Serum levels of thrombomodulin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in the acute phase of Plasmodium vivax malaria

Elevated plasma or serum levels of thrombomodulin (TM), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin have been reported in several diseases. However, plasma or serum levels of TM, ICAM-1, VCAM-1, and E-selectin have not been investigated in the acute phase of Plasmodium vivax malaria. Serum TM, ICAM-1, VCAM-1, E-selectin, and creatinine levels were determined in six Japanese patients in the acute phase of vivax malaria and in seven healthy Japanese controls. Parasitemias of the peripheral blood were < 0.1% in five patients and 0.8% in one patient. The patients' mean +/- SD serum levels of TM, ICAM-1, VCAM-1, and E-selectin were 5.7 +/- 1.3 Fujirebio units/ml, 709 +/- 397 ng/ml, 2,112 +/- 782 ng/ml, and 99 +/- 28 ng/ml, respectively, and all were significantly greater than those in the controls (TM; P < 0.005, ICAM-1; P < 0.025, VCAM-1; P < 0.005, E-selectin; P < 0.025). However, no significant difference was identified between patients and controls for serum creatinine values. The serum levels of TM and VCAM-1 were not related to parasitemia. The elevation of serum TM levels suggests that endothelial cell damage occurs in the acute phase of vivax malaria.     

The effects of dipyridamole stress test on plasma levels of soluble adhesion molecules intracellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin and L-selectin in patients with ischemic heart disease and patients with syndrome X.

BACKGROUND: Adhesion of activated leukocytes to the endothelium as a result of myocardial ischemia/reperfusion has been shown to be involved in the development of tissue injury. Leukocyte adhesion to the endothelium occurs via adhesion molecules expressed on the surface of both cell types. Upon cell activation these proteins may be released into the circulation and measured in a soluble form. AIM: To verify whether the dipyridamole stress test, performed in patients with ischemic heart disease (IHD) and in patients with syndrome X, modifies plasma levels of the soluble adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin and L-selectin. METHODS: Plasma levels of the soluble endothelial adhesion molecules ICAM-1, VCAM-1 and E-selectin, as well as of the soluble leukocyte adhesion molecule L-selectin, were measured in venous blood samples taken before and 7 min after administration of dipyridamole in patients with IHD, patients with syndrome X and healthy individuals. Myocardial perfusion was evaluated using single photon emission tomography. The plasma levels of soluble VCAM-1, ICAM-1, E-selectin and L-selectin were all measured using enzyme-linked immunosorbent assays. RESULTS: After infusion of dipyridamole, plasma levels of ICAM-1 increased significantly in patients with IHD, whereas they remained unchanged in patients with syndrome X and in the control group. In patients with IHD, the initial plasma levels of VCAM-1, E-selectin and L-selectin, before administration of dipyridamole, were higher than those observed in patients with syndrome X and than those in the control group. Plasma levels of soluble VCAM-1, E-selectin and L-selectin decreased significantly in patients with IHD following the dipyridamole stress test, whereas they remained unchanged in patients with syndrome X, and in the control group. CONCLUSION: In patients with IHD, administration of dipyridamole induces myocardial ischemia resulting in modification of plasma levels of the soluble adhesion molecules.     

