomsk, Russia
| | - M A Zhukova
- Department of Pharmacology, Siberian State Medical University, Ministry of Health of the Russian Federation, Tomsk, Russia
| | - A M Dygai
- Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia
| |
Collapse
|
11
|
Tura-Ceide O, Pizarro S, García-Lucio J, Ramírez J, Molins L, Blanco I, Torralba Y, Sitges M, Bonjoch C, Peinado VI, Barberà JA. Progenitor cell mobilisation and recruitment in pulmonary arteries in chronic obstructive pulmonary disease. Respir Res 2019; 20:74. [PMID: 30992021 PMCID: PMC6469212 DOI: 10.1186/s12931-019-1024-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 03/12/2019] [Indexed: 12/22/2022] Open
Abstract
Background Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction. Methods Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45+ cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively. Results COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45+ cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = − 0.35, p < 0.05). In pulmonary arteries, the number of CD45+ cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = − 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels. Conclusion In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD. Electronic supplementary material The online version of this article (10.1186/s12931-019-1024-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. .,Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain. .,Servei de Pneumologia, Hospital Clínic, Villarroel, 170, 08036, Barcelona, Spain.
| | - Sandra Pizarro
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jéssica García-Lucio
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Josep Ramírez
- Department of Pathology, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Laureano Molins
- Department of Thoracic Surgery, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Yolanda Torralba
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Marta Sitges
- Department of Cardiology, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), Madrid, Spain
| | - Cristina Bonjoch
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Victor I Peinado
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Joan Albert Barberà
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. .,Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain. .,Servei de Pneumologia, Hospital Clínic, Villarroel, 170, 08036, Barcelona, Spain.
| |
Collapse
|
12
|
Musri MM, Coll-Bonfill N, Maron BA, Peinado VI, Wang RS, Altirriba J, Blanco I, Oldham WM, Tura-Ceide O, García-Lucio J, de la Cruz-Thea B, Meister G, Loscalzo J, Barberà JA. MicroRNA Dysregulation in Pulmonary Arteries from Chronic Obstructive Pulmonary Disease. Relationships with Vascular Remodeling. Am J Respir Cell Mol Biol 2019; 59:490-499. [PMID: 29757677 DOI: 10.1165/rcmb.2017-0040oc] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Pulmonary vascular remodeling is an angiogenic-related process involving changes in smooth muscle cell (SMC) homeostasis, which is frequently observed in chronic obstructive pulmonary disease (COPD). MicroRNAs (miRNAs) are small, noncoding RNAs that regulate mRNA expression levels of many genes, leading to the manifestation of cell identity and specific cellular phenotypes. Here, we evaluate the miRNA expression profiles of pulmonary arteries (PAs) of patients with COPD and its relationship with the regulation of SMC phenotypic change. miRNA expression profiles from PAs of 12 patients with COPD, 9 smokers with normal lung function (SK), and 7 nonsmokers (NS) were analyzed using TaqMan Low-Density Arrays. In patients with COPD, expression levels of miR-98, miR-139-5p, miR-146b-5p, and miR-451 were upregulated, as compared with NS. In contrast, miR-197, miR-204, miR-485-3p, and miR-627 were downregulated. miRNA-197 expression correlated with both airflow obstruction and PA intimal enlargement. In an in vitro model of SMC differentiation, miR-197 expression was associated with an SMC contractile phenotype. miR-197 inhibition blocked the acquisition of contractile markers in SMCs and promoted a proliferative/migratory phenotype measured by both cell cycle analysis and wound-healing assay. Using luciferase assays, Western blot, and quantitative PCR, we confirmed that miR-197 targets the transcription factor E2F1. In PAs from patients with COPD, levels of E2F1 were increased as compared with NS. In PAs of patients with COPD, remodeling of the vessel wall is associated with downregulation of miR-197, which regulates SMC phenotype. The effect of miR-197 on PAs might be mediated, at least in part, by the key proproliferative factor, E2F1.
Collapse
Affiliation(s)
- Melina M Musri
- 1 Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, University of Barcelona, Barcelona, Spain.,2 Instituto de Investigación Médica Mercedes y Martín Ferreyra, Consejo Nacional de Investigaciones Científicas y Técnicas (INIMEC-CONICET), Universidad Nacional de Córdoba, Cátedra de Genética, Departamento de Fisiología, Facultad de Ciencias Exactas Físicas y Naturales (FCEFyN), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Núria Coll-Bonfill
- 1 Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, University of Barcelona, Barcelona, Spain.,3 Biomedical Research Networking Center for Respiratory Diseases, Madrid, Spain
| | - Bradley A Maron
- 4 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Víctor I Peinado
- 1 Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, University of Barcelona, Barcelona, Spain.,3 Biomedical Research Networking Center for Respiratory Diseases, Madrid, Spain
| | - Rui-Sheng Wang
- 4 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Jordi Altirriba
- 5 Laboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Isabel Blanco
- 1 Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, University of Barcelona, Barcelona, Spain.,3 Biomedical Research Networking Center for Respiratory Diseases, Madrid, Spain
| | - William M Oldham
- 6 Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and
| | - Olga Tura-Ceide
- 1 Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, University of Barcelona, Barcelona, Spain.,3 Biomedical Research Networking Center for Respiratory Diseases, Madrid, Spain
| | - Jessica García-Lucio
- 1 Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, University of Barcelona, Barcelona, Spain
| | - Benjamin de la Cruz-Thea
- 2 Instituto de Investigación Médica Mercedes y Martín Ferreyra, Consejo Nacional de Investigaciones Científicas y Técnicas (INIMEC-CONICET), Universidad Nacional de Córdoba, Cátedra de Genética, Departamento de Fisiología, Facultad de Ciencias Exactas Físicas y Naturales (FCEFyN), Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Gunter Meister
- 7 Biochemistry Center Regensburg, Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany
| | - Joseph Loscalzo
- 4 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Joan A Barberà
- 1 Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, University of Barcelona, Barcelona, Spain.,3 Biomedical Research Networking Center for Respiratory Diseases, Madrid, Spain
| |
Collapse
|
13
|
Coppolino I, Ruggeri P, Nucera F, Cannavò MF, Adcock I, Girbino G, Caramori G. Role of Stem Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Pulmonary Emphysema. COPD 2018; 15:536-556. [DOI: 10.1080/15412555.2018.1536116] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Irene Coppolino
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Paolo Ruggeri
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Francesco Nucera
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Mario Francesco Cannavò
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Ian Adcock
- Airways Disease Section, National Heart and Lung Institute, Royal Brompton Hospital Biomedical Research Unit, Imperial College, London, UK
| | - Giuseppe Girbino
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Gaetano Caramori
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| |
Collapse
|
14
|
García-Lucio J, Peinado VI, de Jover L, del Pozo R, Blanco I, Bonjoch C, Coll-Bonfill N, Paul T, Tura-Ceide O, Barberà JA. Imbalance between endothelial damage and repair capacity in chronic obstructive pulmonary disease. PLoS One 2018; 13:e0195724. [PMID: 29672621 PMCID: PMC5908268 DOI: 10.1371/journal.pone.0195724] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 03/28/2018] [Indexed: 02/07/2023] Open
Abstract
Background Circulating endothelial microparticles (EMPs) and progenitor cells (PCs) are biological markers of endothelial function and endogenous repair capacity. The study was aimed to investigate whether COPD patients have an imbalance between EMPs to PCs compared to controls and to evaluate the effect of cigarette smoke on these circulating markers. Methods Circulating EMPs and PCs were determined by flow cytometry in 27 nonsmokers, 20 smokers and 61 COPD patients with moderate to severe airflow obstruction. We compared total EMPs (CD31+CD42b-), apoptotic if they co-expressed Annexin-V+ or activated if they co-expressed CD62E+, circulating PCs (CD34+CD133+CD45+) and the EMPs/PCs ratio between groups. Results COPD patients presented increased levels of total and apoptotic circulating EMPs, and an increased EMPs/PCs ratio, compared with nonsmokers. Women had less circulating PCs than men through all groups and those with COPD showed lower levels of PCs than both control groups. In smokers, circulating EMPs and PCs did not differ from nonsmokers, being the EMPs/PCs ratio in an intermediate position between COPD and nonsmokers. Conclusions We conclude that COPD patients present an imbalance between endothelial damage and repair capacity that might explain the frequent concurrence of cardiovascular disorders. Factors related to the disease itself and gender, rather than cigarette smoking, may account for this imbalance.
