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Efstathiou N, Koliakos G, Kantziou K, Kyriazis G, Slavakis A, Drossou V, Soubasi V. Kinetics of Circulating Progenitor Cells and Chemotactic Factors in Full-Term Neonates with Encephalopathy: Indications of Participation in the Endogenous Regenerative Process. Biomolecules 2025; 15:427. [PMID: 40149963 PMCID: PMC11940357 DOI: 10.3390/biom15030427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/24/2025] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
Preclinical studies have shown that progenitor cells (PCs) are mobilized toward injured tissues to ameliorate damage and contribute to regeneration. The exogenous therapeutic administration of PCs in children affected by neonatal encephalopathy (NE) is a promising, yet underreported, topic. In this prospective study, we investigated whether endogenous circulating progenitor cells (CPCs) are involved in intrinsic regeneration mechanisms following neonatal brain injury. Thirteen full-term infants with moderate/severe NE, eleven with perinatal stress, and twelve controls were enrolled. Blood samples were collected on days 1, 3, 9, 18, and 45, as well as at 8 and 24 months of life, and were analyzed with a focus on Endothelial Progenitor Cells, Haematopoietic Stem Cells, and Very Small Embryonic-Like Stem Cells, in addition to chemotactic factors (erythropoietin, IGF-1, and SDF-1). Correlations between CPCs, chemotactic factors, and brain injury were assessed using serum levels of brain injury biomarkers (S100B and neuron-specific enolase), brain MRIs, and Bayley III developmental scores. Increased brain injury biomarkers were followed by the upregulation of SDF-1 receptor and erythropoietin and, finally, by elevated CPCs. These findings suggest a potential endogenous regenerative effort, primarily observed in the moderate encephalopathy group, but this is suppressed in cases of severe brain injury. Mimicking and enhancing endogenous regeneration pathways in cases of failure-regarding cell type and timeframe-could provide a novel therapeutic model.
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Affiliation(s)
- Nikolaos Efstathiou
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Georgios Koliakos
- Biochemistry Department, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Katerina Kantziou
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Georgios Kyriazis
- Immunology Department, Pulmonary Clinic, Papanikolaou General Hospital, Aristotle University of Thessaloniki, Exohi, 57010 Thessaloniki, Greece
| | - Aristeidis Slavakis
- Biochemistry Department, Hippokration General Hospital, 54642 Thessaloniki, Greece
| | - Vasiliki Drossou
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Vasiliki Soubasi
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
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Kwon JY, Maeng YS. Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction). Int J Mol Sci 2024; 25:4444. [PMID: 38674031 PMCID: PMC11050478 DOI: 10.3390/ijms25084444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare-through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence-the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development.
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Affiliation(s)
- Ja-Young Kwon
- Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University Health System, Seoul 03722, Republic of Korea;
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Yong-Sun Maeng
- Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University Health System, Seoul 03722, Republic of Korea;
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 03722, Republic of Korea
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He X, Cui Y, Li T, Luo L, Zeng Z, Ma Y, Chen Y. PU.1 alleviates the inhibitory effects of cigarette smoke on endothelial progenitor cell function and lung-homing through Wnt/β-catenin and CXCL12/CXCR4 pathways. Tob Induc Dis 2024; 22:TID-22-27. [PMID: 38274000 PMCID: PMC10809061 DOI: 10.18332/tid/174661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 02/18/2023] [Accepted: 10/30/2023] [Indexed: 01/27/2024] Open
Abstract
INTRODUCTION Endothelial progenitor cells (EPCs) dysfunction is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The transcription factor PU.1 is essential for the maintenance of stem/progenitor cell homeostasis. However, the role of PU.1 in COPD and its effects on EPC function and lung-homing, remain unclear. This study aimed to explore the protective activity of PU.1 and the underlying mechanisms in a cigarette smoke extract (CSE)-induced emphysema mouse model. METHODS C57BL/6 mice were treated with CSE to establish a murine emphysema model and injected with overexpressed PU.1 or negative control adeno-associated virus. Morphometry of lung slides, lung function, and apoptosis of lung tissues were evaluated. Immunofluorescence co-localization was used to analyze EPCs homing into the lung. Flow cytometry was performed to detect EPC count in lung tissues and bone marrow (BM). The angiogenic ability of BM-derived EPCs cultured in vitro was examined by tube formation assay. We determined the expression levels of PU.1, β-catenin, C-X-C motif ligand 12 (CXCL12), C-X-C motif receptor 4 (CXCR4), stem cell antigen-1 (Sca-1), and stemness genes. RESULTS CSE exposure significantly reduced the expression of PU.1 in mouse lung tissues, BM, and BM-derived EPCs. PU.1 overexpression attenuated CSE-induced emphysematous changes, lung function decline, and apoptosis. In emphysematous mice, PU.1 overexpression markedly reversed the decreased proportion of EPCs in BM and promoted the lung-homing of EPCs. The impaired angiogenic ability of BM-derived EPCs induced by CSE could be restored by the overexpression of PU.1. In addition, PU.1 upregulation evidently reversed the decreased expression of β-catenin, CXCL12, CXCR4, Scal-1, and stemness genes in mouse lung tissues, BM, and BM-derived EPCs after CSE exposure. CONCLUSIONS PU.1 alleviates the inhibitory effects of CSE on EPC function and lung-homing via activating the canonical Wnt/β-catenin pathway and CXCL12/CXCR4 axis. While further research is needed, our research may indicate a potential therapeutic target for COPD patients.
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Affiliation(s)
- Xue He
- Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Yanan Cui
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Tiao Li
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Lijuan Luo
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Zihang Zeng
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Yiming Ma
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
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Bostancieri N, Bakir K, Kul S, Eralp A, Kayalar O, Konyalilar N, Rajabi H, Yuncu M, Yildirim AÖ, Bayram H. The effect of multiple outgrowths from bronchial tissue explants on progenitor/stem cell number in primary bronchial epithelial cell cultures from smokers and patients with COPD. Front Med (Lausanne) 2023; 10:1118715. [PMID: 37908857 PMCID: PMC10614425 DOI: 10.3389/fmed.2023.1118715] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 09/25/2023] [Indexed: 11/02/2023] Open
Abstract
Background Although studies suggest a deficiency in stem cell numbers in chronic airway diseases such as chronic obstructive pulmonary disease (COPD), the role of bronchial epithelial progenitor/stem (P/S) cells is not clear. The objectives of this study were to investigate expression of progenitor/stem (P/S) cell markers, cytokeratin (CK) 5, CK14 and p63 in bronchial epithelial explants and cell cultures obtained from smokers with and without COPD following multiple outgrowths, and to study this effect on bronchial epithelial cell (BEC) proliferation. Methods Bronchial epithelial explants were dissected from lung explants and cultured on coverslips. Confluent cultures were obtained after 3-4 weeks' (transfer, Tr1), explants were then transferred and cultured for a second (Tr2) and third (Tr3) time, respectively. At each stage, expression of CK5, CK14 and p63 in explants and BEC were determined by immunostaining. In parallel experiments, outgrowing cells from explants were counted after 4wks, and explants subsequently transferred to obtain new cultures for a further 3 times. Results As the transfer number advanced, CK5, CK14 and p63 expression was decreased in both explants and BEC from both smokers without COPD and patients with COPD, with a more pronounced decrease in BEC numbers in the COPD group. Total cell numbers cultured from explants were decreased with advancing outgrowth number in both groups. Smoking status and lung function parameters were correlated with reduced P/S marker expression and cell numbers. Conclusion Our findings suggest that the number of P/S cells in airway epithelium may play a role in the pathogenesis of COPD, as well as a role in the proliferation of airway epithelial cells, in vitro.
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Affiliation(s)
- Nuray Bostancieri
- Department of Histology and Embryology, School of Medicine, University of Gaziantep, Gaziantep, Türkiye
- Cell Culture Laboratory, Department of Chest Diseases, School of Medicine, University of Gaziantep, Gaziantep, Türkiye
| | - Kemal Bakir
- Department of Pathology, School of Medicine, University of Gaziantep, Gaziantep, Türkiye
| | - Seval Kul
- Department of Biostatistics, School of Medicine, University of Gaziantep, Gaziantep, Türkiye
| | - Ayhan Eralp
- Department of Histology and Embryology, School of Medicine, University of Gaziantep, Gaziantep, Türkiye
| | - Ozgecan Kayalar
- Koc University Research Center for Translational Medicine, Koc University, Istanbul, Türkiye
| | - Nur Konyalilar
- Koc University Research Center for Translational Medicine, Koc University, Istanbul, Türkiye
| | - Hadi Rajabi
- Koc University Research Center for Translational Medicine, Koc University, Istanbul, Türkiye
| | - Mehmet Yuncu
- Department of Histology and Embryology, School of Medicine, University of Gaziantep, Gaziantep, Türkiye
| | - Ali Önder Yildirim
- Koc University Research Center for Translational Medicine, Koc University, Istanbul, Türkiye
- Comprehensive Pneumology Center (CPC), Institute of Lung Health and Immunity (LHI), Member of the German Center for Lung Research (DZL), Helmholtz Munich, Munich, Germany
| | - Hasan Bayram
- Cell Culture Laboratory, Department of Chest Diseases, School of Medicine, University of Gaziantep, Gaziantep, Türkiye
- Koc University Research Center for Translational Medicine, Koc University, Istanbul, Türkiye
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Ahmadi AR, Atiee G, Chapman B, Reynolds L, Sun J, Cameron AM, Wesson RN, Burdick JF, Sun Z. A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects. Cell Rep Med 2023; 4:101169. [PMID: 37633275 PMCID: PMC10518600 DOI: 10.1016/j.xcrm.2023.101169] [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: 02/25/2023] [Revised: 06/13/2023] [Accepted: 08/01/2023] [Indexed: 08/28/2023]
Abstract
Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5 days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).
