Circulating Endothelial Cells as a Marker of Endothelial Injury in Severe COVID -19

Abstract Beside the commonly described pulmonary expression of the coronavirus disease 2019 (COVID-19), major vascular events have been reported. The objective of this study was to investigate whether increased levels of circulating endothelial cells (CECs) might be associated with severe forms of COVID-19. Ninety-nine patients with COVID-19 were enrolled in this retrospective study. Patients in the intensive care units (ICU) had significantly higher CEC counts than non-ICU patients and the extent of endothelial injury was correlated with putative markers of disease severity and inflammatory cytokines. Together, these data provide in vivo evidence that endothelial injury is a key feature of COVID-19.

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Abstract 386: Body Mass Index Exacerbates the Hypertension Mediated Increase in Endothelial Cell Sloughing and Suppression of Antioxidant Heme Oxygenase-1

Hypertension ◽

10.1161/hyp.62.suppl_1.a386 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Ryan Stone ◽

David Chaffin ◽

David Jude ◽

Zeid Khitan ◽

Dong Hyun Kim ◽

...

Keyword(s):

Endothelial Cells ◽

Inflammatory Cytokines ◽

Heme Oxygenase ◽

Vascular Function ◽

Circulating Endothelial Cells ◽

Heme Oxygenase 1 ◽

Diabetic Patients ◽

Obese Patients ◽

Contributing Factors ◽

Hypertensive Patients

Introduction: Endothelial Progenitor cells (EPCs) are bone marrow derived cells that migrate and differentiate into mature endothelial cells and play a significant role in the re-endothelialization and neovascularization of injured endothelium and restoration of vascular function. We examined whether obesity and hypertension exacerbates the levels of biomarkers including circulating endothelial cells (CEC), serum inflammatory cytokines, and the levels of heme oxygenase -1 (HO-1) in EPC. Methods: Peripheral blood from 10 normal, 15 obese, 12 hypertensive, 20 obese-hypertensive and 15 diabetic patients was analyzed for inflammatory cytokines, CEC number, adiponectin and HO-1 levels. Results: The levels of inflammatory cytokines increased with BMI and directly correlated with increasing obesity. Similarly, hypertensive patients have elevated CEC which are further increased in obese hypertensive patients (p<.05). HO-1 was reduced (p<.05) in both hypertensive and obese patients when compared to control. Similarly serum adiponectin levels were lower in hypertensive obese patients when compared to controls (p<.01). Inflammatory cytokines IL-1, IL-6, MCP-1 and TNFα were elevated in obese hypertensive patients compared to non-obese hypertensive patients (p<.05). Conclusion: We demonstrated in hypertension patients that obesity exacerbates vascular dysfunction and increases circulating endothelial cells and inflammatory cytokines. A reduction in the levels of HO-1 and adiponectin imply reduced antioxidant levels which are contributing factors towards vascular and adipocyte dysfunction in hypertension patients. Thus upregulation of HO-1 offers a potential therapeutic approach in the treatment of this population.

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Association of opioid exposure during intensive care unit stays with post-discharge opioid use: A retrospective study and literature review

Journal of Opioid Management ◽

10.5055/jom.2021.0685 ◽

2021 ◽

Vol 17 (6) ◽

pp. 511-516

Author(s):

Yoonsun Mo, MS, PharmD, BCPS, BCCCP ◽

John Zeibeq, MD ◽

Nabil Mesiha, MD ◽

Abou Bakar, PharmD ◽

Maram Sarsour, PharmD ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Retrospective Study ◽

Hospital Discharge ◽

Invasive Mechanical Ventilation ◽

High Dose ◽

Opioid Use ◽

Electronic Health Record Data ◽

Icu Patients ◽

Mechanically Ventilated

Objective: To evaluate whether pain management strategies within intensive care unit (ICU) settings contribute to chronic opioid use upon hospital discharge in opioid-naive patients requiring invasive mechanical ventilation. Design: A retrospective, observational study.Setting: An 18-bed mixed ICU at a community teaching hospital located in Brooklyn, New York.Participants: This study included mechanically ventilated patients requiring continuous opioid infusion from April 25, 2017 to May 16, 2019. Patients were excluded if they received chronic opioid therapy at home or expired during this hospital admission. Eligible patients were identified using an electronic health record data query.Main outcome measure(s): The proportion of ICU patients who continued to require opioids upon ICU and hospital discharge. Results: A total of 196 ICU patients were included in this study. Of these, 22 patients were transferred to a regular floor while receiving a fentanyl transdermal patch. However, the fentanyl patch treatment was continued only for three patients (2 percent) at hospital discharge.Conclusions: This retrospective study suggested that high-dose use of opioids in mechanically ventilated, opioid-naive ICU patients was not associated with continued opioid use upon hospital discharge.

