Smoking is one of the risky behaviours that can increase cardiovascular disease incidence. The long manifestation of smokings adverse effect has to lead the perception among smokers that smoking does not harm health. Therefore, it is necessary to conduct studies that can detect the progression of cardiovascular disorders before the actual manifestation of the disease.
The endothelium has an essential role in regulating the coagulation system and vascular tone.1 Changes in the structure and function of the endothelium are a description of the response to vascular damage.24 Long-term smoking habits can interfere with endothelial function through the oxidative stress pathway.5,6 Nicotine is the most toxic component of cigarettes that can induce endothelial cell death.710 The increasing the number of circulating endothelial cells which is the final stage of the endothelial damage process is a sign for the endothelial cell death.11 Endothelial damage can be preceded by endothelial activation, which is indicated by an increase in the amount of E-selectin.1 E-Selectin or the so-called CD62 antigen-like family member E (CD62E) is an adhesion molecule that expressed when endothelial cells are activated by inflammation.12 E-selectin is also present in activated platelets as a consequence of endothelial injury.13 E-Selectin mediates leucocyte adherence to injury areas and stimulates vascular inflammatory responses.1315 E-Selectin is also considered a component involved in the self-renewal regulation of endothelial injury by Hematopoietic Stem Cell (HSC). Because of this dual role, E-selectin referred to as a regulator of cell-trafficking to areas of inflammation in humans.16 Soluble E-selectin can be identified in blood circulation by the ELISA method.15,17
Endothelial damage causes loss of the primary vascular protective barrier so that circulating platelets adhere to collagen easily beneath the endothelial cells. Attachment of platelets to the area of endothelial injury causes platelets to become activated and produce higher amounts of Platelet-Derived Micro Particles (PMPs). The coagulation effect in the injured area by releasing thrombin, thereby increasing platelet adhesion to endothelial cells. At this stage thrombus formation in the injured area has begun.13,18,19
The presence of PMPs in the blood circulation, both in pathological and physiological conditions, can be identified by identifying the surface marker with the CD41 marker.20 A high circulating CD41 count can also be found in healthy individuals, not accompanied by endothelial/platelet activation. This condition is because megakaryocytes, as platelet precursors, also express CD41. So, the increase of CD41 levels in the circulation has two meanings, as a marker of platelet activation in pathological conditions and an increase in the number of megakaryocytes in physiological conditions.20
Increased circulating CD41 will be detected by bone marrow (BM) as a signal that causes platelet activation to signal increased vascular repair needs. BM will produce high amounts of HSC when an extensive vascular endothelial injury occurs. The presence of HSC in the circulation can be determined using CD133.2123 Circulating HSCs will undergo maturation to become Progenitor Endothelial Cells (EPC). The presence of PMPs plays a role in facilitating the planting of progenitor cells in endothelial areas that experience injury by increasing the attachment of EPC to fibrinogen.24,25 Endothelial damage is known to cause various forms of cellular responses. To maintain vascular homeostasis, as a form of vascular adaptation, can be identified by quantifying the circulating soluble marker as a marker of endothelial activation. This study does not seem to present anything new because the markers used have been established. Still, the study of vascular status in heavy smokers (> 10 cigarettes per day) for five years at the molecular level is a research that has not been widely carried out. This study aims to analyze the differences in the initial view of vascular adaptation in the smoker and non-smoker groups by measuring the amount of E-selectin, PMPs, and HSC in the peripheral blood circulation.
This study used a cross-sectional designrecruitment of participants through filling in the willingness to take part in research via a google form. The google form link is distributed through social media for two weeks to get two groups of participants, namely the smokers and non-smokers. The Google form contains statements about participants objectives, benefits, rights and obligations, as well as research procedures. Prospective participants are given the opportunity to learn the information, if the prospective participant has understood and agreed, they are asked to sign the informed consent electronically to follow the research.