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Affiliation(s)
| | | | | | | | - John Sun
- MedRegen LLC, Baltimore, MD, USA
| | - Andrew M Cameron
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Russell N Wesson
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | | | - Zhaoli Sun
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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Ghafil NY, Dananah FM, Hassan ES, Alkaabi YSA. Comorbidities in patients with chronic obstructive pulmonary disease: a comprehensive study. J Med Life 2023; 16:1013-1016. [PMID: 37900064 PMCID: PMC10600672 DOI: 10.25122/jml-2022-0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 09/30/2022] [Indexed: 10/31/2023] Open
Abstract
In recent years, there has been an increasing interest in understanding the systemic nature of COPD and its frequently associated comorbidities. COPD is characterized by chronic lung disease involving local and systemic inflammation and non-reversible airway obstruction. The disease course is marked by recurrent exacerbations and is often accompanied by various comorbidities. This study aimed to evaluate the prevalence of comorbidities among Iraqi patients with COPD and their association with disease severity. A case-control study was conducted at Al-Sader Hospital in Annajaf from October 2019 to October 2020, involving 200 participants. The study population comprised 100 patients with COPD (COPD group) and 100 individuals without COPD serving as the control group. Patients with COPD were divided into four groups according to the disease severity. The prevalence of type 2 diabetes mellitus (T2DM), atherosclerotic cardiovascular diseases (ASCVD), hypertension, and dyslipidemia was determined in all groups. Patients with COPD had a significantly higher prevalence of T2DM, ASCVD, hypertension, and dyslipidemia, and, except for T2DM, the prevalence was significantly higher in the more severe groups. It was concluded that T2DM, ASCVD, hypertension, and dyslipidemia were commonly associated with COPD.
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Affiliation(s)
- Nagham Yahya Ghafil
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Kufa, Kufa, Iraq
| | - Falah Mahdi Dananah
- Department of Physiology, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | - Ekhlas Sabah Hassan
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Kufa, Kufa, Iraq
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Olesiejuk K, Chałubiński M. How does particulate air pollution affect barrier functions and inflammatory activity of lung vascular endothelium? Allergy 2023; 78:629-638. [PMID: 36588285 DOI: 10.1111/all.15630] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/17/2022] [Accepted: 12/20/2022] [Indexed: 01/03/2023]
Abstract
Both particulate matter and gaseous components of air pollution have already been shown to increase cardiovascular mortality in numerous studies. It is, however, important to note that on their way to the bloodstream the polluting agents pass the lung barrier. Inside the alveoli, particles of approximately 0.4-1 μm are most efficiently deposited and commonly undergo phagocytosis by lung macrophages. Not only the soluble agents, but also particles fine enough to leave the alveoli enter the bloodstream in this finite part of the endothelium, reaching thus higher concentrations in close proximity of the alveoli and endothelium. Additionally, deposits of particulate matter linger in direct proximity of the endothelial cells and may induce inflammation, immune responses, and influence endothelial barrier dysfunction thus increasing PM bioavailability in positive feedback. The presented discussion provides an overview of possible components of indoor PM and how endothelium is thus influenced, with emphasis on lung vascular endothelium and clinical perspectives.
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Affiliation(s)
- Krzysztof Olesiejuk
- Department of Immunology and Allergy, Chair of Pulmonology, Rheumatology and Clinical Immunology, Medical University of Lodz, Lodz, Poland
| | - Maciej Chałubiński
- Department of Immunology and Allergy, Chair of Pulmonology, Rheumatology and Clinical Immunology, Medical University of Lodz, Lodz, Poland
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Kolesnichenko OA, Whitsett JA, Kalin TV, Kalinichenko VV. Therapeutic Potential of Endothelial Progenitor Cells in Pulmonary Diseases. Am J Respir Cell Mol Biol 2021; 65:473-488. [PMID: 34293272 DOI: 10.1165/rcmb.2021-0152tr] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Compromised alveolar development and pulmonary vascular remodeling are hallmarks of pediatric lung diseases such as bronchopulmonary dysplasia (BPD) and alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Although advances in surfactant therapy, corticosteroids, and anti-inflammatory drugs have improved clinical management of preterm infants, still those who suffer with severe vascular complications lack viable treatment options. Paucity of the alveolar capillary network in ACDMPV causes respiratory distress and leads to mortality in a vast majority of ACDMPV infants. The discovery of endothelial progenitor cells (EPCs) in 1997 brought forth the paradigm of postnatal vasculogenesis and hope for promoting vascularization in fragile patient populations, such as those with BPD and ACDMPV. The identification of diverse EPC populations, both hematopoietic and nonhematopoietic in origin, provided a need to identify progenitor cell selective markers which are linked to progenitor properties needed to develop cell-based therapies. Focusing to the future potential of EPCs for regenerative medicine, this review will discuss various aspects of EPC biology, beginning with the identification of hematopoietic, nonhematopoietic, and tissue-resident EPC populations. We will review knowledge related to cell surface markers, signature gene expression, key transcriptional regulators, and will explore the translational potential of EPCs for cell-based therapy for BPD and ACDMPV. The ability to produce pulmonary EPCs from patient-derived induced pluripotent stem cells (iPSCs) in vitro, holds promise for restoring vascular growth and function in the lungs of patients with pediatric pulmonary disorders.
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Affiliation(s)
- Olena A Kolesnichenko
- Cincinnati Children's Hospital Medical Center, 2518, Cincinnati, Ohio, United States
| | - Jeffrey A Whitsett
- The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
| | - Tanya V Kalin
- Cincinnati Children\'s Hospital Medical Center, 2518, Pediatrics, Cincinnati, Ohio, United States
| | - Vladimir V Kalinichenko
- Cincinnati Children's Hospital Medical Center, Pediatrics, Division of Pulmonary Biology, Cincinnati, Ohio, United States;
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He ZH, Chen Y, Chen P, Xie LH, Liang GB, Zhang HL, Peng HH. Cigarette smoke extract affects methylation status and attenuates Sca-1 expression of mouse endothelial progenitor cell in vitro. Tob Induc Dis 2021; 19:08. [PMID: 33542680 PMCID: PMC7842580 DOI: 10.18332/tid/131625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 11/22/2020] [Accepted: 12/12/2020] [Indexed: 01/28/2023] Open
Abstract
INTRODUCTION Endothelial dysfunction appears in many smoking-related diseases, it is also an important pathophysiological feature. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and have a crucial effect on the repair and maintenance of endothelial integrity. Sca-1 is not only common in bone marrow-derived hematopoietic stem cells (HSCs), but it is also expressed in nonhematopoietic organs by tissue-resident stem and progenitor cells. The aim of this study is to investigate the impact of cigarette smoke extract (CSE) on the function of bone marrow-derived EPCs and the expression level of Sca-1 in EPCs, and also whether the methylation of Sca-1 is involved in EPC dysfunction. METHODS We measured EPC capacities including adhesion, secretion and proliferation, the concentration of endothelial nitric oxide synthase (eNOS) and apoptosis-inducing factor (AIF) in cell culture supernatant, and also Sca-1 expression and promoter methylation in EPCs induced by CSE. Decitabine (Dec) was applied to test whether it could alter the impact caused by CSE. RESULTS The adhesion, proliferation and secretion ability of EPCs can be induced to be decreased by CSE in vitro, accompanied by decreased concentrations of AIF and eNOS in cell culture supernatant and decreased Sca-1 expression in EPCs. In addition, Dec could partly attenuate the impact described above. There were no significant differences in the quantitative analysis of Sca-1 promoter methylation among different groups. CONCLUSIONS The decreased Sca-1 expression was related to EPC dysfunction induced by CSE. EPC dysfunction resulting from CSE may be related to methylation mechanism, but not the methylation of Sca-1 promoter.
