Levels of soluble endothelium‐derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality
Gregory J. KatoSabrina MartyrWilliam C. BlackwelderJames S. NicholsWynona ColesLori A. HunterMarie‐Luise BrennanStanley L. HazenMark T. Gladwin
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Summary Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium‐derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end‐organ disease, we found that higher levels of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule‐1 (sICAM‐1), sE‐selectin and sP‐selectin levels indicated partially overlapping associations with sVCAM‐1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM‐1, ICAM‐1, and E‐selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.Keywords:
Endothelial Dysfunction
Endothelial Activation
E-selectin
E-selectin
VCAM-1
Intercellular adhesion molecule
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VCAM-1
Cell–cell interaction
Proinflammatory cytokine
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Abstract Endothelial cells (EC) recruit circulating leukocytes to sites of inflammation, partly by expression of endothelial-leukocyte adhesion molecules. Whereas the regulation of some adhesion molecules is well characterized in cultured HUVEC, similar data for microvascular human test systems are limited. We studied the cytokine-regulated expression of vascular cell adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in cultured human intestinal microvascular endothelial cells (HIMEC). E-selectin and VCAM-1 were induced, and ICAM-1 was enhanced, in a dose-dependent fashion after stimulation with IL-1beta, TNF-alpha, and LPS. Each adhesion molecule displayed characteristic time-related responses comparable to those obtained with HUVEC, and each molecule supported adhesion of leukocytes. Notable disparities between the two endothelial test systems were that 1) expression of total cellular E-selectin (but not surface membrane expression) was sustained after 72 h of IL-1beta stimulation in HIMEC, contrasting a rapid biphasic response in HUVEC; 2) LPS did not maintain prolonged expression of ICAM-1 and VCAM-1 in HIMEC; and 3) VCAM-1 protein was dose-dependently up-regulated by IL-4 in HUVEC, peaking after 8 h, while IL-4 had only a negligible effect on the expression of this protein in HIMEC. In conclusion, the regulation of these adhesion molecules appears to be somewhat different in HIMEC compared with HUVEC, and the differences from available data on skin-derived microvascular endothelial cell cultures are to some extent substantial. Our findings document the importance of using relevant endothelial cell culture systems for studies of leukocyte-endothelial cell interactions.
VCAM-1
E-selectin
Intercellular adhesion molecule
Endothelial Activation
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Data from experimental studies indicate that acute inflammation contributes to ischaemic brain damage. Tethering of neutrophils to brain endothelium is mediated by selectins, and subsequent adhesion and migration by endothelial intercellular adhesion molecule‐1 (ICAM‐1) and neutrophil CD18. In experimental studies of ischaemia‐reperfusion injury, brain damage has been ameliorated by administration of antibodies to these adhesion molecules. We studied the expression of P‐selectin and ICAM‐1 in sections of brain from patients who had experienced cardiac arrest or focal brain infarction, and who died 3.5 h to 9 days later. Endothelial immunopositivity for both adhesion molecules was maximal at about 2–3 days then declined. Between 1 day and 3 days, P‐selectin was also detected on platelets in blood vessels within infarcted tissue. Within infarcts, but not sections of brain from cardiac arrest patients, P‐selectin and ICAM‐1 were again detectable at 1 week, when hyperplastic endothelial cells were labelled in capillaries in and immediately adjacent to the infarcted tissue. The finding that P‐selectin and ICAM‐1 are upregulated within focally infarcted brain tissue supports the concept that blocking neutrophil adhesion may be of benefit in treating atherothrombotic strokes in man.
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Brain ischemia
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During their passage through the circulatory system, tumor cells undergo extensive interactions with various host cells including endothelial cells. The capacity of tumor cells to form metastasis is related to their ability to interact with and extravasate through endothelial cell layers, which involves multiple adhesive interactions between tumor cells and endothelium (EC). Thus it is essential to identify the adhesive receptors on the endothelial and melanoma surface that mediate those specific adhesive interactions. P-selectin and E-selectin have been reported as adhesion molecules that mediate the cell-cell interaction of endothelial cells and melanoma cells. However, not all melanoma cells express ligands for selectins. In this study, we elucidated the molecular constituents involved in the endothelial adhesion and extravasation of sialyl-Lewis x/a -negative melanoma cell lines under flow in the presence and absence of polymorphonuclear neutrophils (PMNs). Results show the interactions of α 4 β 1 (VLA-4) on sialyl-Lewis x/a -negative melanoma cells and vascular adhesion molecule (VCAM-1) on inflamed EC supported melanoma adhesion to and subsequent extravasation through the EC in low shear flow. These findings provide clear evidence for a direct role of the VLA-4/VCAM-1 pathway in melanoma cell adhesion to and extravasation through the vascular endothelium in a shear flow. PMNs facilitated melanoma cell extravasation under both low and high shear conditions via the involvement of distinct molecular mechanisms. In the low shear regime, β 2 -integrins were sufficient to enhance melanoma cell extravasation, whereas in the high shear regime, selectin ligands and β 2 -integrins on PMNs were necessary for facilitating the melanoma extravasation process.