Collapse
Affiliation(s)
- Jéssica García-Lucio
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
| | - Victor I. Peinado
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES); Madrid, Spain
| | - Lluís de Jover
- Biostatistics Unit, Department of Public Health, School of Medicine, University of Barcelona; Barcelona, Spain
| | - Roberto del Pozo
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
| | - Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES); Madrid, Spain
| | - Cristina Bonjoch
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
| | - Núria Coll-Bonfill
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
| | - Tanja Paul
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES); Madrid, Spain
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES); Madrid, Spain
| | - Joan Albert Barberà
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES); Madrid, Spain
- * E-mail:
| |
Collapse
|
15
|
Huertas A, Guignabert C, Barberà JA, Bärtsch P, Bhattacharya J, Bhattacharya S, Bonsignore MR, Dewachter L, Dinh-Xuan AT, Dorfmüller P, Gladwin MT, Humbert M, Kotsimbos T, Vassilakopoulos T, Sanchez O, Savale L, Testa U, Wilkins MR. Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases. Eur Respir J 2018; 51:13993003.00745-2017. [DOI: 10.1183/13993003.00745-2017] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 02/03/2018] [Indexed: 12/15/2022]
Abstract
The European Respiratory Society (ERS) Research Seminar entitled “Pulmonary vascular endothelium: orchestra conductor in respiratory diseases - highlights from basic research to therapy” brought together international experts in dysfunctional pulmonary endothelium, from basic science to translational medicine, to discuss several important aspects in acute and chronic lung diseases. This review will briefly sum up the different topics of discussion from this meeting which was held in Paris, France on October 27–28, 2016. It is important to consider that this paper does not address all aspects of endothelial dysfunction but focuses on specific themes such as: 1) the complex role of the pulmonary endothelium in orchestrating the host response in both health and disease (acute lung injury, chronic obstructive pulmonary disease, high-altitude pulmonary oedema and pulmonary hypertension); and 2) the potential value of dysfunctional pulmonary endothelium as a target for innovative therapies.
Collapse
|
16
|
Liu CY, Parikh M, Bluemke DA, Balte P, Carr J, Dashnaw S, Poor HD, Gomes AS, Hoffman EA, Kawut SM, Lima JAC, McAllister DA, Prince MA, Vogel-Claussen J, Barr RG. Pulmonary artery stiffness in chronic obstructive pulmonary disease (COPD) and emphysema: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study. J Magn Reson Imaging 2018; 47:262-271. [PMID: 28488348 PMCID: PMC5681449 DOI: 10.1002/jmri.25753] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/05/2017] [Indexed: 11/09/2022] Open
Abstract
PURPOSE Chronic obstructive pulmonary disease (COPD) and particularly emphysema are characterized by stiffness of the aorta, due in part to accelerated elastin degradation in the lungs and aorta. Stiffness of the pulmonary arteries (PAs) may also be increased in COPD and emphysema, but data are lacking. We assessed PA stiffness using MRI in patients with COPD and related these measurements to COPD severity and percent emphysema. MATERIALS AND METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited 290 participants, age 50-79 years with 10 or more packyears and free of clinical cardiovascular disease. COPD severity were defined on postbronchodilator spirometry by ATS/ERS criteria. Percent emphysema was defined as the percentage of regions of the lung < -950 Hounsfield units on full-lung computed tomography (CT). PA stain was defined by the percent change in cross-sectional PA area between systole and diastole on MRI. Blood flow across the tricuspid and mitral valves was assessed by phase-contrast MRI for determination of the ventricular diastolic dysfunction (E/A ratio). RESULTS PA strain was reduced in COPD compared with controls (P = 0.002) and was inversely correlated with COPD severity (P = 0.004). PA strain was inversely associated to percent emphysema (P = 0.01). PA strain was also markedly correlated with right ventricular diastolic dysfunction measured by E/A ratios in the fully adjusted mix models (P = 0.02). CONCLUSION PA strain is reduced in COPD, related in part to percent emphysema on CT scan, which may have implications for pulmonary small vessel flow and right ventricular function. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:262-271.
Collapse
Affiliation(s)
- Chia-Ying Liu
- Department of Radiology, Johns Hopkins Hospital, Baltimore, MD
- Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD
| | - Megha Parikh
- Department of Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY
| | - David A Bluemke
- Department of Radiology, Johns Hopkins Hospital, Baltimore, MD
- Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD
| | - Pallavi Balte
- Department of Radiology, Johns Hopkins Hospital, Baltimore, MD
| | - James Carr
- Department of Radiology, Northwestern University, Chicago, IL
| | - Stephen Dashnaw
- Department of Radiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY
| | - Hooman D. Poor
- Division of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai-National Jewish Health Respiratory Institute, New York, NY
| | - Antoinette S Gomes
- Department of Medicine, University of California, Los Angeles, Los Angeles
| | - Eric A Hoffman
- Department of Radiology, University of Iowa, Iowa City, IA
| | - Steven M Kawut
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Joao AC Lima
- Department of Radiology, Johns Hopkins Hospital, Baltimore, MD
| | - David A McAllister
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Martin A Prince
- Department of Radiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY
- Department of Radiology, Weill Cornell Medical College, New York, NY
| | | | - R Graham Barr
- Department of Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY
- Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, NY
| |
Collapse
|
17
|
Malerba M, Nardin M, Radaeli A, Montuschi P, Carpagnano GE, Clini E. The potential role of endothelial dysfunction and platelet activation in the development of thrombotic risk in COPD patients. Expert Rev Hematol 2017; 10:821-832. [PMID: 28693343 DOI: 10.1080/17474086.2017.1353416] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Despite lack of knowledge in the field, several studies have underlined the role of endothelium dysfunction and platelet activation as significant players in the development and progression of chronic obstructive pulmonary disease (COPD). Indeed, endothelium plays a crucial role in vascular homeostasis and impairment, due to the inflammation process enhanced by smoking. Chronic inflammation and endothelial dysfunction have been proved to drive platelet activity. Consequently, thrombotic risk is enhanced in COPD, and might explain the higher percentage of cardiovascular death in such patients. Areas covered: This review aims to clarify the role of endothelium function and platelet hyper-activity as the pathophysiological mechanisms of the increased thrombotic risk in COPD. Expert commentary: In COPD patients, chronic inflammation does not impact only on lung parenchyma, but potentially involves all systems, including the endothelium of blood vessels. Impaired endothelium has several consequences, such as reduced vasodilatation capacity, enhanced blood coagulation, and increased platelet activation resulting in higher risk of thrombosis in COPD patients. Endothelium dysfunction and platelet activation are potential targets of therapy in patients with COPD aiming to reduce their risk of cardiovascular events.
Collapse
Affiliation(s)
- Mario Malerba
- a Department of Internal Medicine , University of Brescia and ASST Spedali Civili , Brescia , Italy
| | - Matteo Nardin
- a Department of Internal Medicine , University of Brescia and ASST Spedali Civili , Brescia , Italy
| | | | - Paolo Montuschi
- c Department of Pharmacology, Faculty of Medicine , University Hospital Agostino Gemelli Catholic University of the Sacred Heart, Pharmacology , Rome , Italy
| | - Giovanna E Carpagnano
- d Department of Medical and Surgical Sciences , Institute of Respiratory Diseases, University of Foggia , Foggia , Italy
| | - Enrico Clini
- e Department of Medical and Surgical Sciences , University of Modena-Reggio Emilia , Modena , Italy
| |
Collapse
|
18
|
Salter B, Sehmi R. The role of bone marrow-derived endothelial progenitor cells and angiogenic responses in chronic obstructive pulmonary disease. J Thorac Dis 2017; 9:2168-2177. [PMID: 28840018 DOI: 10.21037/jtd.2017.07.56] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Increased vascularity of the bronchial sub-mucosa is a cardinal feature of chronic obstructive pulmonary disease (COPD) and is associated with disease severity. Capillary engorgement, leakage, and vasodilatation can directly increase airway wall thickness resulting in airway luminal narrowing and facilitate inflammatory cell trafficking, thereby contributing to irreversible airflow obstruction, a characteristic of COPD. Airway wall neovascularisation, seen as increases in both the size and number of bronchial blood vessels is a prominent feature of COPD that correlates with reticular basement membrane thickening and airway obstruction. Sub-epithelial vascularization may be an important remodelling event for airway narrowing and airflow obstruction in COPD. Post-natal angiogenesis is a complex process, whereby new blood vessels sprouting from extant microvasculature, can arise from the proliferation of resident mature vascular endothelial cells (ECs). In addition, this may arise from increased turnover and lung-homing of circulating endothelial progenitor cells (EPCs) from the bone marrow (BM). Following lung-homing, EPCs can differentiate locally within the tissue into ECs, further contributing to vascular repair, maintenance, and expansion under pathological conditions, governed by a locally elaborated milieu of growth factors (GFs). In this article, we will review evidence for the role of BM-derived EPCs in the development of angiogenesis in the lug and discuss how this may relate to the pathogenesis of COPD.