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Affiliation(s)
- Zhi-Hui He
- Department of Intensive Care Unit, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yan Chen
- Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ping Chen
- Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Hua Xie
- Department of Respiratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Gui-Bin Liang
- Department of Intensive Care Unit, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hong-Liang Zhang
- Department of Emergency, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Huai-Huai Peng
- Department of Intensive Care Unit, The Second Xiangya Hospital, Central South University, Changsha, China
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Niven M, Sivak G, Baytner S, Liberson R, Bulvik S, Porat Y, Frogel M, Shenkman L, Grajower M, Veith F, Belkin M. Changing the Course of Peripheral Arterial Disease Using Adult Stem Progenitor Cells. STEM CELL THERAPY FOR VASCULAR DISEASES 2021:245-280. [DOI: 10.1007/978-3-030-56954-9_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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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.
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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.
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12
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Elżbieta R, Iwona K, Joanna B, Karina JR, Piotr R. Role of fibrocytes and endothelial progenitor cells among low-differentiated CD34+ cells in the progression of lung sarcoidosis. BMC Pulm Med 2020; 20:306. [PMID: 33218322 PMCID: PMC7678043 DOI: 10.1186/s12890-020-01345-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 11/12/2020] [Indexed: 12/18/2022] Open
Abstract
Background Sarcoidosis is a multisystemic granulomatous disease with still unknown etiology. Our previous studies showed a significantly higher percentage of CD34 + cells in the peripheral blood in patients with sarcoidosis (SA) compared to the control group. The objective of the present study was to characterized of the CD34 + cell population in peripheral blood in patients with SA with reference to the control group. Moreover in patients with SA, fibrocytes and endothelial cells were analysed and their relationship to the fibrosis process based on assessment of diffusing capacity for carbon monoxide (DLCO). Methods Data from patients diagnosed with SA at Military Institute of Medicine (Warsaw, Poland) between January 2018 and December 2019 were collected and analysed ongoing basis. Peripheral blood was collected from 26 patients with newly diagnosed pulmonary SA and 16 healthy subjects. The immunomagnetic method and flow cytometry were used. Among the CD34+ progenitor cells were assessed: low-differentiated cells, hematopoietic progenitor cells and endothelial progenitor cells. The Statistica 12.0 software was used for a statistical analysis. Results We observed a significantly higher percentage of low-differentiated cells (13.8 vs. 2.3, P = 0.001) and endothelial cells (0.3 vs. 0.0, P = 0.001) in patients with SA compared to the control group. In the study group the median proportion of fibrocytes was 1.877% (0.983–2.340) in patients with DLCO< 80%, while in patients with DLCO> 80% was 0.795% (0.139–1.951) (P = 0.72). The median proportion of endothelial progenitor cells was higher in patients with DLCO< 80%: 0.889% (0.391–1.741), than in patients with DLCO> 80%: 0.451% (0.177–0.857) (P = 0.44). Conclusions In conclusion we demonstrated for the first time the immunophenotype of peripheral CD34 + cells with the degree of their differentiation. The study confirmed the involvement of low differentiated cells and endothelial cells in patients with SA.
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Affiliation(s)
- Rutkowska Elżbieta
- Department of Internal Medicine and Hematology, Laboratory of Hematology and Flow Cytometry, Military Institute of Medicine, Warsaw, Poland.
| | - Kwiecień Iwona
- Department of Internal Medicine and Hematology, Laboratory of Hematology and Flow Cytometry, Military Institute of Medicine, Warsaw, Poland
| | - Bednarek Joanna
- Department of Internal Medicine, Pulmonology, Allergology and Clinical Immunology, Military Institute of Medicine, Warsaw, Poland
| | - Jahnz-Różyk Karina
- Department of Internal Medicine, Pulmonology, Allergology and Clinical Immunology, Military Institute of Medicine, Warsaw, Poland
| | - Rzepecki Piotr
- Department of Internal Medicine and Hematology, Military Institute of Medicine, Warsaw, Poland
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13
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He M, Cui T, Cai Q, Wang H, Kong H, Xie W. Iptakalim ameliorates hypoxia-impaired human endothelial colony-forming cells proliferation, migration, and angiogenesis via Akt/eNOS pathways. Pulm Circ 2019; 9:2045894019875417. [PMID: 31692706 DOI: 10.1177/2045894019875417] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 08/21/2019] [Indexed: 12/31/2022] Open
Abstract
Hypoxia-associated pulmonary hypertension is characterized by pulmonary vascular remodeling. Pulmonary arterial endothelial cells dysfunction is considered as the initial event. As precursor of endothelial cells, endothelial colony-forming cells (ECFCs) play significant roles in maintenance of endothelium integrity and restoration of normal endothelial cell function. Accumulating data have indicated that hypoxia leads to a decrease in the number and function of ECFCs with defective capacity of endothelial regeneration. Previous studies have reported that the activation of ATP-sensitive potassium channels (KATP) shows therapeutic effects in pulmonary hypertension. However, there have been few reports focusing on the impact of KATP on ECFC function under hypoxic condition. Therefore, the aim of this study was to investigate whether the opening of KATP could regulate hypoxia-induced ECFC dysfunction. Using ECFCs derived from adult peripheral blood, we observed that Iptakalim (Ipt), a novel KATP opener (KCO), significantly promoted ECFC function including cellular viability, proliferation, migration, angiogenesis, and apoptosis compared with ECFCs exposed to hypoxia. Glibenclamide (Gli), a nonselective KATP blocker, could eliminate the effects. The protective role of Ipt is attributed to an increased production of nitric oxide (NO), as well as an enhanced activation of angiogenic transduction pathways, containing Akt and endothelial nitric oxide synthase. Our observations demonstrated that KATP activation could improve ECFC function in hypoxia via Akt/endothelial nitric oxide synthase pathways, which may constitute increase ECFC therapeutic potential for hypoxia-associated pulmonary hypertension treatment.
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Affiliation(s)
- Mengyu He
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ting Cui
- The Inspection Department of the first Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qing Cai
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Wang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hui Kong
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weiping Xie
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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14
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Yoon YS, Jin M, Sin DD. Accelerated lung aging and chronic obstructive pulmonary disease. Expert Rev Respir Med 2019; 13:369-380. [PMID: 30735057 DOI: 10.1080/17476348.2019.1580576] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION The prevalence of chronic obstructive pulmonary disease (COPD) increases exponentially with aging. Its pathogenesis, however, is not well known and aside from smoking cessation, there are no disease-modifying treatments for this disease. Areas covered: COPD is associated with accelerating aging and aging-related diseases. In this review, we will discuss the hallmarks of aging including genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication, which may be involved in COPD pathogenesis. Expert commentary: COPD and the aging process share similar molecular and cellular changes. Aging-related molecular pathways may represent novel therapeutic targets and biomarkers for COPD.
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Affiliation(s)
- Young Soon Yoon
- a Centre for Heart and Lung Innovation , St. Paul's Hospital & University of British Columbia , Vancouver , BC , Canada.,b Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine , Dongguk University Ilsan Hospital , Goyang , South Korea
| | - Minhee Jin
- a Centre for Heart and Lung Innovation , St. Paul's Hospital & University of British Columbia , Vancouver , BC , Canada
| | - Don D Sin
- a Centre for Heart and Lung Innovation , St. Paul's Hospital & University of British Columbia , Vancouver , BC , Canada.,c Division of Respiratory Medicine (Department of Medicine) , University of British Columbia , Vancouver , BC , Canada
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15
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Vasculogenic Stem and Progenitor Cells in Human: Future Cell Therapy Product or Liquid Biopsy for Vascular Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:215-237. [PMID: 31898789 DOI: 10.1007/978-3-030-31206-0_11] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
New blood vessel formation in adults was considered to result exclusively from sprouting of preexisting endothelial cells, a process referred to angiogenesis. Vasculogenesis, the formation of new blood vessels from endothelial progenitor cells, was thought to occur only during embryonic life. Discovery of adult endothelial progenitor cells (EPCs) in 1997 opened the door for cell therapy in vascular disease. Endothelial progenitor cells contribute to vascular repair and are now well established as postnatal vasculogenic cells in humans. It is now admitted that endothelial colony-forming cells (ECFCs) are the vasculogenic subtype. ECFCs could be used as a cell therapy product and also as a liquid biopsy in several vascular diseases or as vector for gene therapy. However, despite a huge interest in these cells, their tissue and molecular origin is still unclear. We recently proposed that endothelial progenitor could come from very small embryonic-like stem cells (VSELs) isolated in human from CD133 positive cells. VSELs are small dormant stem cells related to migratory primordial germ cells. They have been described in bone marrow and other organs. This chapter discusses the reported findings from in vitro data and also preclinical studies that aimed to explore stem cells at the origin of vasculogenesis in human and then explore the potential use of ECFCs to promote newly formed vessels or serve as liquid biopsy to understand vascular pathophysiology and in particular pulmonary disease and haemostasis disorders.