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Intensive Care Admissions and Associated Severity of Influenza B Versus A During Influenza B Vaccine–mismatched Seasons

Clinical Infectious Diseases ◽

10.1093/cid/ciz053 ◽

2019 ◽

Vol 69 (6) ◽

pp. 1049-1052 ◽

Cited By ~ 6

Author(s):

Maya Korem ◽

Efrat Orenbuch-Harroch ◽

Eli Ben-Chetrit ◽

Sarah Israel ◽

Matan J Cohen ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Disease Severity ◽

Influenza B ◽

Icu Patients ◽

Icu Admission ◽

Severe Influenza ◽

Trivalent Vaccine ◽

Quadrivalent Vaccines

Abstract Patients admitted to hospital with influenza B and A in Jerusalem, Israel, during the 2015–2016 and 2017–2018 influenza seasons demonstrated similar rates of intensive care unit (ICU) admission and associated disease severity. Most (63%) influenza B ICU patients received influenza B–mismatched trivalent vaccine. These findings call into question the equivalence of trivalent and quadrivalent vaccines in preventing severe influenza B.

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An Inflammatory Profile Correlates With Decreased Frequency of Cytotoxic Cells in Coronavirus Disease 2019

Clinical Infectious Diseases ◽

10.1093/cid/ciaa577 ◽

2020 ◽

Vol 71 (16) ◽

pp. 2272-2275 ◽

Cited By ~ 17

Author(s):

Veronica Bordoni ◽

Alessandra Sacchi ◽

Eleonora Cimini ◽

Stefania Notari ◽

Germana Grassi ◽

...

Keyword(s):

Intensive Care Unit ◽

T Cells ◽

Intensive Care ◽

Inflammatory Cytokines ◽

Suppressor Cells ◽

Lower Number ◽

Myeloid Derived Suppressor Cells ◽

Icu Patients ◽

Cytotoxic Cells ◽

Inflammatory Profile

Abstract Increased production of inflammatory cytokines and myeloid-derived suppressor cells occurs in patients with coronavirus disease 2019. These inversely correlated with perforin-expressing natural killer (NK) and CD3+ T cells. We observed a lower number of perforin-expressing NK cells in intensive care unit (ICU) patients compared with non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pathogenic mechanism.

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Endothelial injury in vivo: a technical and statistical approach to the study of aortic integrity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.5.h1841 ◽

1996 ◽

Vol 270 (5) ◽

pp. H1841-H1849 ◽

Cited By ~ 1

Author(s):

H. B. Skantze ◽

G. Bondjers ◽

B. Olofsson ◽

K. Pettersson ◽

A. Svensson

Keyword(s):

Endothelial Cells ◽

Cell Count ◽

Count Data ◽

Endothelial Injury ◽

Adherent Cells ◽

Efficient Manner ◽

Exact Counting ◽

Log Normal ◽

Endothelial Integrity

The endothelium can be a link connecting risk factors with the development of cardiovascular disease, and methods for studying endothelial integrity are therefore important. We describe a method of studying endothelial injury in vivo by combining immunohistochemistry with an improved technique of producing “enface” preparations (Hautchens) aortic endothelium of rabbits and guinea pigs. These Hautchens enabled the study of large numbers of endothelial cells and adherent cells (probably leukocytes) at different locations along the aorta. The statistical distributions of the number of injured endothelial cells and adherent cells in a visual field were also investigated, and both closely followed a log-normal distribution. Based on this distribution, a method to estimate endothelial injury by grouping the cell count data, instead of exact counting, was developed. The grouped cell count data were then used to calculate the grouped mean and grouped standard deviation for each animal. The improvements of the technical and statistical methods offer good opportunities to study various aspects of endothelial integrity in a time efficient manner.