Collapse
Affiliation(s)
- Brittany Salter
- CardioRespiratory Research Group, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Roma Sehmi
- CardioRespiratory Research Group, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| |
Collapse
|
19
|
Belyanskaya SL, Ding Y, Callahan JF, Lazaar AL, Israel DI. Discovering Drugs with DNA-Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase. Chembiochem 2017; 18:837-842. [DOI: 10.1002/cbic.201700014] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Indexed: 12/27/2022]
Affiliation(s)
| | - Yun Ding
- GlaxoSmithKline R&D; 830 Winter Street Waltham MA 02451 USA
| | - James F. Callahan
- GlaxoSmithKline R&D; 709 Swedeland Road King of Prussia PA 19406 USA
| | - Aili L. Lazaar
- GlaxoSmithKline R&D; 709 Swedeland Road King of Prussia PA 19406 USA
| | | |
Collapse
|
20
|
Endothelial progenitor cells in chronic obstructive pulmonary disease and emphysema. PLoS One 2017; 12:e0173446. [PMID: 28291826 PMCID: PMC5349667 DOI: 10.1371/journal.pone.0173446] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 02/21/2017] [Indexed: 01/19/2023] Open
Abstract
Endothelial injury is implicated in the pathogenesis of COPD and emphysema; however the role of endothelial progenitor cells (EPCs), a marker of endothelial cell repair, and circulating endothelial cells (CECs), a marker of endothelial cell injury, in COPD and its subphenotypes is unresolved. We hypothesized that endothelial progenitor cell populations would be decreased in COPD and emphysema and that circulating endothelial cells would be increased. Associations with other subphenotypes were examined. The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with COPD and controls age 50–79 years without clinical cardiovascular disease. Endothelial progenitor cell populations (CD34+KDR+ and CD34+KDR+CD133+ cells) and circulating endothelial cells (CD45dimCD31+CD146+CD133-) were measured by flow cytometry. COPD was defined by standard spirometric criteria. Emphysema was assessed qualitatively and quantitatively on CT. Full pulmonary function testing and expiratory CTs were measured in a subset. Among 257 participants, both endothelial progenitor cell populations, and particularly CD34+KDR+ endothelial progenitor cells, were reduced in COPD. The CD34+KDR+CD133+ endothelial progenitor cells were associated inversely with emphysema extent. Both endothelial progenitor cell populations were associated inversely with extent of panlobular emphysema and positively with diffusing capacity. Circulating endothelial cells were not significantly altered in COPD but were inversely associated with pulmonary microvascular blood flow on MRI. There was no consistent association of endothelial progenitor cells or circulating endothelial cells with measures of gas trapping. These data provide evidence that endothelial repair is impaired in COPD and suggest that this pathological process is specific to emphysema.
Collapse
|
21
|
García-Lucio J, Tura-Ceide O, Del Pozo R, Blanco I, Pizarro S, Ferrer E, Díez M, Coll-Bonfill N, Piccari L, Peinado VI, Barberà JA. Effect of targeted therapy on circulating progenitor cells in precapillary pulmonary hypertension. Int J Cardiol 2016; 228:238-243. [PMID: 27865192 DOI: 10.1016/j.ijcard.2016.11.175] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 11/06/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND Endothelial dysfunction is key in the development of pulmonary hypertension (PH) and is associated with reduced number of circulating progenitor cells. Studies to date evaluating levels of circulating progenitor cells in PH have provided conflicting results. Current treatment of pulmonary arterial hypertension (PAH) and medical treatment of chronic thromboembolic pulmonary hypertension (CTEPH) targets endothelium dependent signalling pathways. The effect of PAH-targeted therapy on circulating progenitor cells has not been clearly established. OBJECTIVES To investigate whether levels of circulating progenitor cells in treatment-naïve patients with PAH or CTEPH differ from healthy subjects and to assess the effect of PAH-targeted therapy on the circulating levels of these progenitors. METHODS Thirty controls, 33 PAH and 11 CTEPH treatment-naïve patients were studied. Eighteen patients with PAH and 9 with CTEPH were re-evaluated 6-12months after starting PAH-targeted therapy. Levels of progenitors were measured by flow cytometry as CD45+CD34+ and CD45+CD34+CD133+ cells. RESULTS Compared with controls, the number of circulating progenitor cells was reduced in PAH but not in CTEPH. After 6-12months of treatment, levels of circulating progenitors increased in PAH and remained unchanged in CTEPH. Patients with lower exercise tolerance presented lower levels of circulating progenitors. No other relation was found between levels of progenitors and clinical or hemodynamic parameters. CONCLUSIONS Patients with PAH, but not those with CTEPH, present reduced levels of circulating progenitor cells. PAH-targeted therapy increases levels of progenitors in PAH but not in CTEPH, suggesting different involvement of progenitor cells in the pathobiology of these pulmonary hypertensive disorders.
Collapse
Affiliation(s)
- Jéssica García-Lucio
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.
| | - Roberto Del Pozo
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Sandra Pizarro
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Elisabet Ferrer
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Marta Díez
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Núria Coll-Bonfill
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Lucilla Piccari
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Víctor I Peinado
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Joan Albert Barberà
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| |
Collapse
|
22
|
Iyer KS, Newell JD, Jin D, Fuld MK, Saha PK, Hansdottir S, Hoffman EA. Quantitative Dual-Energy Computed Tomography Supports a Vascular Etiology of Smoking-induced Inflammatory Lung Disease. Am J Respir Crit Care Med 2016; 193:652-61. [PMID: 26569033 DOI: 10.1164/rccm.201506-1196oc] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
RATIONALE Endothelial dysfunction is of interest in relation to smoking-associated emphysema, a component of chronic obstructive pulmonary disease (COPD). We previously demonstrated that computed tomography (CT)-derived pulmonary blood flow (PBF) heterogeneity is greater in smokers with normal pulmonary function tests (PFTs) but who have visual evidence of centriacinar emphysema (CAE) on CT. OBJECTIVES We introduced dual-energy CT (DECT) perfused blood volume (PBV) as a PBF surrogate to evaluate whether the CAE-associated increased PBF heterogeneity is reversible with sildenafil. METHODS Seventeen PFT-normal current smokers were divided into CAE-susceptible (SS; n = 10) and nonsusceptible (NS; n = 7) smokers, based on the presence or absence of CT-detected CAE. DECT-PBV images were acquired before and 1 hour after administration of 20 mg oral sildenafil. Regional PBV and PBV coefficients of variation (CV), a measure of spatial blood flow heterogeneity, were determined, followed by quantitative assessment of the central arterial tree. MEASUREMENTS AND MAIN RESULTS After sildenafil administration, regional PBV-CV decreased in SS subjects but did not decrease in NS subjects (P < 0.05), after adjusting for age and pack-years. Quantitative evaluation of the central pulmonary arteries revealed higher arterial volume and greater cross-sectional area (CSA) in the lower lobes of SS smokers, which suggested arterial enlargement in response to increased peripheral resistance. After sildenafil, arterial CSA decreased in SS smokers but did not decrease in NS smokers (P < 0.01). CONCLUSIONS These results demonstrate that sildenafil restores peripheral perfusion and reduces central arterial enlargement in normal SS subjects with little effect in NS subjects, highlighting DECT-PBV as a biomarker of reversible endothelial dysfunction in smokers with CAE.
Collapse
Affiliation(s)
| | - John D Newell
- 1 Department of Biomedical Engineering.,2 Department of Radiology
| | - Dakai Jin
- 3 Department of Electrical Engineering, and
| | | | - Punam K Saha
- 2 Department of Radiology.,3 Department of Electrical Engineering, and
| | - Sif Hansdottir
- 5 Division of Pulmonary Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and
| | - Eric A Hoffman
- 1 Department of Biomedical Engineering.,2 Department of Radiology.,5 Division of Pulmonary Medicine, Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and
| |
Collapse
|
23
|
Dysregulation of Vascular Endothelial Progenitor Cells Lung-Homing in Subjects with COPD. Can Respir J 2016; 2016:1472823. [PMID: 27445517 PMCID: PMC4904543 DOI: 10.1155/2016/1472823] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 03/23/2016] [Accepted: 04/20/2016] [Indexed: 01/22/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow limitation and progressive decline of lung function and punctuated by occasional exacerbations. The disease pathogenesis may involve activation of the bone marrow stimulating mobilization and lung-homing of progenitor cells. We investigated the hypothesis that lower circulating numbers of vascular endothelial progenitor cells (VEPCs) are a consequence of increased lung-sequestration in COPD. Nonatopic, current or ex-smokers with diagnosed COPD and nonatopic, nonsmoking normal controls were enrolled. Blood and induced sputum extracted primitive hemopoietic progenitors (HPCs) and VEPC were enumerated by flow cytometry. Migration and adhesive responses to fibronectin were assessed. In sputum, VEPC numbers were significantly greater in COPD compared to normal controls. In blood, VEPCs were significantly lower in COPD versus normal controls. There were no differences in HPC levels between the two groups in either compartment. Functionally, there was a greater migrational responsiveness of progenitors from COPD subjects to stromal cell-derived factor-1alpha (SDF-1α) compared to normal controls. This was associated with greater numbers of CXCR4+ progenitors in sputum from COPD. Increased migrational responsiveness of progenitor cells may promote lung-homing of VEPC in COPD which may disrupt maintenance and repair of the airways and contribute to COPD disease pathogenesis.
