scholarly journals Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Savino Spadaro ◽  
Alberto Fogagnolo ◽  
Gianluca Campo ◽  
Ottavio Zucchetti ◽  
Marco Verri ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Endothelial Injury ◽  
University Hospital ◽  
Intercellular Adhesion Molecule ◽  
Secondary Outcome ◽  
Intercellular Adhesion Molecule 1 ◽  
Mechanically Ventilated ◽  
Adhesion Protein ◽  
Alveolar Epithelial ◽  
Angiopoietin 2

Abstract Background Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. Methods This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). Conclusions COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053, Date of registration: April 13, 2020

scholarly journals Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients

2020 ◽  
Author(s):  
Savino Spadaro ◽  
Alberto Fogagnolo ◽  
Gianluca Campo ◽  
Ottavio Zucchetti ◽  
Marco Verri ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Endothelial Injury ◽  
University Hospital ◽  
Intercellular Adhesion Molecule ◽  
Secondary Outcome ◽  
Intercellular Adhesion Molecule 1 ◽  
Mechanically Ventilated ◽  
Adhesion Protein ◽  
Alveolar Epithelial ◽  
Angiopoietin 2

Abstract BackgroundEvaluation of biomarkers in the context of ARDS is used to detect the presence of endothelial and/or alveolar epithelial injuries. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aim of this study was to evaluate whether the trends in plasma concentration of the biomarkers mentioned above were different in survivors and non-survivors of COVID-19-related ARDS. Furthermore, we compared the expression of biomarkers of vascular and endothelial injury in patients with COVID-19-related ARDS and classical ARDS. MethodsThis prospective study was performed in two COVID-19 dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 10 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7±2 days (T2) and 14±2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.ResultsIn COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p=0.04 and p=0.03, respectively) whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS, than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19 related ARDS (all p<0.001).ConclusionsCOVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways.Trial registration: NCT04343053 Date of registration: April 13, 2020

scholarly journals Astragalin Inhibits Pulmonary Inflammation in Cigarette Smoking-Induced Embolism

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1526-1526
Author(s):  
Yun-Ho Kim ◽  
Young-Hee Kang
Keyword(s):  
Pulmonary Embolism ◽  
Cigarette Smoking ◽  
Pulmonary Inflammation ◽  
A549 Cells ◽  
Coagulation Factor ◽  
Alveolar Epithelial Cells ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Alveolar Cells ◽  
Alveolar Epithelial

Abstract Objectives Thrombin generation is crucial to the regulation of hemostasis and thrombosis and is essential to the pathogenesis of cardiovascular disease and venous thrombosis. Pulmonary embolism is a blockage in one of the pulmonary arteries in your lung caused by blood clots due to risk factors including tobacco use. Astragalin (kaempferol 3-O-glucoside) is a flavonoid present in persimmon leaves and green tea seeds and exhibits diverse activities such as asthma and obstructive pulmonary disease. This study investigated that astragalin encumbered pulmonary inflammation caused by cigarette smoking-induced embolism. Methods Pulmonary embolism was evoked through exposure of BALB/c mice to cigarette smoke for 30 min, five days a week for eight weeks. Mice were orally administrated with 10 or 20 mg/kg astragalin for 8 weeks. For the in vitro studies, 10 U/ml thrombin was loaded to alveolar epithelial A549 cells in the absence and presence of 1–20 μM astragalin. Results Oral supplementation of astragalin reduced tissue factor and urokinase-type plasminogen activator elevated in cigarette smoking-exposed lungs. In addition, 1–20 μM astragalin attenuated the induction of protease activated receptor-1 known as coagulation factor II (thrombin) receptor-like-1, in 10 U/ml thrombin-loaded alveolar epithelial cells. Astragalin curtailed induction of the inflammatory mediators of cyclooxygenase-2, intercellular adhesion molecule-1 and inducible nitric oxide synthase in alveolar cells subjected to thrombin. Furthermore, astragalin inhibited inflammatory signaling entailing MAPK/ERK pathway. Conclusions Astragalin may be a potential agent alleviating pulmonary inflammation induced by cigarette smoking-induced embolism. Funding Sources This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1A6A3A01094891).

scholarly journals Lipopolysaccharide induces ICAM-1 expression via a c-Src/NADPH oxidase/ROS-dependent NF-κB pathway in human pulmonary alveolar epithelial cells