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16
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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: 10] [Impact Index Per Article: 1.4] [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
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17
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Barwinska D, Oueini H, Poirier C, Albrecht ME, Bogatcheva NV, Justice MJ, Saliba J, Schweitzer KS, Broxmeyer HE, March KL, Petrache I. AMD3100 ameliorates cigarette smoke-induced emphysema-like manifestations in mice. Am J Physiol Lung Cell Mol Physiol 2018; 315:L382-L386. [PMID: 29745251 DOI: 10.1152/ajplung.00185.2018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
We have shown that cigarette smoke (CS)-induced pulmonary emphysema-like manifestations are preceded by marked suppression of the number and function of bone marrow hematopoietic progenitor cells (HPCs). To investigate whether a limited availability of HPCs may contribute to CS-induced lung injury, we used a Food and Drug Administration-approved antagonist of the interactions of stromal cell-derived factor 1 (SDF-1) with its chemokine receptor CXCR4 to promote intermittent HPC mobilization and tested its ability to limit emphysema-like injury following chronic CS. We administered AMD3100 (5mg/kg) to mice during a chronic CS exposure protocol of up to 24 wk. AMD3100 treatment did not affect either lung SDF-1 levels, which were reduced by CS, or lung inflammatory cell counts. However, AMD3100 markedly improved CS-induced bone marrow HPC suppression and significantly ameliorated emphysema-like end points, such as alveolar airspace size, lung volumes, and lung static compliance. These results suggest that antagonism of SDF-1 binding to CXCR4 is associated with protection of both bone marrow and lungs during chronic CS exposure, thus encouraging future studies of potential therapeutic benefit of AMD3100 in emphysema.
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Affiliation(s)
- Daria Barwinska
- Department of Cellular and Integrative Physiology, Indiana University , Indianapolis, Indiana.,Indiana Center for Vascular Biology and Medicine, Indiana University , Indianapolis, Indiana.,Vascular and Cardiac Center for Adult Stem Cell Therapy Signature Center, Indiana University, Purdue University , Indianapolis, Indiana.,Roudebush Veterans Affairs Medical Center, Indiana University , Indianapolis, Indiana.,Division of Nephrology, Department of Medicine, Indiana University , Indianapolis, Indiana
| | - Houssam Oueini
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University , Indianapolis, Indiana
| | - Christophe Poirier
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University , Indianapolis, Indiana
| | - Marjorie E Albrecht
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University , Indianapolis, Indiana
| | - Natalia V Bogatcheva
- Indiana Center for Vascular Biology and Medicine, Indiana University , Indianapolis, Indiana.,Vascular and Cardiac Center for Adult Stem Cell Therapy Signature Center, Indiana University, Purdue University , Indianapolis, Indiana.,Roudebush Veterans Affairs Medical Center, Indiana University , Indianapolis, Indiana.,Division of Cardiology, Department of Medicine, Indiana University , Indianapolis, Indiana
| | - Matthew J Justice
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University , Indianapolis, Indiana.,Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Jacob Saliba
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University , Indianapolis, Indiana
| | - Kelly S Schweitzer
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University , Indianapolis, Indiana.,Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Hal E Broxmeyer
- Department of Microbiology and Immunology, Indiana University , Indianapolis, Indiana
| | - Keith L March
- Indiana Center for Vascular Biology and Medicine, Indiana University , Indianapolis, Indiana.,Vascular and Cardiac Center for Adult Stem Cell Therapy Signature Center, Indiana University, Purdue University , Indianapolis, Indiana.,Roudebush Veterans Affairs Medical Center, Indiana University , Indianapolis, Indiana.,Division of Cardiology, Department of Medicine, Indiana University , Indianapolis, Indiana.,Division of Cardiovascular Medicine and Center for Regenerative Medicine, University of Florida , Gainesville, Florida
| | - Irina Petrache
- Indiana Center for Vascular Biology and Medicine, Indiana University , Indianapolis, Indiana.,Vascular and Cardiac Center for Adult Stem Cell Therapy Signature Center, Indiana University, Purdue University , Indianapolis, Indiana.,Roudebush Veterans Affairs Medical Center, Indiana University , Indianapolis, Indiana.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University , Indianapolis, Indiana.,Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado.,Department of Medicine, University of Colorado , Denver, Colorado
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18
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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.
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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:
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19
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Very Small Embryonic-like Stem Cells Are Mobilized in Human Peripheral Blood during Hypoxemic COPD Exacerbations and Pulmonary Hypertension. Stem Cell Rev Rep 2018; 13:561-566. [PMID: 28285391 DOI: 10.1007/s12015-017-9732-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Very small embryonic-like stem cells (VSELs) are major pluripotent stem cells involved in vascular and tissue regeneration and constitute a recruitable pool of stem/progenitor cells with putative instrumental role in organ repair. Here, we hypothesized that VSELs might be mobilized from the bone marrow (BM) to peripheral blood (PB) in patients with hypoxic lung disease or pulmonary hypertension (PH). The objective of the present study was then to investigate the changes in VSELs number in peripheral blood of patients with hypoxic lung disease and PH. We enrolled 26 patients with Chronic Obstructive Pulmonary Disease (COPD) with or without hypoxemia, 13 patients with PH and 20 controls without any respiratory or cardiovascular diseases. In PH patients, VSELs levels have been determined during right heart catheterization in pulmonary blood and PB. For this purpose, mononuclear cells were separated by density gradient and VSELs have been quantified by using a multiparametric flow cytometry approach. The number of PB-VSELs in hypoxic COPD patients was significantly increased compared with non-hypoxic COPD patients or controls (p = 0.0055). In patients with PH, we did not find any difference in VSELs numbers between arterial pulmonary blood and venous PB (p = 0.93). However, we found an increase in VSELs in the peripheral blood of patients with PH (p = 0.03). In conclusion, we unraveled that circulating VSELs were increased in peripheral blood of patients with hypoxic COPD or with PH. Thus, VSELs may serve as a reservoir of pluripotent stem cells that can be recruited into PB and may play an important role in promoting lung repair.
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20
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Jin Y, Liu W, Liu X, Ma T, Yang C, Cai Q, Liu Z. Transplantation of endothelial progenitor cells attenuated paraquat-induced acute lung injury via miR-141-3p-Notch-Nrf2 axis. Cell Biosci 2018; 8:21. [PMID: 29568483 PMCID: PMC5859660 DOI: 10.1186/s13578-018-0219-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 03/02/2018] [Indexed: 12/21/2022] Open
Abstract
Background Paraquat (PQ) presents with high toxicity for humans and animals, and the lungs become the main target organ by the poisoning of PQ leading to acute lung injury. Endothelial progenitor cells (EPCs) were proved to have the repair function on acute lung injury (ALI). We aimed to invatigate the underlying mechanism of EPCs in PQ-induced ALI involving miR-141-3p. Methods Endothelial progenitor cells were isolated from peripheral blood of C57BL/6J mice and identified by flow cytometry. Lung wet-to-dry (W/D) weight ratios, lung injury score and the number of total leukocyte and the number of neutrophils in BALF were used to analyze the degree of lung injury. The transfection was performed with Lipofectamine 2000. The levels of miRNA and mRNA were determined by qRT-PCR, and the protein levels were detected by Western blot assay. Results Endothelial progenitor cells alleviated lung wet-to-dry (W/D) weight ratios, lung injury score and the number of total leukocyte and the number of neutrophils in BALF in PQ-induced ALI mice. EPCs inhibited miR-141-3p expression, and enhanced the levels of Notch-Nrf2 axis in PQ-induced ALI mice. MiR-141-3p knockdown reversed the PQ induced-inhibition on Notch-1 and Hesr1 expression. MiR-141-3p over-expression could inhibit the expression of Notch-1 pathway significantly in the pulmonary epithelial cell line MLE-12. Both miR-141-3p over-expression and si-Notch-1 abolished the protection effect of EPCs on lung injury induced by PQ in vivo. Conclusions Endothelial progenitor cells could provide therapeutic effect on PQ-induced ALI via miR-141-3p-Notch-Nrf2 Axis.
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Affiliation(s)
- Yan Jin
- Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 People's Republic of China
| | - Wei Liu
- Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 People's Republic of China
| | - Xiaowei Liu
- Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 People's Republic of China
| | - Tao Ma
- Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 People's Republic of China
| | - Chen Yang
- Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 People's Republic of China
| | - Quan Cai
- Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 People's Republic of China
| | - Zhi Liu
- Department of Emergency, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 People's Republic of China
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21
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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.