Collapse
|
24
|
Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease. Am J Med 2016; 129:366-71. [PMID: 26706386 DOI: 10.1016/j.amjmed.2015.11.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 11/02/2015] [Accepted: 11/03/2015] [Indexed: 02/01/2023]
Abstract
Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis.
Collapse
|
25
|
Blanco I, Piccari L, Barberà JA. Pulmonary vasculature in COPD: The silent component. Respirology 2016; 21:984-94. [PMID: 27028849 DOI: 10.1111/resp.12772] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/06/2015] [Accepted: 12/20/2015] [Indexed: 01/15/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in bronchial and alveolar structures, changes in pulmonary vessels also represent an important component of the disease. Alterations in vessel structure are highly prevalent and abnormalities in their function impair gas exchange and may result in pulmonary hypertension (PH), an important complication of the disease associated with reduced survival and worse clinical course. The prevalence of PH is high in COPD, particularly in advanced stages, although it remains of mild to moderate severity in the majority of cases. Endothelial dysfunction, with imbalance between vasodilator/vasoconstrictive mediators, is a key determinant of changes taking place in pulmonary vasculature in COPD. Cigarette smoke products may perturb endothelial cells and play a critical role in initiating vascular changes. The concurrence of inflammation, hypoxia and emphysema further contributes to vascular damage and to the development of PH. The use of drugs that target endothelium-dependent signalling pathways, currently employed in pulmonary arterial hypertension, is discouraged in COPD due to the lack of efficacy observed in randomized clinical trials and because there is compelling evidence indicating that these drugs may worsen pulmonary gas exchange. The subgroup of patients with severe PH should be ideally managed in centres with expertise in both PH and chronic lung diseases because alterations of pulmonary vasculature might resemble those observed in pulmonary arterial hypertension. Because this condition entails poor prognosis, it warrants specialist treatment.
Collapse
Affiliation(s)
- Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clínic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS); University of Barcelona and Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Lucilla Piccari
- Department of Pulmonary Medicine, Hospital Clínic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS); University of Barcelona and Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Joan Albert Barberà
- Department of Pulmonary Medicine, Hospital Clínic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS); University of Barcelona and Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| |
Collapse
|
26
|
Hoffman EA, Lynch DA, Barr RG, van Beek EJR, Parraga G. Pulmonary CT and MRI phenotypes that help explain chronic pulmonary obstruction disease pathophysiology and outcomes. J Magn Reson Imaging 2016; 43:544-57. [PMID: 26199216 PMCID: PMC5207206 DOI: 10.1002/jmri.25010] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 07/01/2015] [Indexed: 12/12/2022] Open
Abstract
Pulmonary x-ray computed tomographic (CT) and magnetic resonance imaging (MRI) research and development has been motivated, in part, by the quest to subphenotype common chronic lung diseases such as chronic obstructive pulmonary disease (COPD). For thoracic CT and MRI, the main COPD research tools, disease biomarkers are being validated that go beyond anatomy and structure to include pulmonary functional measurements such as regional ventilation, perfusion, and inflammation. In addition, there has also been a drive to improve spatial and contrast resolution while at the same time reducing or eliminating radiation exposure. Therefore, this review focuses on our evolving understanding of patient-relevant and clinically important COPD endpoints and how current and emerging MRI and CT tools and measurements may be exploited for their identification, quantification, and utilization. Since reviews of the imaging physics of pulmonary CT and MRI and reviews of other COPD imaging methods were previously published and well-summarized, we focus on the current clinical challenges in COPD and the potential of newly emerging MR and CT imaging measurements to address them. Here we summarize MRI and CT imaging methods and their clinical translation for generating reproducible and sensitive measurements of COPD related to pulmonary ventilation and perfusion as well as parenchyma morphology. The key clinical problems in COPD provide an important framework in which pulmonary imaging needs to rapidly move in order to address the staggering burden, costs, as well as the mortality and morbidity associated with COPD.
Collapse
Affiliation(s)
- Eric A Hoffman
- Department of Radiology, University of Iowa, Iowa City, Iowa, USA
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
- Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa, USA
| | - David A Lynch
- Department of Radiology, National Jewish Health Center, Denver, Colorado, USA
| | - R Graham Barr
- Division of General Medicine, Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Columbia University Medical Center, New York, New York, USA
- Department of Epidemiology, Columbia University Medical Center, New York, New York, USA
| | - Edwin J R van Beek
- Clinical Research Imaging Centre, Queen's Medical Research Institute, University of Edinburgh, Scotland, UK
| | - Grace Parraga
- Robarts Research Institute, University of Western Ontario, London, Canada
- Department of Medical Biophysics, University of Western Ontario, London, Canada
| |
Collapse
|
27
|
García-Lucio J, Argemi G, Tura-Ceide O, Diez M, Paul T, Bonjoch C, Coll-Bonfill N, Blanco I, Barberà JA, Musri MM, Peinado VI. Gene expression profile of angiogenic factors in pulmonary arteries in COPD: relationship with vascular remodeling. Am J Physiol Lung Cell Mol Physiol 2016; 310:L583-92. [PMID: 26801565 DOI: 10.1152/ajplung.00261.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 01/15/2016] [Indexed: 11/22/2022] Open
Abstract
Pulmonary vessel remodeling in chronic obstructive pulmonary disease (COPD) involves changes in smooth muscle cell proliferation, which are highly dependent on the coordinated interaction of angiogenic-related growth factors. The purpose of the study was to investigate, in isolated pulmonary arteries (PA) from patients with COPD, the gene expression of 46 genes known to be modulators of the angiogenic process and/or involved in smooth muscle cell proliferation and to relate it to vascular remodeling. PA segments were isolated from 29 patients and classified into tertiles, according to intimal thickness. After RNA extraction, the gene expression was assessed by RT-PCR using TaqMan low-density arrays. The univariate analysis only showed upregulation of angiopoietin-2 (ANGPT-2) in remodeled PA (P < 0.05). The immunohistochemical expression of ANGPT-2 correlated with intimal enlargement (r = 0.42, P < 0.05). However, a combination of 10 factors in a multivariate discriminant analysis model explained up to 96% of the classification of the arteries. A network analysis of 46 genes showed major decentralization. In this network, the metalloproteinase-2 (MMP-2) was shown to be the bridge between intimal enlargement and fibrogenic factors. In COPD patients, plasma levels of ANGPT-2 were higher in current smokers or those with pulmonary hypertension. We conclude that an imbalance in ANGPT-2, combined with related factors such as VEGF, β-catenin, and MMP-2, may partially explain the structural derangements of the arterial wall. MMP-2 may act as a bridge channeling actions from the main fibrogenic factors.
Collapse
Affiliation(s)
- Jéssica García-Lucio
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and
| | - Gemma Argemi
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Marta Diez
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and
| | - Tanja Paul
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and
| | - Cristina Bonjoch
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and
| | - Nuria Coll-Bonfill
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and
| | - Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Joan A Barberà
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| | - Melina M Musri
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and
| | - Victor I Peinado
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain
| |
Collapse
|
28
|
Kurtagic E, Rich CB, Buczek-Thomas JA, Nugent MA. Neutrophil Elastase-Generated Fragment of Vascular Endothelial Growth Factor-A Stimulates Macrophage and Endothelial Progenitor Cell Migration. PLoS One 2015; 10:e0145115. [PMID: 26672607 PMCID: PMC4682631 DOI: 10.1371/journal.pone.0145115] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 11/27/2015] [Indexed: 12/19/2022] Open
Abstract
Elastase released from neutrophils as part of the innate immune system has been implicated in chronic diseases such as emphysema and cardiovascular disease. We have previously shown that neutrophil elastase targets vascular endothelial growth factor-A (VEGF) for partial degradation to generate a fragment of VEGF (VEGFf) that has distinct activities. Namely, VEGFf binds to VEGF receptor 1 but not to VEGF receptor 2 and shows altered signaling compared to intact VEGF. In the present study we investigated the chemotactic function of VEGF and VEGFf released from cells by neutrophil elastase. We found that endothelial cells migrated in response to intact VEGF but not VEGFf whereas RAW 264.7 macrophages/monocytes and embryonic endothelial progenitor cells were stimulated to migrate by either VEGF or VEGFf. To investigate the role of elastase-mediated release of VEGF from cells/extracellular matrices, a co-culture system was established. High or low VEGF producing cells were co-cultured with macrophages, endothelial or endothelial progenitor cells and treated with neutrophil elastase. Elastase treatment stimulated macrophage and endothelial progenitor cell migration with the response being greater with the high VEGF expressing cells. However, elastase treatment led to decreased endothelial cell migration due to VEGF cleavage to VEGF fragment. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment.