2016 ◽  
Vol 310 (7) ◽  
pp. L639-L657 ◽  
Author(s):  
Rou-Ling Cho ◽  
Chien-Chung Yang ◽  
I-Ta Lee ◽  
Chih-Chung Lin ◽  
Pei-Ling Chi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Nadph Oxidase ◽  
Adhesion Molecule ◽  
Alveolar Epithelial Cells ◽  
Intercellular Adhesion Molecule ◽  
Ros Generation ◽  
Intercellular Adhesion Molecule 1 ◽  
Mapk Activation ◽  
Promoter Assay ◽  
Alveolar Epithelial

Upregulation of intercellular adhesion molecule-1 (ICAM-1) is frequently implicated in lung inflammation. Lipopolysaccharide (LPS) has been shown to play a key role in inflammation via adhesion molecule induction and then causes lung injury. However, the mechanisms underlying LPS-induced ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unclear. We showed that LPS induced ICAM-1 expression in HPAEpiCs, revealed by Western blotting, RT-PCR, real-time PCR, and promoter assay. Pretreatment with the inhibitor of c-Src (protein phosphatase-1, PP1), reactive oxygen species (ROS) (Edaravone), NADPH oxidase (apocynin and diphenyleneiodonium chloride), EGFR (AG1478), PDGFR (AG1296), phosphatidylinositol-3-kinase (PI3K) (LY294002), MEK1/2 (U0126), or NF-κB (Bay11-7082) and transfection with siRNAs of c-Src, EGFR, PDGFR, Akt, p47 phox, Nox2, Nox4, p42, and p65 markedly reduced LPS-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with LPS. In addition, we established that LPS stimulated phosphorylation of c-Src, EGFR, PDGFR, Akt, or p65, which was inhibited by pretreatment with their respective inhibitors. LPS induced Toll-like receptor 4 (TLR4), MyD88, TNF receptor-associated factor 6 (TRAF6), c-Src, p47 phox, and Rac1 complex formation 2, which was attenuated by transfection with c-Src or TRAF6 siRNA. Furthermore, LPS markedly enhanced NADPH oxidase activation and intracellular ROS generation, which were inhibited by PP1. We established that LPS induced p42/p44 MAPK activation via a c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt-dependent pathway in these cells. Finally, we observed that LPS significantly enhanced NF-κB and IκBα phosphorylation, NF-κB translocation, and NF-κB promoter activity, which were inhibited by PP1, Edaravone, apocynin, diphenyleneiodonium chloride, AG1478, AG1296, LY294002 , or U0126. These results demonstrated that LPS induces p42/p44 MAPK activation mediated through the TLR4/MyD88/TRAF6/c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt pathway, which in turn initiates the activation of NF-κB and ultimately induces ICAM-1 expression in HPAEpiCs.

scholarly journals Immuno-inflammatory predictors of stroke at follow-up in patients with chronic non-valvular atrial fibrillation (NVAF)

2009 ◽  
Vol 116 (10) ◽  
pp. 781-789 ◽  
Author(s):  
Antonio Pinto ◽  
Antonino Tuttolomondo ◽  
Alessandra Casuccio ◽  
Domenico Di Raimondo ◽  
Riccardo Di Sciacca ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ischaemic Stroke ◽  
Adhesion Molecule ◽  
Plasma Levels ◽  
Characteristic Curve ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Il Interleukin ◽  
Tnf Α

The aim of the present study was to determine the rates of stroke in patients with chronic NVAF (non-valvular atrial fibrillation), evaluating the relationship between plasma levels of inflammatory variables at admission and the occurrence of stroke during a 3-year follow-up. A total of 373 consecutive patients with chronic NVAF were enrolled. Blood samples were drawn within 72 h of admission, and we evaluated plasma levels of IL (interleukin)-1β, TNF-α (tumour necrosis factor-α), IL-6, IL-10, E-selectin, P-selectin, ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and vWF (von Willebrand Factor). Subsequent patient events (stroke at follow-up) were monitored over a 3 year period. By multivariate analysis, only age, hypertension and high levels of IL-6, TNF-α and vWF remained significant predictors of a higher risk of experiencing ischaemic stroke at follow-up. Moreover, plasma values of TNF-α, IL-6 and vWF had a significant area under the ROC (receiver operating characteristic) curve. In conclusion, baseline plasma levels of TNF-α, IL-6 and vWF are predictors of new-onset ischaemic stroke at follow-up in patients with chronic NVAF.