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22
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Brandsma CA, de Vries M, Costa R, Woldhuis RR, Königshoff M, Timens W. Lung ageing and COPD: is there a role for ageing in abnormal tissue repair? Eur Respir Rev 2017; 26:26/146/170073. [PMID: 29212834 DOI: 10.1183/16000617.0073-2017] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 09/20/2017] [Indexed: 11/05/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide, with increasing prevalence, in particular in the elderly. COPD is characterised by abnormal tissue repair resulting in (small) airways disease and emphysema. There is accumulating evidence that ageing hallmarks are prominent features of COPD. These ageing hallmarks have been described in different subsets of COPD patients, in different lung compartments and also in a variety of cell types, and thus might contribute to different COPD phenotypes. A better understanding of the main differences and similarities between normal lung ageing and the pathology of COPD may improve our understanding of the mechanisms driving COPD pathology, in particular in those patients that develop the most severe form of COPD at a relatively young age, i.e. severe early-onset COPD patients.In this review, after introducing the main concepts of lung ageing and COPD pathology, we focus on the role of (abnormal) ageing in lung remodelling and repair in COPD. We discuss the current evidence for the involvement of ageing hallmarks in these pathological features of COPD. We also highlight potential novel treatment strategies and opportunities for future research based on our current knowledge of abnormal lung ageing in COPD.
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Affiliation(s)
- Corry-Anke Brandsma
- University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands .,University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | - Maaike de Vries
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Dept of Epidemiology, Groningen, The Netherlands
| | - Rita Costa
- Comprehensive Pneumology Center, Helmholtz Zentrum München, University Hospital of the Ludwig Maximilians University, Munich, Germany
| | - Roy R Woldhuis
- University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | - Melanie Königshoff
- Comprehensive Pneumology Center, Helmholtz Zentrum München, University Hospital of the Ludwig Maximilians University, Munich, Germany.,Division of Pulmonary Sciences and Critical Care Medicine, Dept of Medicine, University of Colorado, Denver, CO, USA.,Both authors contributed equally
| | - Wim Timens
- University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands.,University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands.,Both authors contributed equally
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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.
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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
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24
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Tura-Ceide O, Lobo B, Paul T, Puig-Pey R, Coll-Bonfill N, García-Lucio J, Smolders V, Blanco I, Barberà JA, Peinado VI. Cigarette smoke challenges bone marrow mesenchymal stem cell capacities in guinea pig. Respir Res 2017; 18:50. [PMID: 28330488 PMCID: PMC5363047 DOI: 10.1186/s12931-017-0530-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/03/2017] [Indexed: 01/03/2023] Open
Abstract
Background Cigarette smoke (CS) is associated with lower numbers of circulating stem cells and might severely affect their mobilization, trafficking and homing. Our study was designed to demonstrate in an animal model of CS exposure whether CS affects the homing and functional capabilities of bone marrow-derived mesenchymal stem cells (BM-MSCs). Methods Guinea pigs (GP), exposed or sham-exposed to CS, were administered via tracheal instillation or by vascular administration with 2.5 × 106 BM-MSCs obtained from CS-exposed or sham-exposed animal donors. Twenty-four hours after cell administration, animals were sacrificed and cells were visualised into lung structures by optical microscopy. BM-MSCs from 8 healthy GP and from 8 GP exposed to CS for 1 month were isolated from the femur, cultured in vitro and assessed for their proliferation, migration, senescence, differentiation potential and chemokine gene expression profile. Results CS-exposed animals showed greater BM-MSCs lung infiltration than sham-exposed animals regardless of route of administration. The majority of BM-MSCs localized in the alveolar septa. BM-MSCs obtained from CS-exposed animals showed lower ability to engraft and lower proliferation and migration. In vitro, BM-MSCs exposed to CS extract showed a significant reduction of proliferative, cellular differentiation and migratory potential and an increase in cellular senescence in a dose dependent manner. Conclusion Short-term CS exposure induces BM-MSCs dysfunction. Such dysfunction was observed in vivo, affecting the cell homing and proliferation capabilities of BM-MSCs in lungs exposed to CS and in vitro altering the rate of proliferation, senescence, differentiation and migration capacity. Additionally, CS induced a reduction in CXCL9 gene expression in the BM from CS-exposed animals underpinning a potential mechanistic action of bone marrow dysfunction. Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0530-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain.,Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Borja Lobo
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Tanja Paul
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Raquel Puig-Pey
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Núria Coll-Bonfill
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Jéssica García-Lucio
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Valérie Smolders
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain
| | - Isabel Blanco
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain.,Biomedical Research Networking Center in 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, Villarroel, 170, Barcelona, 08036, Spain.,Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Víctor I Peinado
- Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Villarroel, 170, Barcelona, 08036, Spain. .,Biomedical Research Networking Center in Respiratory Diseases (CIBERES), Madrid, Spain.
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25
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Shi Z, Chen Y, Cao J, Zeng H, Yang Y, Chen P, Luo H, Peng H, Cai S, Guan C. Intratracheal transplantation of endothelial progenitor cells attenuates smoking-induced COPD in mice. Int J Chron Obstruct Pulmon Dis 2017; 12:947-960. [PMID: 28360519 PMCID: PMC5365327 DOI: 10.2147/copd.s110781] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background Endothelial progenitor cells (EPCs) might play a protective role in COPD. The aim of this study was to investigate whether intratracheal allogeneic transplantation of bone-marrow-derived EPCs would attenuate the development of smoking-induced COPD in mice. Methods Isolated mononuclear cells from the bone marrow of C57BL/6J mice were cultured in endothelial cell growth medium-2 for 10 days, yielding EPCs. A murine model of COPD was established by passive 90-day exposure of cigarette smoke. On day 30, EPCs or phosphate-buffered saline alone was administered into the trachea. On day 90, EPCs or 30 μL phosphate-buffered saline alone was administered into the trachea, and on day 120, inflammatory cells, antioxidant activity, apoptosis, matrix metalloproteinase (MMP)-2, and MMP-9 were measured. Results After EPC treatment, the lung function of the mice had improved compared with the untreated mice. Mean linear intercept and destructive index were reduced in the EPCs-treated group compared with the untreated group. In addition, the EPCs-treated mice exhibited less antioxidant activity in bronchoalveolar lavage fluid compared with the untreated mice. Moreover, decreased activities of MMP-2, MMP-9, and TUNEL-positive cells in lung tissues were detected in EPCs-treated mice. Conclusion Intratracheal transplantation of EPCs attenuated the development of pulmonary emphysema and lung function disorder probably by alleviating inflammatory infiltration, decelerating apoptosis, inhibiting proteolytic enzyme activity, and improving antioxidant activity.
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Affiliation(s)
- Zhihui Shi
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Yan Chen
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Jun Cao
- Department of Internal Medicine, Division of Respiratory Disease, The People's Hospital of Hunan Province
| | - Huihui Zeng
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Yue Yang
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Ping Chen
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Hong Luo
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Hong Peng
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Shan Cai
- Department of Internal Medicine, Division of Respiratory Disease, The Second Xiangya Hospital, Central-South University
| | - Chaxiang Guan
- Department of Physiology, Xiangya Medical School, Central-South University, Changsha, Hunan, People's Republic of China
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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.
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27
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Sirt1 expression is associated with CD31 expression in blood cells from patients with chronic obstructive pulmonary disease. Respir Res 2016; 17:139. [PMID: 27784320 PMCID: PMC5081972 DOI: 10.1186/s12931-016-0452-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 10/14/2016] [Indexed: 12/31/2022] Open
Abstract
Background Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34+ progenitor cells to examine whether these genes are associated with COPD development. Methods This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34+ progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR. Results The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells. Conclusion Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD.
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The role of 20-HETE in cardiovascular diseases and its risk factors. Prostaglandins Other Lipid Mediat 2016; 125:108-17. [PMID: 27287720 DOI: 10.1016/j.prostaglandins.2016.05.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/20/2016] [Accepted: 05/31/2016] [Indexed: 01/03/2023]
Abstract
Arachidonic acid (AA) is metabolized in mammals by enzymes of the CYP4A and 4F families to 20-hydroxyeicosatetraeonic acid (20-HETE) which plays an important role in the regulation of renal function, vascular tone and arterial pressure. In the vasculature, 20-HETE is a potent vasoconstrictor, the up-regulation of which contributes to inflammation, oxidative stress, endothelial dysfunction and an increase in peripheral vascular resistance in models of obesity, diabetes, ischemia/reperfusion, and vascular oxidative stress. Recent studies have established a role for 20-HETE in normal and pathological angiogenic conditions. We discuss in this review the synthesis of 20-HETE and how it and various autacoids, especially the renin-angiotensin system, interact to promote hypertension, vasoconstriction, and vascular dysfunction. In addition, we examine the molecular mechanisms through which 20-HETE induces these actions and the clinical implication of inhibiting 20-HETE production and activity.
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29
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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.