Collapse
Affiliation(s)
- Elma Kurtagic
- Department of Biochemistry Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Celeste B. Rich
- Department of Biochemistry Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Jo Ann Buczek-Thomas
- Department of Biochemistry Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Matthew A. Nugent
- Department of Biochemistry Boston University School of Medicine, Boston, Massachusetts, United States of America
- Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, United States of America
- * E-mail:
| |
Collapse
|
29
|
Adventitial alterations are the main features in pulmonary artery remodeling due to long-term chronic intermittent hypobaric hypoxia in rats. BIOMED RESEARCH INTERNATIONAL 2015; 2015:169841. [PMID: 25738150 PMCID: PMC4337174 DOI: 10.1155/2015/169841] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Revised: 10/21/2014] [Accepted: 11/05/2014] [Indexed: 11/17/2022]
Abstract
Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, n = 9) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, n = 10) in a chamber (428 Torr, 4,600 m of altitude) for 46 days and compared to rats under normoxia (NX, n = 10). Body weight, hematocrit, and right ventricle ratio were measured. Pulmonary artery remodeling was assessed using confocal microscopy of tissues stained with a nuclear dye (DAPI) and CD11b antibody. Both hypoxic conditions exhibited increased hematocrit and hypertrophy of the right ventricle, tunica adventitia, and tunica media, with no changes in lumen size. The medial hypertrophy area (larger in CH) depicted a significant increase in smooth muscle cell number. Additionally, CIH2x2 increased the adventitial hypertrophy area, with an increased cellularity and a larger prevalence of clustered inflammatory cells. In conclusion, CIH2x2 elicits milder effects on pulmonary artery medial layer muscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layer.
Collapse
|
30
|
Pulmonary vascular changes in asthma and COPD. Pulm Pharmacol Ther 2014; 29:144-55. [DOI: 10.1016/j.pupt.2014.09.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 09/10/2014] [Accepted: 09/12/2014] [Indexed: 12/11/2022]
|
31
|
Pizarro S, García-Lucio J, Peinado VI, Tura-Ceide O, Díez M, Blanco I, Sitges M, Petriz J, Torralba Y, Marín P, Roca J, Barberà JA. Circulating progenitor cells and vascular dysfunction in chronic obstructive pulmonary disease. PLoS One 2014; 9:e106163. [PMID: 25171153 PMCID: PMC4149524 DOI: 10.1371/journal.pone.0106163] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 07/28/2014] [Indexed: 01/22/2023] Open
Abstract
Background In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown. Objectives To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function. Methods 62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45+CD34+CD133+ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects. Results Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries. Conclusions Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.
Collapse
MESH Headings
- AC133 Antigen
- Aged
- Antigens, CD/metabolism
- Antigens, CD34/metabolism
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Female
- Glycoproteins/metabolism
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/pathology
- Humans
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/physiopathology
- Leukocyte Common Antigens/metabolism
- Male
- Middle Aged
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/physiopathology
- Peptides/metabolism
- Pulmonary Disease, Chronic Obstructive/metabolism
- Pulmonary Disease, Chronic Obstructive/pathology
- Pulmonary Disease, Chronic Obstructive/physiopathology
- Smoking
Collapse
Affiliation(s)
- Sandra Pizarro
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jéssica García-Lucio
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Víctor I. Peinado
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Marta Díez
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Marta Sitges
- Department of Cardiology, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jordi Petriz
- Department of Cytometry, Institut de Recerca, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Yolanda Torralba
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Pedro Marín
- Department of Cryopreservervation, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Josep Roca
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Joan Albert Barberà
- Department of Pulmonary Medicine, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- * E-mail:
| |
Collapse
|
32
|
Liu Y, Liu X, Lin G, Sun L, Li H, Xie C. Decreased CD34+ cell number is correlated with cardiac dysfunction in patients with acute exacerbation of COPD. Heart Lung Circ 2014; 23:875-82. [PMID: 24875532 DOI: 10.1016/j.hlc.2014.03.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 02/25/2014] [Accepted: 03/04/2014] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND PURPOSE Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with a higher risk of cardiovascular disease (CVD). Previous studies have indicated that the reduction of bone marrow-derived multipotent progenitors (CD34+ cells) may lead to reduced vascular repair capacity and may help to identify patients that pose an increased cardiovascular risk. However, the relationship between CD34+cells and CVD risk in AECOPD remains unclear. The aim of the present study was to assess CD34+ cell counts and their relationship with classical adverse cardiac outcome predictors in AECOPD. METHODS For our study, 27 patients with AECOPD (GOLD stage III, IV), 26 with stable COPD (GOLD stage III, IV), and 24 healthy controls were enrolled. CD34+ cells were enumerated, and plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a systemic inflammation marker (high-sensitivity C-reactive protein, hsCRP) and mobilisation marker (matrix metalloproteinase-9, MMP-9), were measured. Echocardiography was performed to evaluate cardiac dysfunction and pulmonary hypertension. RESULTS Compared with healthy controls, AECOPD patients had a significantly decreased CD34+ cell count (5.1 ± 2.6 versus 9.4 ± 3.6 × 10³/ml), especially in patients with a prior history of acute exacerbation. For patients with AECOPD, the CD34+ cell count was inversely correlated with NT-proBNP levels, pulmonary artery systolic pressure (PASP) and resting heart rate, and positively correlated with left ventricular ejection fraction (LVEF). In all three groups, CD34+ cell count was negatively correlated with hsCRP. CONCLUSIONS The circulating CD34+ cell count was decreased and correlated with cardiac dysfunction in AECOPD patients, and thus may account for the increased cardiovascular risk in this population.
Collapse
Affiliation(s)
- Yangli Liu
- Respiratory Department, The First Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Zhongshan Road, Guangzhou, Guangdong Province, People's Republic of China.
| | - Xiaoran Liu
- Respiratory Department, The First Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Zhongshan Road, Guangzhou, Guangdong Province, People's Republic of China; Respiratory Department, The Affiliated Hospital of Hainan Medical College, Xueyuan Road, Haikou, Hainan Province, People's Republic of China.
| | - Gengpeng Lin
- Respiratory Department, The First Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Zhongshan Road, Guangzhou, Guangdong Province, People's Republic of China
| | - Longhua Sun
- Respiratory Department, The First Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Zhongshan Road, Guangzhou, Guangdong Province, People's Republic of China
| | - Hui Li
- Respiratory Department, The First Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Zhongshan Road, Guangzhou, Guangdong Province, People's Republic of China
| | - Canmao Xie
- Respiratory Department, The First Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Diseases of Sun Yat-sen University, Zhongshan Road, Guangzhou, Guangdong Province, People's Republic of China.
| |
Collapse
|
33
|
Dual effects of cigarette smoke extract on proliferation of endothelial progenitor cells and the protective effect of 5-aza-2'-deoxycytidine on EPCs against the damage caused by CSE. BIOMED RESEARCH INTERNATIONAL 2014; 2014:640752. [PMID: 24696861 PMCID: PMC3947928 DOI: 10.1155/2014/640752] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 01/07/2014] [Accepted: 01/07/2014] [Indexed: 01/08/2023]
Abstract
Cigarette smoke is a major public health problem associated with multitude of diseases, including pulmonary and vascular diseases. Endothelial progenitor cells (EPCs) contribute to neovascularization and play an important role in the development of these diseases. The effect of CSE on EPCs is seldom studied. The aim of the current study is to observe the effect of CSE on biological behavior of EPCs and, further, to search for potential candidate agent in protection of proliferation of EPCs against the damage caused by CSE exposure in vitro. Methods. The proliferations of EPCs isolated from bone marrow of C57BL/6J mice were assessed by MTT after incubating the EPCs with a series of concentrations of CSE (1.0%, 2.5%, 5.0%, and 10.0%) for different times (3, 6, and 24 hours) as well as with 1.0% CSE in presence of 5-AZA-CdR for 24 hours. Results. The proliferations of EPCs were significantly enhanced after 3 hours of exposure to concentrations of 1.0% and 2.5% CSE but depressed when exposed to concentrations of 5.0% and 10.0% CSE. Furthermore, the 5-AZA-CdR in concentrations of 2.0 μmol/L and 5.0 μmol/L partly protected against the depression of proliferation of EPCs caused by CSE exposure. Conclusions. The CSE showed dual effects on proliferation of EPCs isolated from mice. The 5-AZA-CdR partly protected the proliferation of EPCs against the damage caused by CSE exposure in vitro, suggesting that DNA methylation may be involved in the dysfunction of EPCs induced by CSE.