Prediction of VOD Using Biomarkers of Endothelial Injury.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3267-3267
Author(s):  
Corey Cutler ◽  
J. Aldridge ◽  
H. T. Kim ◽  
S. Ayanian ◽  
G. Bradwin ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Elevated Serum ◽  
Endothelial Damage ◽  
Endothelial Injury ◽  
Intercellular Adhesion Molecule ◽  
P Value ◽  
Intercellular Adhesion Molecule 1 ◽  
Wilcoxon Rank Sum Test ◽  
Gvhd Prophylaxis ◽  
Von Willebrand

Abstract Veno-occlusive disease (VOD) of the liver occurs with a frequency of 5–15% after myeloablative conditioning and allogeneic stem cell transplantation (SCT). While risk factors for VOD are well known, predicting the occurrence of VOD in individuals remains challenging. Since the primary mechanism of injury in VOD is conditioning-related damage to hepatic sinusoidal endothelial cells and hepatocytes, we measured soluble biomarkers of endothelial injury in the peri-transplant period to determine if they correlated with the occurrence of VOD. Methods: 59 patients received cyclophosphamide (1800 mg/m2 x 2) and TBI (14 Gy) as conditioning therapy, and tacrolimus with sirolimus (Sir+) or methotrexate (Sir-) as GVHD prophylaxis. Only patients with HLA-matched donors were included and selected for analysis based on the occurrence of VOD (VOD+ n=18, VOD- n=41), diagnosed by clinical, radiologic and pathologic criteria. Banked samples collected after conditioning but prior to SCT (day -1) and weekly after SCT (day 7, 14, 21) were thawed and analyzed by ELISA using commercially available kits and quantified using a VersaMax plate reader. Von Willebrand Factor (vWF) and thrombomodulin were assayed in plasma, and E-selectin and soluble intercellular adhesion molecule-1 (ICAM) were assayed in serum. Assays were performed in duplicate and results are the mean of two assays. Not all patients had every time point analyzed due to missing specimens. The within-sample results were compared using the 2-sided Wilcoxon rank-sum test, and the Bonferroni method was used to adjust for multiple comparisons (p value for significance=0.0125). Results: Comparing patients who did and did not develop VOD, patients with VOD had significantly elevated levels of vWF suggestive of endothelial damage at all timepoints prior to the development of VOD in comparison with controls (p≤0.0118, Figure). Thrombomodulin levels were predictive of VOD at all post-SCT timepoints (p≤0.0013, Figure). ICAM levels were significantly elevated up to Day 21 (p≤0.0028). E-selectin was less useful and statistically significant increases in levels were not observed. Since sirolimus has effects on endothelial function that may contribute to VOD through mechanisms different than the conditioning regimen, we stratified the analyses by sirolimus exposure, comparing Sir+VOD+ patients with Sir+VOD- controls. vWF levels in Sir+VOD+ patients were predictive for VOD at all timepoints when compared with controls (p≤0.003). Thrombomodulin levels were informative against controls for all post-SCT timepoints (p≤0.003). ICAM was informative as well (p≤0.003 pre-SCT, day 7, 14), while E-selectin levels were uninformative. The discriminative value of elevated serum and plasma biomarkers was limited to Sir+ patients in this small dataset, since other than some vWF timepoints, biomarkers could not distinguish Sir- patients who developed VOD patients from control groups without VOD. There were no differences in biomarkers among VOD- patients, suggesting that in the absence of VOD, markers of endothelial injury are not elevated even when sirolimus is used. Conclusions: Plasma vWF and thrombomodulin and serum ICAM elevations before and early after SCT can be used to predict the occurrence of VOD. These assays are most useful in patients receiving sirolimus. This analysis demonstrates the contribution of sirolimus to endothelial injury and VOD after SCT, and may help select patients in whom prophylactic or pre-emptive strategies against endothelial damage and VOD may be useful. Figure Figure

scholarly journals Plasma BDNF Levels Are Associated with Stroke in Children with SCD