Adhesion molecules as a prognostic marker of liver cirrhosis

OBJECTIVE: Endothelial activation plays an active role in modifications of the circulatory status of cirrhotic patients. Soluble endothelial adhesion molecules, induced by pro-inflammatory cytokines, could be considered markers of endothelial activation. Their role in the natural history of cirrhosis and portal hypertension has not been reported. Our objective was to analyze the prognostic value of soluble adhesion molecules in cirrhotic patients. MATERIAL AND METHODS: Serum concentrations of soluble CD14, soluble receptors of tumor necrosis factor alpha and adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule 1) as well as mean blood pressure, plasma renin activity, aldosterone, vasopressin and norepinephrine concentrations were determined in 64 cirrhotic patients (Child-Pugh class: A 48.4%, B 34.4%, C 17.2%), without any evidence of infection, and in 25 healthy controls. Patients were followed-up for a mean of 36.4 (range 6-60) months. RESULTS: Increased concentrations of soluble CD14, tumor necrosis factor receptors and ICAM-1 and VCAM-1 were detected in cirrhotic patients when compared with healthy controls. Tumor necrosis factor receptors and adhesion molecule concentrations were both significantly higher in advanced phases of cirrhosis (Child Pugh class C and B versus A). Fifteen patients died as a related consequence of liver cirrhosis. Multivariate analysis demonstrated that Child-Pugh score and serum levels of tumor necrosis factor receptor I and ICAM-1 were associated with mortality. CONCLUSIONS: In addition to the classic factor implicated in mortality (Child-Pugh class), alterations in inflammation-related components and soluble adhesion molecules, as representatives of hemodynamic alterations, are of prognostic significance in cirrhotic patients.     

Adhesion molecules as a prognostic marker of liver cirrhosis

Objective Endothelial activation plays an active role in modifications of the circulatory status of cirrhotic patients. Soluble endothelial adhesion molecules, induced by pro-inflammatory cytokines, could be considered markers of endothelial activation. Their role in the natural history of cirrhosis and portal hypertension has not been reported. Our objective was to analyze the prognostic value of soluble adhesion molecules in cirrhotic patients.

Material and methods Serum concentrations of soluble CD14, soluble receptors of tumor necrosis factor alpha and adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule 1) as well as mean blood pressure, plasma renin activity, aldosterone, vasopressin and norepinephrine concentrations were determined in 64 cirrhotic patients (Child Pugh class: A 48.4%, B 34.4%, C 17.2%), without any evidence of infection, and in 25 healthy controls. Patients were followed-up for a mean of 36.4 (range 6–60) months.

Results Increased concentrations of soluble CD14, tumor necrosis factor receptors and ICAM-1 and VCAM-1 were detected in cirrhotic patients when compared with healthy controls. Tumor necrosis factor receptors and adhesion molecule concentrations were both significantly higher in advanced phases of cirrhosis (Child Pugh class C and B versus A). Fifteen patients died as a related consequence of liver cirrhosis. Multivariate analysis demonstrated that Child-Pugh score and serum levels of tumor necrosis factor receptor I and ICAM-1 were associated with mortality.

Conclusions In addition to the classic factor implicated in mortality (Child-Pugh class), alterations in inflammation-related components and soluble adhesion molecules, as representatives of hemodynamic alterations, are of prognostic significance in cirrhotic patients.     

Increased plasma soluble adhesion molecules; ICAM-1, VCAM-1, and E-selectin levels in patients with slow coronary flow

BACKGROUND: Inflammation has been reported to be a major contributing factor to many cardiovascular events. In the present study, we aimed to evaluate plasma soluble adhesion molecules; intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin as possible indicators of endothelial activation or inflammation in patients with slow coronary flow. METHOD: Study population included 17 patients with angiographically proven normal coronary arteries and slow coronary flow in all three coronary vessels (group I, 11 male, 6 female, mean age=48+/-9 years), and 20 subjects with angiographically proven normal coronary arteries without associated slow coronary flow (group II, 11 male, 9 female, mean age=50+/-8 years). Coronary flow rates of all patients and control subjects were documented by Thrombolysis In Myocardial Infarction frame count (TIMI frame count). All patients in group I had TIMI frame counts greater than two standard deviation above those of control subjects (group II) and, therefore, were accepted as exhibiting slow coronary flow. Serum levels of ICAM-1, VCAM-1, and E-selectin were measured in all patients and control subjects using commercially available ELISA kits. RESULTS: Serum ICAM-1, VCAM-1, and E-selectin levels of patients with slow coronary flow were found to be significantly higher than those of control subjects with normal coronary flow (ICAM-1: 545+/-198 ng/ml vs. 242+/-113 ng/ml respectively, p<0.001, VCAM-1: 2040+/-634 ng/ml vs. 918+/-336 ng/ml respectively, p<0.001, E-selectin: 67+/-9 ng/ml vs. 52+/-8 ng/ml respectively, p<0.001). Average TIMI frame count was detected to be significantly correlated with plasma soluble ICAM-1 (r=0.550, p<0.001), VCAM-1 (r=0.569, p<0.001) and E-selectin (r=0.443, p=0.006). CONCLUSION: Increased levels of soluble adhesion molecules in patients with slow coronary flow may be an indicator of endothelial activation and inflammation and are likely to be in the causal pathway leading to slow coronary flow.     