The smoking group is consisted of people who had a smoking history of no more than five years at the time of the study. Meanwhile, the non-smoking group were people who had never smoked at all until the study ends. All participants in both the smoking and non-smoking groups had no history of cardiovascular and metabolic diseases such as diabetes mellitus, hypertension, infection, obesity, or cancer. The history of the disease was retrieved from the medical records of each participant. After two weeks of recruitment, there were 30 and 31 participants in the smoker and non-smoker groups, respectively.
Participants were confirmed not to be taking drugs before blood collection was carried out. Then vital signs (blood pressure, pulse, respiration, and body temperature) are examined. Blood collection is carried out in the Central Laboratory of Biomedical, Faculty of Medicine, Brawijaya University. Laboratory analysts did not know the smoking status of each participant during the process of collecting and analyzing the studied blood samples.
A total of 5 mL of peripheral blood which has been taken using the venous punction procedure, then accommodated in an Ethylene Diamine Tetra Acetic (EDTA) tube. Blood was diluted with Axisxhields Lymphoperm in the same volume ratio in a 15 mL tube, then centrifuged for 30 minutes at 6000 rpm. Buffy coat, which is the result of PBMNC centrifugation, was taken with a clean pipette and accommodated in a new tube and added up to 10 mL of phosphate-buffered saline (PBS), centrifuged again for 10 min at 1200 rpm. The PBS washing procedure repeated for two times. The pellets are ready for staining.
Blood samples for measurement of E-selectin, CD41, and CD133 were obtained from the participants peripheral blood from both smokers and non-smokers. None of the participants took antiplatelet drugs, anti-inflammatory drugs, or hypolipidemic agents. This screening excludes any conditions thought to influence the number of platelets microparticles as a parameter in the present study.
The detection of E-selectin was confirmed by staining Phycoerythrin (PE)-conjugated monoclonal anti-human CD62E Biolegend Cat No. 322606 on the obtained PBMNC. Platelet microparticles carried out by adding 5 L of Peridinin Chlorophyll (PerCP)-conjugated anti-human von Willebrand Factor (vWF/CD41) from (Biolegend, UK; catalogue number: 303720). Meanwhile, measurement of HSC counts was confirmed by adding 5L of anti-human CD133 Allophycocyanine (APC mouse-conjugated monoclonal antibody IgG2A clone # 170411 [FAB cat no. 11331A]. The flowcytometric analyzed using the BD FACSMelody Cell Sorter, and BD FACSChorusTM software simplifies sorting by using a streamlined workflow.
All data were presented as mean value standard deviation. The comparison between the two groups was analyzed by independent t-test. The statistical significance was assumed if the null hypothesis failed to reject based on p-value <0.05.
This research has been approved by the Research Ethics Committee of Brawijaya University with Reference Number 1206-KEP-UB-2019. All of the patients participate in this study provided informed consent that has been in accordance with the Declaration of Helsinki.
Characteristics of smokers and non-smokers: height, weight, and pulse can be seen in Table 1. Each of these characteristics was not significantly different in the two groups. The analysis then continued by identifying the differences in the number of E-Selectin, PMPs, and HSC between the smokers and non-smokers (Figure 1 and Table 2).
Table 1 The Baseline Characteristics of Smoker and Non-Smoker Group
Table 2 The Quantification of the Mean E-Selectin, PMPs, and HSC
Figure 1 Scatter plot diagram of the results of the analysis of E-selectin (CD62E), PMPS (CD41), and HSC (CD133) with flow cytometry. (A) Gate view of E-selectin analysis in smoker group. (B) Gate view of PMPs analysis in smokers group. (C) Gate view of HSC analysis in smokers group. (D) Gate view of E-selectin analysis in non-smokers analysis of PMPs in the non-smoker group. (E) Gate view of PMPs analysis in non-smokers group. (F) Gate view of HSCs analysis in non-smokers group.
Based on Figure 1, it is known that the mean number of E-selectin (measured by the CD62E marker) in the smoker group was higher than in the non-smoker group. Meanwhile, the mean number of PMPs (measured through the CD41 marker) in the smoker group was lower than that of non-smokers. Meanwhile, the mean number of HSCs (measured using the CD133 marker) in the smoker group was lower in the non-smoker group. This condition indicates endothelial activation, which indicates vascular inflammation in the smoker group.