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Abstract Background Cell adhesion molecules, such as E‐selectin or intercellular adhesion molecule 1 (ICAM‐1), play an important role in mediating leucocyte capture and rolling on the surface of blood vessels in atopic skin. The effectiveness of Avène hydrotherapy in patients suffering from atopic dermatitis has previously been demonstrated. Thus, we examined the effect of Avène Thermal Spring Water (TSW) on adhesion molecules to understand its mechanism of action. Methods Human endothelial cells EA.hy926 were treated with tumour necrosis factor‐α (TNFα) in the presence or not of Avène TSW during 4 h. As nuclear factor ‐κB (NF‐κB) is involved in the signalisation of inflammatory mediators such as the adhesion molecules, the translocation of NF‐κB in endothelial cells was assessed by immunohistochemistry with anti‐NF‐κBp65. The protein and mRNA levels of TNFα‐induced ICAM‐1 and E‐selectin were assessed by ELISA assay and RT‐PCR. These adhesion molecules were also detected by immunohistochemistry. Results Tumour necrosis factor‐α induced the activation of p65 NF‐κB nuclear translocation. TNFα also induced E‐selectin and ICAM‐1 in a dose‐dependant manner in EA.hy926 endothelial cells. In the presence of Avène TSW, a significant inhibition of the TNFα‐induced E‐selectin and ICAM‐1 expression (−22% and −7%, respectively, P < 0.05) was observed. Conclusion These data suggest that Avène TSW mediated inhibition of TNFα‐induced E‐selectin and ICAM‐1 expression. The inhibition of such adhesion molecules is attributable to the suppression of NF‐κB transcription factor pathway activation.
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Adhesion is crucial in the metastatic process of malignant tumours. Recently, the expression of certain selectins on intratumoral vessels has been shown to be associated with the clinical outcome of melanoma patients.For the first time, this study examines the serum concentrations of circulating soluble vascular cellular adhesion molecule 1 (CD 106), endothelial leucocyte adhesion molecule (CD62E), sP-selectin (CD62P) and sCD44v5 in comparison to soluble intercellular adhesion molecule 1 (sICAM-1, CD54) in a series of 34 melanoma patients at different clinical stages and 11 normal donors using ELISA:sICAM-1 and sP-selectin levels were statistically elevated in all subgroups of melanoma patients compared to controls (p < 0.01). Circulating ICAM-1 as well as sP-selectin might be valuable additional serological tumour markers which correspond to tumour load and correlate with progression of malignant melanoma.Measurement of sICAM-1 and sP-selectin serum levels might therefore provide a sensitive tool for monitoring the clinical course of melanoma.
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Hypoxemia is a common event in many vascular diseases, especially vascular ischemia. Since endothelial cells of blood vessels are exposed to conditions within the vascular space and leucocytes play a key role in ischemia/reperfusion injury, we hypothesized that endothelial exposure to hypoxia may regulate expression of surface proteins important in leucocyte-endothelial interactions, such as E-selectin and intercellular adhesion molecule (ICAM-1). In this study, we used isolated bovine aortic endothelial monolayers to examine endothelial surface alterations of E-selectin and ICAM-1 induced by tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) and hypoxia using a whole cell enzyme-linked immunosorbent assay (ELISA). Bovine endothelial exposure to TNF-alpha (50 ng/mL) induced a time dependent increase (range 0-24h) in specific E-selection surface expression. Endothelial exposure to hypoxia alone (pO2 approximately 3 mmHg, range 0-24 h), however, failed to elicit endothelial E-selectin expression. Endothelial exposure to LPS brought about a dose- and time-dependent (range 0.5 ng/mL and 2-8 h) increase in specific ICAM-1 surface expression (max. 3.5 +/- 0.15-fold increase over no cytokine control at 10 ng/mL, 4 h). Hypoxia (pO2 approximately 3 mmHg, 8h), however, did not induce ICAM-1 surface expression over normoxia levels.i) bovine endothelial E-selectin and ICAM-1 surface expression are regulated molecules, ii) hypoxia, per se, does not regulate surface expression of either E-selectin or ICAM-1. These results suggest that hypoxic endothelia may require additional external signals for generation of adaptive inflammatory responses.
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