Collapse
|
34
|
Agustí A, Barberà JA, Wouters EFM, Peinado VI, Jeffery PK. Lungs, bone marrow, and adipose tissue. A network approach to the pathobiology of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 188:1396-406. [PMID: 24175885 DOI: 10.1164/rccm.201308-1404pp] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant disorders, such as cardiovascular diseases and metabolic disorders, that influence significantly (and independently of lung function) their health status and prognosis. Thus, COPD is not a single organ condition, and disturbances of a complex network of interorgan connected responses occur and modulate the natural history of the disease. Here, we propose a novel hypothesis that considers a vascularly connected network with (1) the lungs as the main external sensor of the system and a major source of "danger signals"; (2) the endothelium as an internal sensor of the system (also a potential target tissue); and (3) two key responding elements, bone marrow and adipose tissue, which produce both inflammatory and repair signals. According to the model, the development of COPD, and associated multimorbidities (here we focus on cardiovascular disease as an important example), depend on the manner in which the vascular connected network responds, adapts, or fails to adapt (dictated by the genetic and epigenetic background of the individual) to the inhalation of particles and gases, mainly in cigarette smoke. The caveats and limitations of the hypothesis, as well as the experimental and clinical research needed to test and explore the proposed model, are also briefly discussed.
Collapse
Affiliation(s)
- Alvar Agustí
- 1 Thorax Institute, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | | | | | | | | |
Collapse
|
35
|
Zhang J, Zhang Z, Zhang DY, Zhu J, Zhang T, Wang C. microRNA 126 inhibits the transition of endothelial progenitor cells to mesenchymal cells via the PIK3R2-PI3K/Akt signalling pathway. PLoS One 2013; 8:e83294. [PMID: 24349482 PMCID: PMC3862723 DOI: 10.1371/journal.pone.0083294] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 11/11/2013] [Indexed: 11/19/2022] Open
Abstract
Aims Endothelial progenitor cells (EPCs) are capable of proliferating and differentiating into mature endothelial cells, and they have been considered as potential candidates for coronary heart disease therapy. However, the transition of EPCs to mesenchymal cells is not fully understood. This study aimed to explore the role of microRNA 126 (miR-126) in the endothelial-to-mesenchymal transition (EndMT) induced by transforming growth factor beta 1 (TGFβ1). Methods and Results EndMT of rat bone marrow-derived EPCs was induced by TGFβ1 (5 ng/mL) for 7 days. miR-126 expression was depressed in the process of EPC EndMT. The luciferase reporter assay showed that the PI3K regulatory subunit p85 beta (PIK3R2) was a direct target of miR-126 in EPCs. Overexpression of miR-126 by a lentiviral vector (lenti-miR-126) was found to downregulate the mRNA expression of mesenchymal cell markers (α-SMA, sm22-a, and myocardin) and to maintain the mRNA expression of progenitor cell markers (CD34, CD133). In the cellular process of EndMT, there was an increase in the protein expression of PIK3R2 and the nuclear transcription factors FoxO3 and Smad4; PI3K and phosphor-Akt expression decreased, a change that was reversed markedly by overexpression of miR-126. Furthermore, knockdown of PIK3R2 gene expression level showed reversed morphological changes of the EPCs treated with TGFβ1, thereby giving the evidence that PIK3R2 is the target gene of miR-126 during EndMT process. Conclusions These results show that miR-126 targets PIK3R2 to inhibit EPC EndMT and that this process involves regulation of the PI3K/Akt signalling pathway. miR-126 has the potential to be used as a biomarker for the early diagnosis of intimal hyperplasia in cardiovascular disease and can even be a therapeutic tool for treating cardiovascular diseases mediated by the EndMT process.
Collapse
Affiliation(s)
- Junfeng Zhang
- Department of Cardiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zongqi Zhang
- Department of Cardiology, Third People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - David Y. Zhang
- Section of Cardiology, Department of Medicine, The University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States of America
| | - Jianbing Zhu
- Department of Cardiology, Third People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tiantian Zhang
- Department of Cardiology, Third People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changqian Wang
- Department of Cardiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- * E-mail:
| |
Collapse
|
36
|
Janssen WJ, Yunt ZX, Muldrow A, Kearns MT, Kloepfer A, Barthel L, Bratton DL, Bowler RP, Henson PM. Circulating hematopoietic progenitor cells are decreased in COPD. COPD 2013; 11:277-89. [PMID: 24182349 DOI: 10.3109/15412555.2013.841668] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
RATIONALE Bone marrow derived progenitor cells participate in the repair of injured vessels. The lungs of individuals with emphysema have reduced alveolar capillary density and increased endothelial apoptosis. We hypothesized that circulating levels of endothelial and hematopoietic progenitor cells would be reduced in this group of patients. OBJECTIVES The goal of this study was to measure circulating levels of endothelial progenitor cells (EPCs) and hematopoietic progenitor cells (HPCs) in subjects with COPD and to determine if progenitor levels correlated with disease severity and the presence of emphysema. METHODS Peripheral blood mononuclear cells were isolated from 61 patients with COPD and 32 control subjects. Levels of EPCs (CD45(dim) CD34+) and HPCs (CD45(+) CD34(+) VEGF-R2(+)) were quantified using multi-parameter flow cytometry. Progenitor cell function was assessed using cell culture assays. All subjects were evaluated with spirometry and CT scanning. MEASUREMENTS AND MAIN RESULTS HPC levels were reduced in subjects with COPD compared to controls, whereas circulating EPC levels were similar between the two groups. HPC levels correlated with severity of obstruction and were lowest in subjects with severe emphysema. These associations remained after correction for factors known to affect progenitor cell levels including age, smoking status, the use of statin medications and the presence of coronary artery disease. The ability of mononuclear cells to form endothelial cell colony forming units (EC-CFU) was also reduced in subjects with COPD. CONCLUSIONS HPC levels are reduced in subjects with COPD and correlate with emphysema phenotype and severity of obstruction. Reduction of HPCs may disrupt maintenance of the capillary endothelium, thereby contributing to the pathogenesis of COPD.
Collapse
Affiliation(s)
- William J Janssen
- 1Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, CO, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
37
|
Thomashow MA, Shimbo D, Parikh MA, Hoffman EA, Vogel-Claussen J, Hueper K, Fu J, Liu CY, Bluemke DA, Ventetuolo CE, Doyle MF, Barr RG. Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study. Am J Respir Crit Care Med 2013; 188:60-8. [PMID: 23600492 DOI: 10.1164/rccm.201209-1697oc] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
RATIONALE Basic research implicates alveolar endothelial cell apoptosis in the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. However, information on endothelial microparticles (EMPs) in mild COPD and emphysema is lacking. OBJECTIVES We hypothesized that levels of CD31(+) EMPs phenotypic for endothelial cell apoptosis would be elevated in COPD and associated with percent emphysema on computed tomography (CT). Associations with pulmonary microvascular blood flow (PMBF), diffusing capacity, and hyperinflation were also examined. METHODS The Multi-Ethnic Study of Atherosclerosis COPD Study recruited participants with COPD and control subjects age 50-79 years with greater than or equal to 10 pack-years without clinical cardiovascular disease. CD31(+) EMPs were measured using flow cytometry in 180 participants who also underwent CTs and spirometry. CD62E(+) EMPs phenotypic for endothelial cell activation were also measured. COPD was defined by standard criteria. Percent emphysema was defined as regions less than -950 Hounsfield units on full-lung scans. PMBF was assessed on gadolinium-enhanced magnetic resonance imaging. Hyperinflation was defined as residual volume/total lung capacity. Linear regression was used to adjust for potential confounding factors. MEASUREMENTS AND MAIN RESULTS CD31(+) EMPs were elevated in COPD compared with control subjects (P = 0.03) and were notably increased in mild COPD (P = 0.03). CD31(+) EMPs were positively related to percent emphysema (P = 0.045) and were inversely associated with PMBF (P = 0.047) and diffusing capacity (P = 0.01). In contrast, CD62E(+) EMPs were elevated in severe COPD (P = 0.003) and hyperinflation (P = 0.001). CONCLUSIONS CD31(+) EMPs, suggestive of endothelial cell apoptosis, were elevated in mild COPD and emphysema. In contrast, CD62E(+) EMPs indicative of endothelial activation were elevated in severe COPD and hyperinflation.