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30
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Fujinaga H, Fujinaga H, Watanabe N, Kato T, Tamano M, Terao M, Takada S, Ito Y, Umezawa A, Kuroda M. Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol 2016; 310:L1143-54. [PMID: 27130531 DOI: 10.1152/ajplung.00357.2015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 04/22/2016] [Indexed: 01/07/2023] Open
Abstract
Vascular growth is necessary for normal lung development. Although endothelial progenitor cells (EPCs) play an important role in vascularization, little is known about EPC function in congenital diaphragmatic hernia (CDH), a severe neonatal condition that is associated with pulmonary hypoplasia. We hypothesized that the function of endothelial colony-forming cells (ECFCs), a type of EPC, is impaired in CDH. Cord blood (CB) was collected from full-term CDH patients and healthy controls. We assessed CB progenitor cell populations as well as plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1α (SDF1α) levels. CB ECFC clonogenicity; growth kinetics; migration; production of VEGF, SDF1α, and nitric oxide (NO); vasculogenic capacity; and mRNA expression of VEGF-A, fms-related tyrosine kinase 1 (FLT1), kinase insert domain receptor (KDR), nitric oxide synthase (NOS) 1-3, SDF1, and chemokine (C-X-C motif) receptor 4 (CXCR4) were also assessed. Compared with controls, CB ECFCs were decreased in CDH. CDH ECFCs had reduced potential for self-renewal, clonogenicity, proliferation, and migration. Their capacity for NO production was enhanced but their response to VEGF was blunted in CDH ECFCs. In vivo potential for de novo vasculogenesis was reduced in CDH ECFCs. There was no difference in CB plasma VEGF and SDF1α concentrations, VEGF and SDF1α production by ECFCs, and ECFC mRNA expression of VEGF-A, FLT1, KDR, NOS1-3, SDF1, and CXCR4 between CDH and control subjects. In conclusion, CB ECFC function is disrupted in CDH, but these changes may be caused by mechanisms other than alteration of VEGF-NO and SDF1-CXCR4 signaling.
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Affiliation(s)
- Hideshi Fujinaga
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan; Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan; Division of Neonatology, Center for Maternal-Fetal and Neonatal Medicine, National Center for Child Health and Development, Tokyo, Japan;
| | - Hiroko Fujinaga
- Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan
| | - Nobuyuki Watanabe
- Department of Human Genetics, National Institute for Child Health and Development, Tokyo, Japan; and
| | - Tomoko Kato
- Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan
| | - Moe Tamano
- Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan
| | - Miho Terao
- Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan
| | - Shuji Takada
- Department of Systems BioMedicine, National Institute for Child Health and Development, Tokyo, Japan
| | - Yushi Ito
- Division of Neonatology, Center for Maternal-Fetal and Neonatal Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Akihiro Umezawa
- Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
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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.
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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
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Sradnick J, Rong S, Luedemann A, Parmentier SP, Bartaun C, Todorov VT, Gueler F, Hugo CP, Hohenstein B. Extrarenal Progenitor Cells Do Not Contribute to Renal Endothelial Repair. J Am Soc Nephrol 2015; 27:1714-26. [PMID: 26453608 DOI: 10.1681/asn.2015030321] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 08/18/2015] [Indexed: 12/14/2022] Open
Abstract
Endothelial progenitor cells (EPCs) may be relevant contributors to endothelial cell (EC) repair in various organ systems. In this study, we investigated the potential role of EPCs in renal EC repair. We analyzed the major EPC subtypes in murine kidneys, blood, and spleens after induction of selective EC injury using the concanavalin A/anti-concanavalin A model and after ischemia/reperfusion (I/R) injury as well as the potential of extrarenal cells to substitute for injured local EC. Bone marrow transplantation (BMTx), kidney transplantation, or a combination of both were performed before EC injury to allow distinction of extrarenal or BM-derived cells from intrinsic renal cells. During endothelial regeneration, cells expressing markers of endothelial colony-forming cells (ECFCs) were the most abundant EPC subtype in kidneys, but were not detected in blood or spleen. Few cells expressing markers of EC colony-forming units (EC-CFUs) were detected. In BM chimeric mice (C57BL/6 with tandem dimer Tomato-positive [tdT+] BM cells), circulating and splenic EC-CFUs were BM-derived (tdT+), whereas cells positive for ECFC markers in kidneys were not. Indeed, most BM-derived tdT+ cells in injured kidneys were inflammatory cells. Kidneys from C57BL/6 donors transplanted into tdT+ recipients with or without prior BMTx from C57BL/6 mice were negative for BM-derived or extrarenal ECFCs. Overall, extrarenal cells did not substitute for any intrinsic ECs. These results demonstrate that endothelial repair in mouse kidneys with acute endothelial lesions depends exclusively on local mechanisms.
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Affiliation(s)
- Jan Sradnick
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Song Rong
- Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
| | - Anika Luedemann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Simon P Parmentier
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Christoph Bartaun
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Vladimir T Todorov
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Faikah Gueler
- Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
| | - Christian P Hugo
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
| | - Bernd Hohenstein
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; and
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Glynn JJ, Jones CM, Anderson DEJ, Pavcnik D, Hinds MT. In vivo assessment of two endothelialization approaches on bioprosthetic valves for the treatment of chronic deep venous insufficiency. J Biomed Mater Res B Appl Biomater 2015; 104:1610-1621. [PMID: 26316151 DOI: 10.1002/jbm.b.33507] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 08/06/2015] [Accepted: 08/14/2015] [Indexed: 12/28/2022]
Abstract
Chronic deep venous insufficiency is a debilitating disease with limited therapeutic interventions. A bioprosthetic venous valve could not only replace a diseased valve, but has the potential to fully integrate into the patient with a minimally invasive procedure. Previous work with valves constructed from small intestinal submucosa (SIS) showed improvements in patients' symptoms in clinical studies; however, substantial thickening of the implanted valve leaflets also occurred. As endothelial cells are key regulators of vascular homeostasis, their presence on the SIS valves may reduce the observed thickening. This work tested an off-the-shelf approach to capture circulating endothelial cells in vivo using biotinylated antikinase insert domain receptor antibodies in a suspended leaflet ovine model. The antibodies on SIS were oriented to promote cell capture and showed positive binding to endothelial cells in vitro; however, no differences were observed in leaflet thickness in vivo between antibody-modified and unmodified SIS. In an alternative approach, valves were pre-seeded with autologous endothelial cells and tested in vivo. Nearly all the implanted pre-seeded valves were patent and functioning; however, no statistical difference was observed in valve thickness with cell pre-seeding. Additional cell capture schemes or surface modifications should be examined to find an optimal method for encouraging SIS valve endothelialization to improve long-term valve function in vivo. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1610-1621, 2016.
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Affiliation(s)
- Jeremy J Glynn
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239
| | - Casey M Jones
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239.,Department of Chemistry, Lewis & Clark College, Portland, Oregon, 97219
| | - Deirdre E J Anderson
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239
| | - Dusan Pavcnik
- Dotter Interventional Institute, Oregon Health & Science University, Portland, Oregon, 97239
| | - Monica T Hinds
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, 97239. .,Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, 97239. .,Department of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006.
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Fujita M. New therapies for chronic obstructive pulmonary disease, lung regeneration. World J Respirol 2015; 5:34-39. [DOI: 10.5320/wjr.v5.i1.34] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 12/15/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow limitations that are not fully reversible and is a major cause of chronic morbidity and mortality worldwide. Although there has been extensive research examining the molecular mechanisms underlying the development of COPD, there is no proven clinically effective treatment for promoting recovery from established COPD. At present, regeneration is the only hope for a cure in patients with COPD. In this article, we review current treatments for COPD, focusing particularly on recent advances in lung regeneration based on two major approaches: regeneration-promoting agents and cell therapy. Retinoic acids are the major focus among regeneration-promoting agents, while mesenchymal stem cells are the main topic in the field of cell-based therapy. This article aims to provide valuable information for developing new therapies for COPD.
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Paschalaki KE, Starke RD, Hu Y, Mercado N, Margariti A, Gorgoulis VG, Randi AM, Barnes PJ. Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence. Stem Cells 2015; 31:2813-26. [PMID: 23897750 PMCID: PMC4377082 DOI: 10.1002/stem.1488] [Citation(s) in RCA: 129] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 05/03/2013] [Accepted: 05/15/2013] [Indexed: 01/04/2023]
Abstract
Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA double-strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin-1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU-55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention.
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Affiliation(s)
- Koralia E Paschalaki
- Airway Disease Section and National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; Vascular Sciences, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; Histology-Embryology Department, Faculty of Medicine, University of Athens, Athens, Greece
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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.