Perfusion with sickle erythrocytes up-regulates ICAM-1 and VCAM-1 gene expression in cultured human endothelial cells

Sickle cell anemia is characterized by periodic vasoocclusive crises. Increased adhesion of sickle erythrocytes to vascular endothelium is a possible contributing factor to vasoocclusion. This study determined the effect of sickle erythrocyte perfusion at a venous shear stress level (1 dyne/cm(2)) on endothelial cell (EC) monolayers. Sickle erythrocytes up-regulated intercellular adhesion molecule-1 (ICAM-1) gene expression in cultured human endothelial cells. This was accompanied by increased cell surface expression of ICAM-1 and also elevated release of soluble ICAM-1 molecules. Expression of vascular cell adhesion molecule-1 (VCAM-1) messenger RNA (mRNA) was also strikingly elevated in cultured ECs after exposure to sickle cell perfusion, although increases in membrane-bound and soluble VCAM-1 levels were small. The presence of cytokine interleukin-1beta in the perfusion system enhanced the production of ICAM-1 and VCAM-1 mRNA, cell surface expression, and the concentrations of circulating forms. This is the first demonstration that sickle erythrocytes have direct effects on gene regulation in cultured human ECs under well-defined flow environments. The results suggest that perfusion with sickle erythrocytes increases the expression of cell adhesion molecules on ECs and stimulates the release of soluble cell adhesion molecules, which may serve as indicators of injury and/or activation of endothelial cells. The interactions between sickle red blood flow, inflammatory cytokines, and vascular adhesion events may render sickle cell disease patients vulnerable to vasoocclusive crises.     

Soluble intercelluar adhesion molecule-1, E-selectin, vascular cell adhesion molecule-1 and von Willebrand factor in stroke.

We investigated the role of endothelial cell and leukocyte adhesion in the pathophysiology of acute stroke. The immunocytochemical expression of adhesion molecules in brain tissue from six patients who died following acute ischaemic stroke showed weak endothelial expression of intercellular adhesion molecule-1 (ICAM-1), but intense expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and endothelial cells from the infarcted, but not the non-infarcted areas. We also measured soluble adhesion molecules E-selectin, ICAM-1, VCAM-1 and von Willebrand factor (all by enzyme-linked immunosorbent assay) in 21 patients after an acute ischaemic stroke (ictus < 12 h), and again 3 months later. Blood levels in the stroke patients were compared with 82 healthy controls and 22 subjects with carotid atherosclerosis. Compared with healthy controls, both patient groups had raised levels of von Willebrand factor (P < 0.02) but the level of soluble VCAM-1 was raised only in patients with acute stroke (P < 0.02). Levels of von Willebrand factor and soluble VCAM-1 in the stroke patients were still high at 3 months follow-up. We suggest that there might be changes in adhesion molecule expression and release in the acute and chronic stages of ischaemic stroke, where blood levels are related to immunocytochemical findings on infarcted brain. These changes may perhaps be part of the complex pathophysiological responses to infarction and repair of brain tissue following stroke.     