Table 2 shows that there is a significant difference between the mean E-selectin, PMPs, and HSC between the smoker and non-smoker groups. The mean of circulating E-selectin in smokers was higher than that of non-smokers. On the other hand, the mean of PMPs and HSCs in smokers was lower than that of non-smokers.
Atherosclerotic disease is associated with endothelium function changes that occur in some CVD risk groups such as smokers, diabetes, hypertension and hyperlipidemia. Various previous studies have suggested that smoking can cause damage endothelium function.26 Damage to endothelium function due to long-term smoking habits is caused by increased production of free radicals that cause endothelial cell degradation resulting in decreased nitric oxide production.5,6 Some endothelial activation markers become the initial stage of vascular lesions development.27
The endothelial cells activate several Endothelial Microparticles (EMPs) released into circulation. The EMPs can be measure through surface makers such as E-selectin (CD62E), vascular cell adhesion molecules-1 (VCAM-1), and intercellular adhesion molecules-1 (ICAM-1).28 The platelets will increase rapidly to respond to endothelial injuries and secrete granule content into circulation called PMPs. Some platelet activation markers in circulation include P-selectin, CD40L, PF4, and GP IIb/IIIa (CD41)29,30 So, it is known that PMPs reflect platelet activation while EMPs markers become a representation of activation or endothelial dysfunction.31 The interaction of leukocytes and platelets in vascular endothelium induces inflammatory pathways, thrombosis and atherogenesis.32,33
This study showed that the number of mononuclear cells expressing E-selectin in the blood edge of smokers was higher than the non-smoker group. The increase in E-selectin in smokers in this study can be attributed to the results of previous studies that mentioned that smoking habits cause dysfunction and endothelial activation.34,35 Detection of endothelial activation can be measured through circulating markers including one of them is by measuring soluble E-selectin.3638 In this study, the circulating of cells that expressed E-selectin in the smoker group showed the same pattern as the soluble E-selectin measurement in another study describing the endothelial injury. The number of E-selectin circulated results from an increase in active proteolytic cleavage from the surface of endothelial cells that have been activated. Still, there is no explanation of E-selectins biological activity and clearance.39 In addition to showing endothelial activation, E-selectins increase may provide an overview of vascular inflammatory alteration.17
Active smoking of one cigarette caused an immediate and significant increase in the numbers of circulating PMPs (CD41), CD45 and VE-cadherin (CD144).19 Platelet-derived MPs (PMPs) are also called platelet dust, are ultramicro-membranous vesicles that are 0.11.0 m in diameter. PMPs are involved in various physiological functions, including endothelial repair.40 To evaluate PMPs role in the restoration of endothelial injury in the smoker group, quantification of circulating PMPs positive cell using flow cytometry in PBMNC smokers. This studys results are different from previous studies, the number of mononuclear cells that express markers of PMPs in smokers in this study tends to be lower compared to the non-smoker group. Some study mentioned that PMPs can improve adherence on the walls of the damaged vascular endothelium to stimulate the expression of adhesion receptors gene, such as epithelial membrane protein-1 and increased ICAM-1 expression, thereby mediating platelet recruitment and leukocytes to repair endothelial damage.4,41,42
The decrease in the number of PMPs in smokers this time can be attributed to previous study statements regarding the possibility of increasing the number of PMPs in vascular endothelial dysfunction due to smoking habits. Platelets become the largest source of microparticle production in circulation. The number of PMPs in circulation can reach 70% to 90% of the total existing microparticles; this indicates the vital role of platelet function in shaping the homeostasis response of vascular systems.4,20
According to the present study, smoking is a potentially reversible risk factor and seems to be causally associated with the hematopoietic system.43,44 The CD133, also known as prominin or AC133, is a highly conserved antigen expressed on hematopoietic stem cells.45 This protein is absent on mature endothelial cells and monocytic cells and expressed in EPCs.21,46 Evaluation of the effects of smoking on circulating human hematopoietic stem cells using CD133 markers remains unclear. This study showed that the number of CD133 positive cell circulating in the group of smokers tended to be lower compared to the non-smoker group.