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Human Endothelial Cells Generated In Vitro from Circulating Progenitors Represent a Safe Tool for Targeting of Myocardial Tissue.

Blood ◽

10.1182/blood.v104.11.4138.4138 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4138-4138

Author(s):

Ruth Koeck ◽

Dominik G.F. Wolf ◽

Holger F. Rumpold ◽

Harald Ott ◽

Gerold Untergasser ◽

...

Keyword(s):

Endothelial Cells ◽

Replicative Senescence ◽

Circulating Endothelial Cells ◽

Early Passage ◽

Intramyocardial Injection ◽

Cell Based Therapy ◽

Relative Safety ◽

Passage Cells

Abstract Various cell sources, culture protocols and characerization steps are being used in the research field of endothelial progenitors and circulating endothelial cells. We generated EPC by plating the mononuclear fraction onto a collagen I-coated well of a six-well-plate in endothelial cell medium. After 6 to 12 days, 1–10 clones with cobblestone morphology appeared and grew rapidly to confluency within a few days. The rapid proliferation of EPC decelerated after 30–40 days, remaining on the same level for additional 30 days and finally stopped after 70–80 days of culture. Immunofluorescence staining and FACS analysis revealed an endothelial phenotype: EC stained positive for vWF, CD31, CD34, KDR, CD105, CD146, bound UEA-1 lectin and took up acetylated LDL. Of note, CD14 and CD45, which are surrogate markers of monocytes and leukocytes, respectively were negative. The expression of ICAM-1 was upregulated by incubation with TNF-a. In addition, EC formed tubes on Matrigel and expressed VEGF-R1 as well as VEGF-R2-mRNA proven by RT-PCR. To gain deeper insight into the regulation of cellular senescence, we performed western blot analyses of cell cycle regulating proteins. In contrast to early passage cells, growth arrested cells from late passages up-regulated p15, p16, p21, whereas p27 and Id1 were significantly dowregulated. Moreover, late-passage cells highly expressed SA-ß-galactosidase. The obvious replicative senescence together with the regular karyogram indicates a relative safety aspect of their application in vivo. To study their homing behaviour to ischemic tissue, we established a model of myocardial infarction, which was induced by ligation of the left anterior descending coronary artery in Rowett nude rats. 5–10x106 PKH red-labeled EPC were injected into the tail vein. Intramyocardial injection served as positive control, while administation of EPC without prior infarction represented the negative control. Rats were sacrificed on day 14 after the operation and cryosections of their hearts were prepared. PKH-positive cells were almost exclusively found in the infarcted left ventricle after i.v.-application, thus showing a high specifity for ischemic myocardium. The results were confirmed by immunohistochemical staining of human CD31. In summary, EPC generated according to the described protocol represent a possible tool for safe cell-based therapy strategies.

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Therapeutic Inhibition of Endothelial Cell Tissue Factor Expression In Vivo by Nitric Oxide and Arginine in Sickle Transgenic Mice.

Blood ◽

10.1182/blood.v106.11.210.210 ◽

2005 ◽

Vol 106 (11) ◽

pp. 210-210

Author(s):