Relation of C-reactive protein to oxidative stress and to endothelial activation in essential hypertension

BACKGROUND: C-reactive protein (CRP) predicts cardiovascular outcome. Oxidative stress is considered to be involved in endothelial alteration. We hypothesized that in essential hypertension (EH), oxidative stress, as measured by 8-iso-prostaglandin-F(2alpha) (8-iso-PGF(2alpha)), should be associated with increased CRP and endothelial activation, as evaluated by soluble intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) plasma levels. METHODS: In 83 subjects with mild EH and in 50 healthy control subjects we measured, in basal conditions, plasma levels of hs-CRP, 8-iso-PGF(2alpha), ICAM-1 and VCAM-1, and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Subjects with EH had higher levels of 8-iso-PGF(2alpha) (P < .0001), CRP (P < .001), ICAM-1 and VCAM-1 (P < .001), and TNF-alpha (P < .001) than did control subjects. We divided successively EH according to CRP values (<1, 1-3, >3 mg/L), and we observed increasing and significantly different levels of the endothelial parameters and of TNF-alpha along with increasing CRP. Linear analysis of correlation pointed out significant correlation of CRP with 8-iso-PGF(2alpha) (r = 0.730, P < .001), ICAM-1 and VCAM-1 (r = 0.642 and 0.468, P < .001 respectively), and TNF-alpha (r = 0.609, P < .001). Multiple regression analysis using CRP as a dependent variable confirmed the relationship of CRP with systolic blood pressure (beta 0.216, P = 0.039) and with 8-iso-PGF(2alpha) (beta 0.602, P = .0001). CONCLUSIONS: Our data demonstrate that in EH, inflammatory molecules such as CRP and TNF-alpha are increased and related to both oxidative stress and endothelial activation.     

Percutaneous transluminal mitral valvuloplasty reduces circulating vascular cell adhesion molecule-1 in rheumatic mitral stenosis

BACKGROUND: The circulating levels of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), have been demonstrated to be elevated in patients with rheumatic mitral stenosis (MS). However, the impact of percutaneous transluminal mitral valvuloplasty (PTMV) on the elevated circulating levels of VCAM-1 and ICAM-1 in patients with MS has never been investigated. METHODS: and results: A total of 19 patients with symptomatic MS undergoing PTMV were studied (group 1) [15 patients in chronic atrial fibrillation, and 4 patients in sinus rhythm]. The plasma levels of soluble VCAM-1 and ICAM-1 in the femoral vein and artery, and right and left atria before PTMV, and those in the peripheral venous blood at the 1-week and 4-week follow-ups after PTMV were determined by solid-phase sandwich enzyme-linked immunosorbent assay. The mitral valve area was calculated by means of the Doppler pressure half-time method. In addition, we measured plasma concentrations of soluble VCAM-1 and ICAM-1 in the peripheral venous blood samples obtained from 22 control patients (including 14 healthy volunteers in sinus rhythm [group 2] and 8 patients in chronic lone atrial fibrillation [group 3]). The plasma level of soluble VCAM-1 was significantly elevated in group 1 patients (1,205.4 +/- 462.4 ng/mL [mean +/- SD]) compared with group 2 (580.9 +/- 208.0 ng/mL) and group 3 patients (716.4 +/- 221.6 ng/mL) [p < 0.0001]. In group 1 patients, the plasma levels of soluble VCAM-1 and ICAM-1 in the left atrium did not differ from those in the right atrium, femoral vein, or femoral artery (p = 0.668 for VCAM-1, and p = 0.232 for ICAM-1). The area of mitral valve increased significantly after PTMV (1.08 +/- 0.14 cm(2) vs 1.48 +/- 0.33 cm(2), p < 0.0001). The mean left atrial pressure fell significantly after PTMV (22.9 +/- 5.2 mm Hg vs 17.7 +/- 6.0 mm Hg, p < 0.0001). The peripheral venous plasma level of soluble VCAM-1 obtained before PTMV fell significantly after PTMV (before, 1,205.4 +/- 462.4 ng/mL; 1 week after PTMV, 915.7 +/- 280.2 ng/mL; 4 weeks after PTMV, 859.0 +/- 298.7 ng/mL; p < 0.0001). CONCLUSIONS: In patients with moderate-to-severe MS, the venous plasma level of soluble VCAM-1 fell significantly after PTMV, and the elevated plasma soluble VCAM-1 concentration was associated with hemodynamic abnormality rather than with rheumatic activity.     