Tobacco components in cigarettes can directly affect various organs functioning because they contain pro-inflammatory effects and cytotoxic effects. Inhalation of oxidant molecules in cigarettes causes various damage that can activate inflammatory responses (increased TNF-, IL-1, IL-6 and IL-8).47 When systemic inflammation occurs, HSCs located in bone marrow will undergo activation, expansion and proliferation.48 The mobilization of bone marrow HSCs intended for tissue repair mechanisms that occur dynamically and are self-regulated by stem cells.
The mechanism of proliferation and differentiation of HSCs due to inflammatory stimulus is part of the acute immune response. The accumulation of exposure to inflammatory cytokines causes disruption and loss of function of HSCs.49
Another study mentioned that pro-inflammatory cytokines are associated with decreased of stem cell factor (SCF), which are molecules that play a role in the mobilization of HSCs from bone marrow to circulation.50,51 So, it is likely that the mechanisms involved in decreasing the number of CD133 positive cells in smokers circulation are related to previous studies that stated that the accumulation of oxidants in smokers leads to increased production of inflammatory cytokines that can inhibit the signalling in the bone marrow.
Measurements of vascular endothelial damage and inflammatory cytokines in smokers not measured in this study may continue the next research process. The correlation of research parameters in this study is associated with several previous studies that discussed the effects of cigarettes on endothelial damage and the impact of cigarette components on inflammatory induction of oxidative stress related to bone marrow failure.
The increase in circulating E-selectin positive cells in smokers indicates activation and endothelial injury as an indicator of the early stages of vascular lesions formation. Platelets respond to the presence of injury in the endothelium through an increase in the number of positive PMPs cells, followed by adhesion of positive PMPs cells in the endothelial area experiencing an injury. Thus, the number of positive PMPs cells in the circulation tends to decrease. The low number of PMPs in the circulation cannot stimulate the bone marrow to release HSCs into the circulation. When the number of PMPs in the circulation decreases, it cannot provide sufficient signalling for the bone marrow to release adequate circulating HSCs to mediate endothelial injury repair.
The authors report no conflicts of interest in this work.
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- Mouse embryos grow for days in culture, but the requirements are a bit nuts - Ars Technica - March 22nd, 2021
- Cell Transplant Market 2021 Will Reflect Significant Growth in Future with Size, Share, Growth, and Key Companies Analysis- Regen Biopharma, Global... - March 22nd, 2021
- Global Hematopoietic Stem Cell Transplantation (HSCT) Market Size by Top Key Players are including in this report: Regen Biopharma Inc, China Cord... - March 18th, 2021
- Stem Cell Therapy Market expected to reach USD 16.51 Billion by 2025 with the CAGR of 8.5% FLA News - FLA News - March 18th, 2021
- Research on Stem Cells Cryopreservation Equipments Market 2021 : By Growing Rate, Type, Applications, Geographical Regions, and Forecast to 2026 KSU... - March 18th, 2021
- Father, daughter honored for their work supporting nonprofit - dayton.com - March 18th, 2021
- Stem Cell Therapy Market Size | Growth, Opportunities, Trends And Forecast To 2027 Cabell Standard - Cabell Standard - March 18th, 2021
- Global Cell Transplant Market 2020 Overview of Vital Industry Drivers | Top Players Regen Biopharma , Global Cord Blood Corporation , Escape... - March 18th, 2021
- This is not science fiction. Israeli researchers have grown an embryo outside the womb - Haaretz - March 18th, 2021