Robert P. Hebbel ◽

Rahn Kollander ◽

Anna Solovey ◽

Stephana Choong ◽

Robert J. Kelm

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Tissue Factor ◽

Pulmonary Veins ◽

Dietary Supplementation ◽

Ambient Air ◽

Circulating Endothelial Cells ◽

Coagulation System ◽

Mild Phenotype

Abstract Sickle cell anemia is accompanied by biochemical activation of the coagulation system and by clinical thromboses. Therefore, we have focused on the expression of tissue factor (TF), the trigger of the coagulation system, in this disease. Previous studies from our laboratories described abnormal TF expression by monocytes and by circulating endothelial cells in human sickle blood. More recently, we reported (Blood104:840, 2004) that severe-phenotype (BERK) sickle mice abnormally express TF on pulmonary vein endothelium; mild-phenotype (NY1DD) sickle mice are normal in this regard but assume the abnormal phenotype after exposure to hypoxia (3 hr at 8% O2) followed by reoxygenation for 18 hr at ambient air (H/R). Monitoring the % of pulmonary veins positive for TF on triple stained tissue sections (for nuclei, for murine TF, for murine CD31 to identify endothelial cells), we have now evaluated the role of NO in TF expression, employing these two models. In the NY1DD H/R model, NO inhalation (34 ppm) administered during the entire reoxygenation period led to 68±18% reduction (P<.001) of TF expression. Consistent with this, dietary supplementation with arginine (substrate for nitric oxide synthase [NOS]) prior to H/R led to 93±25% reduction (P<.001) of the H/R induced TF response. Conversely, dietary supplementation with L-NAME (inhibitor of NOS) converted the NY1DD mouse to a TF positive phenotype (P=.047) without even requiring H/R. Interestingly, inhalation of NO was not protective in the NY1DD H/R model if given only during the hypoxia period itself or only during the last 3 hours of the reoxygenation period, but it was protective if given only during the first 3 hours of the reoxgygenation period (68±24% reduction; P=.0008). Thus, the timing of clinical intervention is probably critical. In the BERK model at ambient air, treatment with dietary arginine for 2 weeks diminished TF expression by 60±33% (P=.04), an effect that was countervailed by concurrent administration of L-NAME. Data will soon be available on eNOS over-expressing sickle mice. Also in BERK mice, L-NAME largely prevented the TF inhibiting therapeutic benefit of lovastatin, suggesting that lovastatin’s beneficial effect on TF is mediated via NO biology. These results suggest that NO biology determines endothelial TF expression in vivo in sickle mice. We note that NO is reported to suppress endothelial TF expression in vitro. We find that sickle mice have elevated plasma free Hb levels (increased by 40% in NY1DD mice and 57% in BERK mice), a risk factor for diminished NO bioavailability. On the other hand, H/R in NY1DD mice is not associated with a further increase in free plasma Hb. So it seems that the NO biology of sickle mice is not simply explained by plasma Hb. NO biology seems to exert a major role in regulating endothelial TF expression in the sickle mouse. Long-term NO modulating therapy, such as dietary arginine or lovastatin, may be beneficial in terms of the coagulopathy and thrombosis risk of sickle patients and should be tested with this in mind.

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Direct evidence of endothelial injury during cardiopulmonary bypass by demonstration of circulating endothelial cells

Perfusion ◽

10.1191/0267659106pf860oa ◽

2006 ◽

Vol 21 (3) ◽

pp. 133-137 ◽

Cited By ~ 11

Author(s):

Franz-Xaver Schmid ◽

Bernhard Floerchinger ◽

Nalini Kumar Vudattu ◽

Günther Eissner ◽

Marion Haubitz ◽

...

Keyword(s):

Endothelial Cells ◽

Cardiopulmonary Bypass ◽

Direct Evidence ◽

Artery Bypass ◽

Endothelial Activation ◽

Endothelial Damage ◽

Endothelial Injury ◽

Circulating Endothelial Cells ◽

Whole Body ◽

Maximum Increase

Endothelial activation is considered a key process in the development of a whole body inflammatory response secondary to cardiopulmonary bypass (CPB). Increased levels of a multitude of soluble mediators have been described as being released during and after cardiac surgery. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders. Blood samples from 20 patients undergoing elective coronary artery bypass surgery were obtained preoperatively and 1, 6, 12, 24, and 48 h after termination of CPB. Control samples were obtained from ten healthy volunteers. Circulating endothelial cells (CEC) were isolated with immunomagnetic anti-CD146-coated Dynabeads, and counted in a Nageotte chamber. Low numbers of CEC were observed in healthy control volunteers (12±6 cells/mL; median: 9 cells/mL). CEC numbers were already significantly elevated in all patients before CPB, and there was a further significant increase after weaning from CPB (maximum increase at 6 h after CPB: 73±30 cells/mL; range: 30-153 cells/mL, p < 0.001). The number of CEC provides further and direct evidence that CPB is associated with a pronounced endothelial injury and/or damage. CEC appear to be most useful markers for vascular endothelial activation because they are specific, stable, and circulating components of injured vessel wall.

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