Human eosinophil adherence to vascular endothelium mediated by binding to vascular cell adhesion molecule 1 and endothelial leukocyte adhesion molecule 1.

Adherence of human eosinophils to cytokine-stimulated endothelial cells, which was only partially due to CD18-dependent pathways, was also mediated by binding to endothelial leukocyte adhesion molecule 1 (ELAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Eosinophils bound specifically to both recombinant soluble ELAM-1 and recombinant soluble VCAM-1. Eosinophil binding to recombinant soluble VCAM-1 and to transfected CHO cells expressing VCAM-1 was inhibited with anti-VCAM-1 (4B9) and anti-very late activation antigen 4 (anti-VLA-4; HP1/2 or HP2/1) monoclonal antibodies. Eosinophils, but not neutrophils, expressed VLA-4 detected by cytofluorography. Eosinophil adherence to tumor necrosis factor alpha-stimulated human umbilical vein endothelial cells was partially blocked by monoclonal antibodies against ELAM-1 (BB11) and VCAM-1 (4B9) and against VLA-4 (HP2/1). Thus, while both eosinophils and neutrophils can bind to activated endothelial cells by adherence to ICAM-1 and ELAM-1, only eosinophils expressed VLA-4 and adhered to VCAM-1 on activated endothelial cells. Eosinophil adherence to VCAM-1 might provide a mechanism contributing to the selective recruitment of eosinophils into tissue sites of inflammation.     

Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality

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.     

Microalbuminuria and early endothelial activation in essential hypertension

We hypothesized that in essential hypertensive patients (EHs), plasma levels of pro-atherogenic adhesion molecules would be increased and related with urine albumin excretion (UAE). Thus, this study was aimed at evaluating biochemical markers of endothelial activation and their relationship with UAE in a group of patients with uncomplicated EH. In basal condition soluble forms of adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, as well as 24-h UAE were assayed. One hundred patients with essential hypertension and no diabetes or ultrasonographic evidence of atherosclerosis were included in the study. Seventy normotensive healthy subjects served as controls. EHs were first studied overall, than were divided into two subgroups: those with UAE > or =20 mcg/min MAUs and those with UAE <20 mcg/min (non-MAUs). ICAM-1 (P<0.001) and VCAM-1 (P<0.0001) plasma concentrations were higher in EHs than in controls. Microalbuminuric EHs had greater levels of adhesion molecules than non-MAUs (ICAM-1 P=0.04; VCAM-1 P=0.02, respectively). In EHs UAE was correlated with ICAM-1 (r=0.29, P=0.003), and VCAM-1 (r=0.30, P=0.002). These associations were confirmed in multiple regression models (P=0.02 for both ICAM-1 and VCAM-1) including, along with adhesion molecules, age, body mass index and blood pressures. Our findings show that in essential hypertension there is a very early activation of endothelial adhesion molecules favouring atherosclerosis.     