Collapse
|
38
|
The Renoprotective Effect of Bone Marrow-Derived Endothelial Progenitor Cell Transplantation on Acute Ischemia-Reperfusion Injury in Rats. Transplant Proc 2013; 45:2034-9. [DOI: 10.1016/j.transproceed.2013.01.096] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 01/29/2013] [Indexed: 11/19/2022]
|
39
|
Abstract
Pulmonary hypertension is a prevalent complication of chronic obstructive pulmonary disease (COPD) that is associated with poor prognosis. Although pulmonary hypertension is usually diagnosed in patients with advanced disease, changes in pulmonary vessels are already apparent at early disease stages, and in smokers without airflow obstruction. Changes in pulmonary vessels include intimal hyperplasia, resulting from proliferating mesenchymal cells, and elastic and collagen deposition as well as endothelial dysfunction. Dysregulation of endothelium-derived mediators and growth factors and inflammatory mechanisms underlie the endothelial dysfunction and vessel remodeling. Circumstantial and experimental evidence suggests that cigarette smoke products can initiate pulmonary vascular changes in COPD and that, at advanced disease stages, hypoxia may amplify the effects of cigarette smoke on pulmonary arteries. Bone marrow-derived progenitor cells may contribute to vessel repair and to vessel remodeling, a process that appears to be facilitated by transforming growth factor-β.
Collapse
Affiliation(s)
- Joan Albert Barberà
- Department of Pulmonary Medicine, Hospital Clinic, University of Barcelona; Biomedical Research Institute August Pi i Sunyer (IDIBAPS); Research Center Network for Respiratory Diseases (CIBERES); Barcelona, Spain
| |
Collapse
|
40
|
Tzouvelekis A, Ntolios P, Bouros D. Stem cell treatment for chronic lung diseases. Respiration 2013; 85:179-92. [PMID: 23364286 DOI: 10.1159/000346525] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will not only help to relieve patient symptoms but will also affect the natural course of the respective disease. Regenerative medicine represents a promising option with several fruitful therapeutic applications in patients suffering from chronic lung diseases. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administered stem cells within chronically injured lung as well as the mechanisms regulating the activation of resident progenitor cells. On the other hand, salient data arising from few 'brave' pilot investigations of the safety of stem cell treatment in chronic lung diseases seem promising. The main scope of this review article is to summarize the current state of knowledge regarding the application status of stem cell treatment in chronic lung diseases, address important safety and efficacy issues and present future challenges and perspectives. In this review, we argue in favor of large multicenter clinical trials setting realistic goals to assess treatment efficacy. We propose the use of biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn.
Collapse
Affiliation(s)
- Argyris Tzouvelekis
- Department of Pneumonology, University Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
| | | | | |
Collapse
|
41
|
Koutroumpi M, Dimopoulos S, Psarra K, Kyprianou T, Nanas S. Circulating endothelial and progenitor cells: Evidence from acute and long-term exercise effects. World J Cardiol 2012; 4:312-326. [PMID: 23272272 PMCID: PMC3530787 DOI: 10.4330/wjc.v4.i12.312] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Revised: 10/31/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
Circulating bone-marrow-derived cells, named endothelial progenitor cells (EPCs), are capable of maintaining, generating, and replacing terminally differentiated cells within their own specific tissue as a consequence of physiological cell turnover or tissue damage due to injury. Endothelium maintenance and restoration of normal endothelial cell function is guaranteed by a complex physiological procedure in which EPCs play a significant role. Decreased number of peripheral blood EPCs has been associated with endothelial dysfunction and high cardiovascular risk. In this review, we initially report current knowledge with regard to the role of EPCs in healthy subjects and the clinical value of EPCs in different disease populations such as arterial hypertension, obstructive sleep-apnea syndrome, obesity, diabetes mellitus, peripheral arterial disease, coronary artery disease, pulmonary hypertension, and heart failure. Recent studies have introduced the novel concept that physical activity, either performed as a single exercise session or performed as part of an exercise training program, results in a significant increase of circulating EPCs. In the second part of this review we provide preliminary evidence from recent studies investigating the effects of acute and long-term exercise in healthy subjects and athletes as well as in disease populations.
Collapse
Affiliation(s)
- Matina Koutroumpi
- Matina Koutroumpi, Stavros Dimopoulos, Serafim Nanas, Cardiopulmonary Exercise Testing and Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece
| | | | | | | | | |
Collapse
|
42
|
Anjum F, Lazar J, Zein J, Jamaleddine G, Demetis S, Wadgaonkar R. Characterization of altered patterns of endothelial progenitor cells in sickle cell disease related pulmonary arterial hypertension. Pulm Circ 2012; 2:54-60. [PMID: 22558520 PMCID: PMC3342749 DOI: 10.4103/2045-8932.94834] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Endothelial dysfunction plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH) in sickle cell disease (SCD). A variety of evidence suggests that circulating endothelial progenitor cells (EPCs) play an integral role in vascular repair. We hypothesized that SCD patients with PAH are deficient in EPCs, potentially contributing to endothelial dysfunction and disease progression. The number of circulating CD34+/CD14−/CD106+ EPCs was significantly lower in SCD patients with PAH than without PAH (P=0.025). CD34+/CD14−/CD106+ numbers significantly correlated with tricuspid regurgitation velocity (TRV, r=−0.44, P=0.033) 6-minute walk distance (6MWD, r= 0.72, P=0.001), mean pulmonary artery pressure (mPAP, r= −0.43, P=0.05), and pulmonary vascular resistance (PVR, r=−0.45, P=0.05). Other EPC subsets including CD31+/CD133+/CD146+ were similar between both groups. Numbers of EPCs did not correlate with age, sex, hemoglobin, WBC count, reticulocyte count, lactate dehydrogenase (LDH), iron/ferritin levels, and serum creatinine. These data indicate that subsets of EPC are lower in SCD patients with PAH than in those without PAH. Fewer EPCs in PAH patients may contribute to the pulmonary vascular pathology. Reduced number of EPCs in SCD patients with PAH might not only give potential insight into the pathophysiological mechanisms but also might be useful for identifying suitable therapeutic targets in these patients.
Collapse
Affiliation(s)
- Fatima Anjum
- SUNY Downstate Medical Center and VA Medical Center, Brooklyn, New York, USA
| | | | | | | | | | | |
Collapse
|
43
|
Jones RC, Capen DE. A quantitative ultrastructural study of circulating (monocytic) cells interacting with endothelial cells in high oxygen-injured and spontaneously re-forming (FVB) mouse lung capillaries. Ultrastruct Pathol 2012; 36:260-79. [DOI: 10.3109/01913123.2012.662820] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
44
|
Hayden MR, Habibi J, Joginpally T, Karuparthi PR, Sowers JR. Ultrastructure Study of Transgenic Ren2 Rat Aorta - Part 1: Endothelium and Intima. Cardiorenal Med 2012; 2:66-82. [PMID: 22493605 PMCID: PMC3318941 DOI: 10.1159/000335565] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 12/05/2011] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND: The renin-angiotensin-aldosterone system plays an important role in the development and progression of hypertension and accelerated atherosclerosis (atheroscleropathy) associated with the cardiorenal metabolic syndrome and type 2 diabetes mellitus. Additionally, the renin-angiotensin-aldosterone system plays an important role in vascular-endothelial-intimal cellular and extracellular remodeling. METHODS: Thoracic aortas of young male transgenic heterozygous (mRen2)27 (Ren2) rats were utilized for this ultrastructural study. This lean model of hypertension, insulin resistance and oxidative stress harbors the mouse renin gene with increased local tissue (aortic) levels of angiotensin II and angiotensin type 1 receptors and elevated plasma aldosterone levels. RESULTS: The ultrastructural observations included marked endothelial cell retraction, separation, terminal nuclear lifting, adjacent duplication, apoptosis and a suggestion of endothelial progenitor cell attachment. The endothelium demonstrated increased caveolae, microparticles, depletion of Weibel-Palade bodies, loss of cell-cell and basal adhesion hemidesmosome-like structures, platelet adhesion and genesis of subendothelial neointima. CONCLUSION: These observational ultrastructural studies of the transgenic Ren2 vasculature provide an in-depth evaluation of early abnormal remodeling changes within conduit-elastic arteries under conditions of increased local levels of angiotensin II, oxidative stress, insulin resistance and hypertension.