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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
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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:
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Nakamura N, Naruse K, Kobayashi Y, Matsuki T, Hamada Y, Nakashima E, Kamiya H, Hata M, Nishikawa T, Enomoto A, Takahashi M, Murohara T, Matsubara T, Oiso Y, Nakamura J. High glucose impairs the proliferation and increases the apoptosis of endothelial progenitor cells by suppression of Akt. J Diabetes Investig 2014; 2:262-70. [PMID: 24843496 PMCID: PMC4014965 DOI: 10.1111/j.2040-1124.2010.00093.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
UNLABELLED Aims/Introduction: Endothelial progenitor cells (EPC) play a critical role in adult vasculogenesis and vascular repair. Previous studies have described the dysfunction of EPC in diabetic patients, but the precise mechanism is still unclear. To elucidate the dysfunction of EPC in diabetic patients, we investigated the functions and intracellular signaling of EPC under normal or high glucose conditions. We also examined the number of EPC in the peripheral blood of Japanese type 2 diabetic patients. MATERIALS AND METHODS EPC were cultured with normal or high glucose. Subsequently, the proliferation and the apoptosis of EPC were assessed in the presence or absence of vascular endothelial growth factor (VEGF). The phosphorylation of Akt was assessed by western blot analyses. We compared the number of CD34(+)CD45(low) progenitor cells, which is considered as a marker of EPC in non-diabetic and type 2 diabetic subjects, using flow cytometry. RESULTS High glucose decreased the proliferation of EPC and increased the number of apoptotic cells. VEGF significantly increased the proliferation and suppressed the apoptosis of EPC, both of which were abolished by PI 3-kinase inhibitor, LY294002. High glucose significantly suppressed the basal and VEGF-stimulated phosphorylation of Akt in EPC. Furthermore, the number of circulating EPC was decreased in type 2 diabetic patients, although there were no significant differences in the serum levels of VEGF between control subjects and diabetic patients. CONCLUSIONS These findings suggest that high glucose impairs the functions of EPC through the suppression of Akt phosphorylation stimulated by VEGF. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00093.x, 2011).
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Affiliation(s)
| | - Keiko Naruse
- Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University ; Endocrinology and Diabetes
| | - Yasuko Kobayashi
- Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University
| | | | | | | | - Hideki Kamiya
- CKD Initiatives, Nagoya University School of Medicine
| | - Masaki Hata
- Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University
| | - Toru Nishikawa
- Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University
| | | | | | | | - Tatsuaki Matsubara
- Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University
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Alphonse RS, Vadivel A, Fung M, Shelley WC, Critser PJ, Ionescu L, O'Reilly M, Ohls RK, McConaghy S, Eaton F, Zhong S, Yoder M, Thébaud B. Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth. Circulation 2014; 129:2144-57. [PMID: 24710033 DOI: 10.1161/circulationaha.114.009124] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. METHODS AND RESULTS Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth-arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood-derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. CONCLUSIONS Impaired ECFC function may contribute to arrested alveolar growth. Cord blood-derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.
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Affiliation(s)
- Rajesh S Alphonse
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Arul Vadivel
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Moses Fung
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - William Chris Shelley
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Paul John Critser
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Lavinia Ionescu
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Megan O'Reilly
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Robin K Ohls
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Suzanne McConaghy
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Farah Eaton
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Shumei Zhong
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Merv Yoder
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.)
| | - Bernard Thébaud
- From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.). bthebaud@ohri
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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.
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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.
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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.
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Affiliation(s)
- Alvar Agustí
- 1 Thorax Institute, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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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.
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Affiliation(s)
- William J Janssen
- 1Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, CO, USA
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Brittan M, Hoogenboom MM, Padfield GJ, Tura O, Fujisawa T, Maclay JD, Macnee W, Mills NL. Endothelial progenitor cells in patients with chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 2013; 305:L964-9. [PMID: 24142520 DOI: 10.1152/ajplung.00183.2013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The pathogenesis of chronic obstructive pulmonary disease is not fully understood. The objective of this study was to compare circulating endothelial progenitor cells in patients with chronic obstructive pulmonary disease to age, sex, and cigarette smoking matched healthy controls. Patients with chronic obstructive pulmonary disease (n = 37) and healthy controls (n = 19) were matched by age, sex, and smoking status. Circulating hematopoietic progenitor cells (CD34(+) or CD133(+) mononuclear cells) and endothelial progenitor cells (CD34(+)KDR(+) or CD34(+)CD133(+)KDR(+) mononuclear cells) were quantified by flow cytometry. Endothelial cell-colony forming units from peripheral blood mononuclear cells were quantified in vitro and phenotypic analysis carried out using immunocytochemistry. Patients with chronic obstructive pulmonary disease had more circulating mononuclear cells compared with controls (8.4 ± 0.6 vs. 5.9 ± 0.4 × 10(9) cells/l; P = 0.02). CD34(+) hematopoietic progenitor cells were reduced as a proportion of mononuclear cells in patients compared with controls (0.99 ± 0.12 vs. 1.9 ± 0.12%; P = 0.02); however, there were no differences in the absolute number of CD34(+), CD34(+)KDR(+), or CD34(+)CD133(+)KDR(+) cells (P > 0.05 for all). Endothelial cell-colony forming units were increased in patients with chronic obstructive pulmonary disease compared with controls (13.7 ± 5.2 vs. 2.7 ± 0.9 colonies; P = 0.048). In contrast to previous studies, the number of circulating progenitor cells was not reduced in patients with chronic obstructive pulmonary disease compared with carefully matched controls. It seems unlikely that circulating endothelial progenitor cells or failure of angiogenesis plays a central role in the development of emphysema.
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Affiliation(s)
- Mairi Brittan
- BHF/Univ. Centre for Cardiovascular Science, The Univ. of Edinburgh, Scottish Centre for Regenerative Medicine, Little France Crescent, Edinburgh EH16 4UU, UK.
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He S, He Z, Chen Y, Ye J, Zong D, Zhang Y, Chen P. C-Kit/c-Kit ligand interaction of bone marrow endothelial progenitor cells is influenced in a cigarette smoke extract-induced emphysema model. Exp Lung Res 2013; 39:258-67. [PMID: 23786491 DOI: 10.3109/01902148.2013.802828] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Smoking causes lung endothelial cell apoptosis and emphysema. Derived from bone marrow, circulating endothelial progenitor cells (EPCs) maintain vascular integrity by replacing and repairing damaged endothelial cells. Smoking influences the number of circulating EPCs. Recruitment of EPCs from bone marrow to peripheral blood depends on the interaction of c-Kit/soluble c-Kit ligand (sKitL). We hypothesized that smoking might influence c-Kit(+) EPCs/sKitL interaction in bone marrow in the development of smoking-related emphysema. In this study, we used a cigarette smoke extract (CSE)-induced emphysema model. METHODS Mice were injected intraperitoneally with PBS/CSE and sacrificed at day 28. Lung function and pathology of lung tissue were measured to characterize the model. Expressions of c-Kit in the lung tissue were assayed. Bone marrow cells were isolated by red blood cell lysis. EPCs/c-Kit(+) EPCs in nonred blood cells were analyzed by flow cytometry. Expressions of KitL and MMP-9, and activity MMP-9 in bone marrow were measured. RESULTS Our data demonstrated that gene and protein expressions of c-Kit were decreased in the lung tissue in this model. Compared with the control group, the number of bone marrow nonred blood cells was unchanged following CSE treatment, while the depletion of bone marrow EPCs/c-Kit(+) EPCs was significant. The level of sKitL was reduced in the bone marrow in the model. The reduction of sKitL was associated with deregulated KitL expression and decreased MMP-9 activity. CONCLUSIONS The interaction between c-Kit and sKitL in bone marrow EPCs, a critical step in endothelial repair, is negatively affected in a CSE-induced emphysema model.
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Affiliation(s)
- Shengdong He
- Department of Pulmonary Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
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Habibzay M, Weiss G, Hussell T. Bacterial superinfection following lung inflammatory disorders. Future Microbiol 2013; 8:247-56. [PMID: 23374129 DOI: 10.2217/fmb.12.143] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The lung environment is designed to prevent innate responses to harmless commensal microorganisms and environmental antigens. Features of an intact respiratory epithelium are critical to this process. A damaged or altered lung epithelial surface will therefore remove or alter the suppressive signals delivered to local innate immune cells, and inflammation ensues. Timely resolution of inflammation is important to prevent bystander tissue damage. However, if resolving pathways themselves are prolonged or repeated, they too can cause undesirable consequences, including bacterial superinfections, which we discuss here.