Soluble VCAM-1 and E-selectin, but not ICAM-1 discriminate endothelial injury in patients with documented coronary artery disease

It has been shown that endothelial cell adhesion molecules play an important role in the development of coronary atherosclerosis and inflammatory disease. We sought to test whether soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin are increased in patients with documented coronary artery disease (CAD). Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured in 40 patients with documented CAD, 20 subjects with angiographically documented normal coronary arteries, and 14 healthy volunteers. Patients with documented CAD exhibited significant elevation of VCAM-1 (535 +/- 227.1 ng/ml, p = 0.0001), E-selectin (69.4 +/- 29.4 ng/ml, p = 0.006), but not ICAM-1 (320.5 +/- 65.1 ng/ml, p = 0.9) concentrations as compared to subjects with normal coronary arteries (252.3 +/- 79.8, 49.7 +/- 22.0 and 311.4 +/- 40.2 ng/ml), and healthy controls (110.0 +/- 17.7, 29.0 +/- 2.0 and 237.5 +/- 46.5 ng/ml), respectively. Soluble markers of endothelial injury are not uniformly increased in patients with documented CAD as compared to those with normal coronary arteries and healthy controls. However, VCAM-1 and E-selectin, but not ICAM-1 could identify endothelial injury in such patients.     

High serum concentrations of soluble E-selectin correlate with obesity but not fat distribution in patients with type 2 diabetes mellitus

Serum concentrations of soluble adhesion molecules, eg, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are elevated in patients with type 2 diabetes. However, little is known about the role of obesity or abnormal fat distribution in inducing upregulation of adhesion molecules. To investigate this issue, soluble ICAM-1, VCAM-1, and E-selectin levels were evaluated in 40 obese and 30 nonobese patients with type 2 diabetes. Both groups were matched for age, sex, and glycosylated hemoglobin (HbA(1c)) levels. Computed tomography (CT) was used to measure the abdominal subcutaneous and visceral fat areas. Soluble ICAM-1 and VCAM-1 levels did not differ significantly between obese and nonobese patients. However, serum concentrations of soluble E-selectin were significantly higher in obese than in nonobese patients (90 +/- 7 v 56 +/- 4 ng/mL, P <.01). Soluble E-selectin levels significantly correlated with body mass index, subcutaneous fat area, and visceral fat area (Rho = 0.48, 0.37, and 0.30, respectively). Stepwise multiple regression analysis showed that body mass index (F = 16.7), but not subcutaneous and visceral fat areas (F = 0.29 and 0.01, respectively), significantly and independently correlated with soluble E-selectin levels. Our results suggest that obesity may induce endothelial activation or increased shedding of cell surface E-selectin that leads to subsequent increase in soluble E-selectin levels. The high serum concentrations of E-selectin closely correlated with increased total fat volume, but not with regional fat distribution.     

Plasma soluble adhesion molecules; intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin levels in patients with isolated coronary artery ectasia