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3565-3565
Author(s):  
Julia A. Drexelius ◽  
Celeste K. Kanne ◽  
Huy D Tran ◽  
Hyacinth I Hyacinth ◽  
Vivien A. Sheehan
Keyword(s):  
Adhesion Molecule ◽  
Plasma Levels ◽  
Stroke Risk ◽  
Intercellular Adhesion Molecule ◽  
Vascular Cell Adhesion ◽  
Intercellular Adhesion Molecule 1 ◽  
Transfusion Therapy ◽  
Significant Difference ◽  
Cell Adhesion Molecule 1 ◽  
Trans Cranial Doppler

Background: Cerebrovascular disease, particularly overt stroke, is one of the most critical clinical complications of sickle cell disease (SCD). Individual stroke risk for patients with SCD is assessed by measuring trans-cranial Doppler ultrasound (TCD) velocity. While TCD screening and resulting use of chronic blood transfusion therapy in patients with abnormal TCDs has reduced stroke incidence in patients with SCD from 11% to 1%, the test has significant limitations. It can only be performed on children old enough to remain still for the assessment, or young enough to have open bony windows; typically 2-16 years of age. Additionally the test has poor positive predictive value, causing patients to be placed on chronic transfusion therapy who would not have gone on to have a stroke. Hydroxyurea (HU) is replacing chronic transfusion therapy in many institutions for primary stroke prevention, but many sites initiate a "cooling off" period of transfusions prior to initiating HU, and transfusion therapy may be indicated for abnormal TCD velocities in patients already on HU. The pathophysiology of stroke in SCD patients is not completely understood, but vascular remodeling, abnormal cerebral blood flow, and vaso-occlusion all play a role. Plasma levels of Brain derived neurotrophic factor (BDNF), myeloperoxidase (MPO), vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) have been shown to be associated with high trans-cranial Doppler ultrasound (TCD) velocity in children with SCD; but there is limited data on their potential association with stroke in this population. BDNF is a neurotropin that is responsive to hypoxia and promotes neurogenesis as well as playing a key role in the regulation of the cell survival pathway; myeloperoxidase (MPO) promotes vascular injury by oxygen radical generation, leukocyte/neutrophil recruitment, and oxidative stress; vascular cell adhesion molecule 1 (VCAM-1) is and endothelial adhesion molecule involved in the pathophysiology of vaso-occlusion in SCD through promoting RBC adhesion; and intercellular adhesion molecule 1 (ICAM-1) is expressed on endothelial and immune system cells and is thought to be a ligand for leukocyte adhesion. We hypothesized that BDNF, MPO, VCAM-1 and ICAM-1 may be involved in stroke in SCD, and may be potential biomarkers to be used to assess an individual with SCD's stroke risk in addition to TCD. Methods: We collected plasma samples from the peripheral blood of fifteen SCD patients (HbSS) at the time of either silent cerebral infarct (SCI) or stroke. Stroke (n=8) or SI was confirmed by MRI using diffusion imaging and T2 FLAIR. The cohort included 6 females and 9 males between the ages of 3 and 20 years. Plasma from fifteen age and gender matched control patients with HbSS but had normal MRIs and TCD velocities less than 170 m/s. We measured plasma levels of BDNF, MPO, VCAM-1 and ICAM-1 using antibody immobilized fluorescent beads (Millipore, Billerica, MA) and Luminex xMAP technology (Bio-Rad, Hercules, CA). Student's t-test was used to analyze the difference in plasma levels between the stroke and control groups. Results and Conclusions: BDNF levels were significantly higher in the stroke group than in the control group; 2978.2 ± 960.3 pg/ml compared to 2200.8 ± 758.4 pg/ml, p=0.005. Difference in MPO levels between the two groups approached significance; 36617.2 ± 14828.9 pg/ml compared to 29521.9 ± 7889.6 pg/ml, p=0.07. Difference in VCAM-1 levels also approached significance; 143997.0 ± 9963.8 pg/ml compared to 138126.9 ± 11902.0 pg/ml, p=0.08, but there was no significant difference in ICAM-1 levels. Only BDNF plasma levels positively correlated with the area and volume of the infarct, p=0.009. These results further support the assertion that BDNF is involved in the pathophysiology of cerebrovascular disease in SCD. It is possible that MPO and VCAM-1 may also play a role, and that a significant difference was not found due to sample size limitations. Plasma BDNF levels, and possibly MPO and VCAM-1 plasma levels, have potential as biomarkers for stroke risk to improve the positive predictive value of TCD velocities in patients with SCD, or to assess risk in patients unable to receive TCDs. Disclosures No relevant conflicts of interest to declare.

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