Collapse
Affiliation(s)
- Melvin R. Hayden
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Department of Endocrinology Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Diabetes and Cardiovascular Disease Center, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
| | - Javad Habibi
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Department of Endocrinology Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Diabetes and Cardiovascular Disease Center, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Harry S. Truman VA Medical Center, Columbia, Mo., USA
| | - Tejaswini Joginpally
- Diabetes and Cardiovascular Disease Center, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
| | - Poorna R. Karuparthi
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Department of Cardiovascular Disease, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
| | - James R. Sowers
- Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Department of Endocrinology Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Department of Medical Physiology and Pharmacology, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Diabetes and Cardiovascular Disease Center, University of Missouri-Columbia School of Medicine, Columbia, Mo., USA
- Harry S. Truman VA Medical Center, Columbia, Mo., USA
| |
Collapse
|
45
|
Liu X, Xie C. Human endothelial progenitor cells isolated from COPD patients are dysfunctional. Mol Cell Biochem 2011; 363:53-63. [PMID: 22139347 DOI: 10.1007/s11010-011-1157-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 11/23/2011] [Indexed: 11/25/2022]
Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). More than 44% of these patients present with generalized atherosclerosis at autopsy. It is accepted that endothelial progenitor cells (EPCs) participate in the repair of dysfunctional endothelium and thus protects against atherosclerosis. However, whether COPD affects the repairing capacity of EPCs is unknown. Therefore, the objective of this study was to determine whether and how EPCs are involved in the vascular repair process in patients with COPD. In our study, EPCs from 25 COPD and 16 control patients were isolated by Ficoll density-gradient centrifugation and identified using fluorescence activated cell sorting. Transwell Migratory Assay was performed to determine the number of EPC colony-forming units and the adherent capacity late-EPCs to human umbilical vein endothelial cells. Following arterial damage in NOD/SCID mice, the number of EPCs incorporated at the injured vascular site was determined using a fluorescence microscope. We found that the number of EPC clusters and cell migration, as well as the expression of CXCR4, was significantly decreased in patients with COPD. Additionally, the number of late-EPCs adherent to HUVEC tubules was significantly reduced, and fewer VEGFR2(+)-staining cells were incorporated into the injured site in COPD patients. Our study demonstrates that EPC capacity of repair was affected in COPD patients, which may contribute to altered vascular endothelium in this patient population.
Collapse
Affiliation(s)
- Xiaoran Liu
- Respiratory Department, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road, Guangzhou 51008, Guangdong Province, People's Republic of China.
| | | |
Collapse
|
46
|
Martinez FJ, Donohue JF, Rennard SI. The future of chronic obstructive pulmonary disease treatment--difficulties of and barriers to drug development. Lancet 2011; 378:1027-37. [PMID: 21907866 DOI: 10.1016/s0140-6736(11)61047-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Although chronic obstructive pulmonary disease (COPD) is a major global health problem with a rising incidence and morbidity, few pharmacotherapeutic advances have been made over the past several decades. The challenges of development of such agents are multifactorial and include rudimentary understanding of the biological genesis of human disease, inadequate in-vitro and in-vivo models, unvalidated biomarkers, inefficient physiological and clinical endpoints, and variable regulatory review worldwide. Blockade of various inflammatory pathways and mediators is a reasonable therapeutic strategy to alter the natural history of COPD. Substantial heterogeneity is evident with respect to clinical presentation, physiology, imaging, response to therapy, decline in lung function, and survival. Numerous endpoints have been proposed for clinical studies in COPD, with new approaches under study. The novel strategy that seems most promising is the use of biomarkers. We hope that with these approaches novel pharmacotherapies will be developed in the near future.
Collapse
Affiliation(s)
- Fernando J Martinez
- Department of Internal Medicine and Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
| | | | | |
Collapse
|
47
|
Mechanisms of cellular therapy in respiratory diseases. Intensive Care Med 2011; 37:1421-31. [PMID: 21656291 DOI: 10.1007/s00134-011-2268-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Accepted: 05/05/2011] [Indexed: 01/08/2023]
Abstract
PURPOSE Stem cells present a variety of clinical implications in the lungs. According to their origin, these cells can be divided into embryonic and adult stem cells; however, due to the important ethical and safety limitations that are involved in the embryonic stem cell use, most studies have chosen to focus on adult stem cell therapy. This article aims to present and clarify the recent advances in the field of stem cell biology, as well as to highlight the effects of mesenchymal stem cell (MSC) therapy in the context of acute lung injury/acute respiratory distress syndrome and chronic disorders such as lung fibrosis and chronic obstructive pulmonary disease. METHODS For this purpose, we performed a critical review of adult stem cell therapies, covering the main clinical and experimental studies published in Pubmed databases in the past 11 years. Different characteristics were extracted from these articles, such as: the experimental model, strain, cellular type and administration route used as well as the positive or negative effects obtained. RESULTS There is evidence for beneficial effects of MSC on lung development, repair, and remodeling. The engraftment in the injured lung does not occur easily, but several studies report that paracrine factors can be effective in reducing inflammation and promoting tissue repair. MSC releases several growth factors and anti-inflammatory cytokines that regulate endothelial and epithelial permeability and reduce the severity of inflammation. CONCLUSION A better understanding of the mechanisms that control cell division and differentiation, as well as of their paracrine effects, is required to enable the optimal use of bone marrow-derived stem cell therapy to treat human respiratory diseases.
Collapse
|
48
|
Gao X, Chen W, Liang Z, Chen L. Autotransplantation of circulating endothelial progenitor cells protects against lipopolysaccharide-induced acute lung injury in rabbit. Int Immunopharmacol 2011; 11:1584-90. [PMID: 21628004 DOI: 10.1016/j.intimp.2011.05.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Revised: 05/17/2011] [Accepted: 05/17/2011] [Indexed: 12/31/2022]
Abstract
Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are leading causes of morbidity and mortality in critically ill patients. Recent studies suggest that endothelial progenitor cells (EPCs) transplantation could become a novel cell-based therapeutic strategy for ALI/ARDS, but the exact therapeutic effect and possible mechanisms still need to be elucidated. In the present study, autologous circulating EPCs were obtained from rabbits using Ficoll centrifugation and cultured in vitro for 7 days. ALI was induced in rabbits by lipopolysaccharide (LPS), and EPCs were administered systemically. Fluorescence microscopy showed that CM-DiI labelled EPCs could migrate to the injured lung tissues. Reduced pulmonary edema level, inflammation, hemorrhage and hyaline membrane formation were present in rabbit treated with EPCs. EPCs autotransplantation significantly decreased the expression of adhesion molecules of sICAM-1 and P-selectin. Furthermore, EPCs administration mediated a down-regulation of proinflammatory responses (reducing IL-1β and TNF-α) while increasing the anti-inflammatory cytokine IL-10. Apoptosis of endothelial and epithelial cells was substantially reduced in EPCs-treated rabbit. Those findings suggest that autotransplantation of circulating EPCs can reduce the severity of LPS-induced ALI. Possible mechanisms include EPCs engraftment and reendothelization, down-regulation of adhesion molecules, alleviation of inflammatory response and apoptosis prevention.
Collapse
Affiliation(s)
- Xiaofang Gao
- Department of Respiratory Medicine, Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853, PR China
| | | | | | | |
Collapse
|
49
|
[Structural abnormalities and inflammation in COPD: a focus on small airways]. Rev Mal Respir 2011; 28:749-60. [PMID: 21742236 DOI: 10.1016/j.rmr.2011.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Accepted: 01/13/2011] [Indexed: 11/21/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation associated with airway remodelling and inflammation of both large and small airways. The site of airflow obstruction in COPD is located in the small airways, justifying a focus on this compartment. The structural abnormalities that are found in bronchioles with a diameter less than 2mm are characterized by increased airway wall thickness with peribronchial fibrosis, and by luminal obstruction by mucous exudates. Destruction of alveolar walls, the hallmark of emphysema, may be related to protease-antiprotease imbalance, and to mechanisms involving apoptosis, senescence, and autoimmunity. Cigarette smoke inhalation triggers the recruitment of innate immune cells (neutrophils and macrophages) and putatively adaptive immunity mediated via T and B lymphocytes and lymphoid follicles in the small airways. These data suggest a potential role for therapies that can target remodelling and inflammation in the small airways of patients with COPD.
Collapse
|
50
|
Abstract
Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow-derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow-derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure.
Collapse
Affiliation(s)
- Michael E. Yeager
- Department of Pediatrics and Critical Care, University of Colorado at Denver and Health Sciences Center, Colorado, USA
| | - Maria G. Frid
- Developmental Lung Biology Laboratory, Denver, Colorado, USA
| | | |
Collapse
|