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Affiliation(s)
- Maryam Habibzay
- Imperial College London, Leukocyte Biology Section, National Heart & Lung Institute, London, UK
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Mobilization of endothelial progenitor cells from bone marrow is impaired in a piglet model of acute respiratory distress syndrome. Pediatr Crit Care Med 2013; 14:e233-42. [PMID: 23867444 DOI: 10.1097/pcc.0b013e31828a7242] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To characterize the endothelial progenitor cell mobilization in the models of moderate and severe lung injury, we hypothesized that there were differences in endothelial progenitor cell levels and mobilizing cytokines between moderate and severe lung injury. DESIGN Prospective, randomized, and controlled experimental study. SETTING University research laboratory center. SUBJECTS Fifteen healthy piglets. INTERVENTIONS Piglets were randomly allocated to control, moderate lung injury (acute lung injury), and severe lung injury (acute respiratory distress syndrome) groups. Lung injury was established by intravenous infusion of oleic acid. Animals were mechanically ventilated for 24-48 hours, and then animals were weaned from ventilation and cared for until day 7. MEASUREMENTS AND MAIN RESULTS Endothelial progenitor cells were quantified by flow cytometry. After 24 hours, the number of endothelial progenitor cells in peripheral blood increased in the acute lung injury group but was not altered in the acute respiratory distress syndrome group compared to the control group. The number of CD34KDR, KDRCD133, and CD34KDRCD133 cells was higher in the acute lung injury group than in the acute respiratory distress syndrome group. In bone marrow, the number of CD34KDR and KDRCD133 cells was greater in acute respiratory distress syndrome animals but not altered in acute lung injury animals at 24 hours. Furthermore, plasma stromal cell-derived factor-1 and vascular endothelial growth factor concentrations were higher in acute lung injury than in acute respiratory distress syndrome at 24 hours. Matrix metalloproteinase-9 and soluble kit ligand levels in bone marrow were reduced in acute respiratory distress syndrome compared with acute lung injury. Lung CD34, KDR, and lung stromal cell-derived factor-1 messenger RNA expression were higher in the acute lung injury group than in the acute respiratory distress syndrome group. Furthermore, the expression of CD34, KDR, and CD133 messenger RNA in lung tissue was correlated with stromal cell-derived factor-1 in the lung. CONCLUSIONS There was a rapid release of endothelial progenitor cells from bone marrow into circulation in moderate acute lung injury, and endothelial progenitor cell mobilization was impaired in acute respiratory distress syndrome.
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Baker CD, Seedorf GJ, Wisniewski BL, Black CP, Ryan SL, Balasubramaniam V, Abman SH. Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2013; 305:L73-81. [PMID: 23666751 DOI: 10.1152/ajplung.00400.2012] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Late-outgrowth endothelial colony-forming cells (ECFCs), a type of circulating endothelial progenitor cell (EPC), may contribute to pulmonary angiogenesis during development. Cord blood ECFCs from preterm newborns proliferate more rapidly than term ECFCs but are more susceptible to the adverse effects of hyperoxia. Recent studies suggest that bone marrow-derived EPCs protect against experimental lung injury via paracrine mechanisms independent of vascular engraftment. To determine whether human umbilical cord blood ECFCs from preterm and term newborns have therapeutic benefit in experimental neonatal lung injury, we isolated cord blood ECFCs from full-term and preterm newborns and prepared ECFC-conditioned medium (CM) to test its therapeutic benefit on fetal pulmonary artery endothelial cell (PAEC) proliferation and function as well as alveolar type 2 (AT2) cell growth. PAECs and AT2 cells were isolated from late-gestation fetal sheep. Additionally, we administered both ECFCs and ECFC-CM to bleomycin-exposed newborn rats, an experimental model of bronchopulmonary dysplasia (BPD). Both term ECFC-CM and preterm ECFC-CM promoted cell growth and angiogenesis in vitro. However, when ECFC-CM was collected during exposure to mild hyperoxia, the benefit of preterm ECFC-CM was no longer observed. In the bleomycin model of BPD, treatment with ECFC-CM (or CM from mature EC) effectively decreased right ventricular hypertrophy but had no effect on alveolar septation. We conclude that term ECFC-CM is beneficial both in vitro and in experimental BPD. During oxidative stress, preterm ECFC-CM, but not term ECFC-CM, loses its benefit. The inability of term ECFC-CM to promote alveolarization may limit its therapeutic potential.
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Affiliation(s)
- Christopher D Baker
- Pediatric Heart Lung Center, University of Colorado School of Medicine, Mail Stop 8614, 12700 E. 19th Ave., Aurora, CO 80045, USA.
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Conese M, Carbone A, Castellani S, Di Gioia S. Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases. Cells Tissues Organs 2013; 197:445-73. [PMID: 23652321 DOI: 10.1159/000348831] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2013] [Indexed: 11/19/2022] Open
Abstract
Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders.
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Affiliation(s)
- Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
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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.
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Affiliation(s)
- Argyris Tzouvelekis
- Department of Pneumonology, University Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
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Malli F, Koutsokera A, Paraskeva E, Zakynthinos E, Papagianni M, Makris D, Tsilioni I, Molyvdas PA, Gourgoulianis KI, Daniil Z. Endothelial progenitor cells in the pathogenesis of idiopathic pulmonary fibrosis: an evolving concept. PLoS One 2013; 8:e53658. [PMID: 23341966 PMCID: PMC3544914 DOI: 10.1371/journal.pone.0053658] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2012] [Accepted: 12/04/2012] [Indexed: 11/25/2022] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) has been associated with abnormal vascular remodeling. Bone marrow derived endothelial progenitor cells (EPCs) are considered to possess lung tissue repair and vascular remodeling properties. Objectives The study aimed to assess early EPCs levels and EPCs endogenous vascular endothelial growth factor (VEGF) expression in IPF. In order to examine alterations in the mobilization of EPCs from the bone marrow we measured plasma VEGF. Main Results Twenty-three patients with IPF and fifteen healthy subjects were included. The number of early EPCs colonies was markedly reduced in IPF patients vs controls (6.00±6.49 vs 49.68±16.73, respectively, p<0.001). EPCs were further decreased in patients presenting systolic pulmonary arterial pressure (sPAP)≥35 mmHg. The number of colonies per well correlated negatively with P(A-a)O2 (r = −0.750, p<0.001). Additionally, VEGF mRNA levels were significantly increased in IPF patients. There were no differences observed in VEGF plasma levels in IPF patients when compared to controls. Conclusions The current data suggest that inadequate levels of early EPCs may potentially contribute to suppressed repair and recovery of the damaged pulmonary endothelium and thereby may drive the sequence of events in profibrogenic direction. Increased VEGFmRNA levels in the clinical context of IPF may represent a compensatory mechanism to overcome reduced EPCs levels.
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Affiliation(s)
- Foteini Malli
- Respiratory Medicine Department, School of Medicine, University of Thessaly, Larissa, Greece
| | - Angela Koutsokera
- Respiratory Medicine Department, School of Medicine, University of Thessaly, Larissa, Greece
| | - Efrosini Paraskeva
- Department of Physiology, School of Medicine, University of Thessaly, Larissa, Greece
| | - Epaminondas Zakynthinos
- Department of Critical Care Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Maria Papagianni
- Department of Physiology, School of Medicine, University of Thessaly, Larissa, Greece
| | - Dimosthenes Makris
- Department of Critical Care Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Irene Tsilioni
- Respiratory Medicine Department, School of Medicine, University of Thessaly, Larissa, Greece
| | | | | | - Zoe Daniil
- Respiratory Medicine Department, School of Medicine, University of Thessaly, Larissa, Greece
- * E-mail:
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Schiavon M, Fadini GP, Lunardi F, Agostini C, Boscaro E, Calabrese F, Marulli G, Rea F. Increased tissue endothelial progenitor cells in end-stage lung diseases with pulmonary hypertension. J Heart Lung Transplant 2013; 31:1025-30. [PMID: 22884387 DOI: 10.1016/j.healun.2012.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 05/23/2012] [Accepted: 06/06/2012] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Diffuse lung diseases promote the development of vascular changes and pulmonary hypertension (PH). Endothelial progenitor cells (EPCs) seem to be involved in pulmonary vascular remodeling. We evaluated circulating and intra-pulmonary EPCs in end-stage lung diseases in relation to pulmonary arterial pressure (PAP). METHODS The study included 19 patients affected by different end-stage lung diseases, with or without PH. Six lung donors were considered as control group. EPCs were measured in blood samples taken at the time of transplant from pulmonary arteries and veins (by flow cytometry) as well as in lung specimen sections (by confocal microscopy) and expressed as percentage of total number of cells. RESULTS The amount of EPC in lung specimens was significantly different according to type of disease (p = 0.001). Specifically, a higher number of EPCs was detected in idiopathic pulmonary hypertension and idiopathic pulmonary fibrosis with high (> 25 mm Hg) mean PAP (p = 0.03 for both) compared with chronic obstructive pulmonary disease and control group. There was a direct correlation between intrapulmonary EPCs and PAP. According to receiver operating characteristic curve analysis, the presence of > 3% EPCs had a 91% sensitivity and 93% specificity in identifying high mean PAP. There were no differences in circulating arterial or venous EPCs among groups. CONCLUSIONS Intra-pulmonary EPCs are increased in lung diseases with high PAP, suggesting that EPCs may contribute to vascular remodeling in end-stage pulmonary disease.
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Affiliation(s)
- Marco Schiavon
- Department of Cardio-Thoracic and Vascular Sciences, University of Padua, Padua, Italy
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