- Global Stem Cells Cryopreservation Equipments Industry Market 2021 Overview, Opportunities, In-Depth Analysis by 2027:Sichuan mountain vertical, Cesca... - March 18th, 2021
- One step closer to treating spinal cord injury with our own stem cells - Speaking of Research - March 17th, 2021
- Global Stem Cell Therapy Market to Reach $242.3 Million by 2027 - GlobeNewswire - March 17th, 2021
- Global Cord Stem Cell Banking Market Is Expected To Bring In USD 13.8 Billion By 2026 - PharmiWeb.com - March 17th, 2021
- Global Stem Cells Banking Market 2026 : Analyse the Industry Developments and Investment Decisions of Esperite, Neostem, Smart Cells International ... - March 17th, 2021
- Gamida Cell Presents Efficacy and Safety Results of Phase 3 Study of Omidubicel in Patients with Hematologic Malignancies at the 47th Annual Meeting... - March 17th, 2021
- Research Antibodies Market is Driven by Increasing Incidence of Chronic Diseases and Life-threatening Diseases KSU | The Sentinel Newspaper - KSU |... - March 17th, 2021
- Hematopoietic Stem Cell Transplantation (HSCT) Market Analysis, Growth, Emerging Trends, Opportunity and Forecast To 2027 FLA News - FLA News - March 17th, 2021
- Placental Stem Cell Therapy Market: Regenerative Ability to Develop into Other Types of Cells to Drive Global Market - BioSpace - March 13th, 2021
- Global Stem Cell Banking Market Comprehensive Study Explores Huge Growth Near in The Future||SMART CELLS PLUS, LifeCell International, Global Cord... - March 13th, 2021
- The Insight Partners's Detailed Report on Stem Cell Umbilical Cord Blood (UCB) Market Offers Projections of Potential Impact of Corona Virus Outbreak ... - March 11th, 2021
- Affimed Announces Presentations at the AACR Annual Meeting 2021 - GlobeNewswire - March 11th, 2021
- Cord Blood Stem Cells Market Trends 2021-2026 with Opportunities, Challenges and Companies' Profile Advanced Cell Technology, California Stem Cell,... - March 9th, 2021
- Stem Cell Therapy Useful In The Treatment Of A Range Of Diseases - Nerd's Magazine - March 9th, 2021
- Cord Blood Stem Cells: An Overview | The Center for ... - March 7th, 2021
- Stem cells can give new life to ovaries and potentially restore fertility - Salon - March 7th, 2021
- Chromosomal translocation t(11;14) and p53 deletion induced by the CRISPR/Cas9 system in normal B cell-derived iPS cells - DocWire News - March 7th, 2021
- Hematopoietic Stem Cell Transplantation (HSCT) Market 2021 Will Reflect Significant Growth in Future with Size, Share, Growth, and Key Companies... - March 5th, 2021
- Black people are three times less likely to find a bone marrow donor than white people - WLNS - March 5th, 2021
- Therapeutic Solutions International Spin-off Campbell Neurosciences Announces Umbilical Cord Derived Monocyte Immunotherapy Candidate for Suicide... - March 5th, 2021
- Global Hematopoietic Stem Cells Transplantation Market 2020 In-depth study, Size, Trends, Emerging Growth Factors and Regional Forecast to 2025 The... - March 5th, 2021
- Why Global Cord Blood Corporation Stock Is Jumping Today - Motley Fool - March 3rd, 2021
- NYCU shares lung therapy data with firms - - March 3rd, 2021
- Covid-19 Impact on Global Stem Cells Cryopreservation Equipments Market (2020-2025) | Potential growth, attractive valuation make it is a long-term... - March 3rd, 2021
- Autologous Stem Cell Based Therapies Market Analysis By Industry Value, Size, Top Companies And Growth Forecast To 2025 KSU | The Sentinel Newspaper... - March 3rd, 2021
- Global Cord Blood Corp.: Subscriber Growth Continues With 23% EPS CAGR And 25% FCF Yield - Seeking Alpha - March 3rd, 2021
- Overcoming chemotherapy resistance in leukemia with a diarrhea drug from Merck - FierceBiotech - March 3rd, 2021
- Global Cord Blood Banking Services Market 2021 | Growing Rapidly with Significant CAGR, Leading Players, Innovative Trends and Expected Revenue by... - February 21st, 2021