Plasma soluble adhesion molecules, intercellular adhesion molecule-1 (ICAM)-1, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin leves of patients with isolated coronary artery ectasia (CAE), patients with obstructive coronary artery disease without CAE and subjects with angiographically normal coronary arteries were evaluated. Patients with isolated CAE were detected to have significantly higher levels of plasma soluble ICAM-1, VCAM-1 and E-selectin in comparison with patients with obstructive coronary artery disease without CAE (ICAM, 673 +/- 153 versus 381 +/- 106, respectively, P < 0.001; VCAM-1, 2366 +/- 925 versus 1136 +/- 208, respectively, P < 0.001; E-selectin, 74 +/- 21 versus 61 +/- 18, respectively, P = 0.01) and subjects with normal coronary arteries (ICAM-1, 673 +/- 153 versus 303 +/- 131, respectively, P < 0.001; VCAM-1, 2366 +/- 925 versus 729 +/- 231, respectively, P < 0.001; E-selectin, 74 +/- 21 versus 49 +/- 9, respectively, P < 0.001), suggesting the presence of a more severe and extensive chronic inflammation in the coronary circulation in patients with isolated CAE. BACKGROUND: The common coexistence of coronary artery ectasia (CAE) with coronary artery disease (CAD) suggests that it may be a variant of CAD. However, it is not clear why some patients with obstructive CAD develop CAE whereas most do not. Inflammation has been reported to be a major contributing factor to both obstructive and aneurysmatic vascular disorders and therefore, in the present study, the plasma soluble adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin levels in isolated CAE were investigated. METHODS: The study population consisted of three groups: the first consisted of 32 patients with isolated CAE without stenotic lesion; the second of 32 patients with obstructive CAD without CAE; and the third group of 30 control subjects with normal coronary arteries. Coronary diameters were measured as the maximum diameter of the ectasic segment by use of a computerized quantitative coronary angiography analysis system. According to the angiographic definition used in the Coronary Artery Surgery Study, a vessel is considered to be ectasic when its diameter is > or =1.5 times that of the adjacent normal segment in segmental ectasia. Plasma soluble ICAM-1, VCAM-1 and E-selectin levels were measured in all patients and control subjects using commercially available enzyme-linked immunosorbent assay kits. RESULTS: Patients with isolated CAE were found to have significantly higher levels of plasma soluble ICAM-1, VCAM-1, and E-selectin in comparison with patients with obstructive CAD without CAE (ICAM, 673 +/- 153 versus 381 +/- 106, respectively; P < 0.001; VCAM-1, 2366 +/- 925 versus 1136 +/- 208, respectively; P < 0.001; E-selectin, 74 +/- 21 versus 61+/-18, respectively; P = 0.01) and control subjects with normal coronary arteries (ICAM-1, 673 +/- 153 versus 303 +/- 131, respectively;, P < 0.001; VCAM-1, 2366 +/- 925 versus 729 +/- 231, respectively; P < 0.001; E-selectin, 74 +/- 21 versus 49 +/- 9, respectively; P < 0.001). In addition, we detected statistically significant positive correlation between the total length of ectasic segments and the levels of plasma soluble ICAM-1 (r = 0.625; P < 0.001), VCAM-1 (r = 0.548; P = 0.001) and E-selectin (r = 0.390; P = 0.027). Multivariate logistic regression analysis revealed a significant independent relation between isolated CAE and ICAM-1 [odds ratio (OR) = 1.023; 95% confidence interval (CI) = 1.0048-1.0414; P = 0.0129] and VCAM-1 (OR = 1.0057; 95% CI = 1.0007-1.0106; P = 0.0240). CONCLUSIONS: We have shown that patients with isolated CAE have raised levels of plasma soluble ICAM-1, VCAM-1 and E-selectin in comparison with patients with obstructive CAD without CAE and control subjects with normal coronary arteries, suggesting the presence of a more severe and extensive chronic inflammation in the coronary circulation in these patients.     

Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products.

Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI-1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion, whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were slightly decreased, 5% on average, suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products, and separately of fibrin degradation products and fibrinogen degradation products, was found. This indicates that fibrinolysis persisted, at least partly, in the presence of high levels of PAI activity. Whereas PAI-1 production increased, t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore, it is possible that thrombin, not TNF, is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients.     

Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation.

The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Inducible endothelial cell adhesion molecules may participate in this process. In aortas of normal chow-fed wild-type mice and rabbits, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), but not E-selectin, were expressed by endothelial cells in regions predisposed to atherosclerotic lesion formation. En face confocal microscopy of the mouse ascending aorta and proximal arch demonstrated that VCAM-1 expression was increased on the endothelial cell surface in lesion-prone areas. ICAM-1 expression extended into areas protected from lesion formation. Hypercholesterolemia induced atherosclerotic lesion formation in rabbits, LDL receptor and apolipoprotein E knockout mice, and Northern blot analysis demonstrated increased steady-state mRNA levels of VCAM-1 and ICAM-1, but not of E-selectin. Immunohistochemical staining revealed that VCAM-1 and ICAM-1 were expressed predominantly by endothelium in early lesions and by intimal cells in more advanced lesions. In early and advanced lesions, staining was most intense in endothelial cells at and adjacent to lesion borders. ICAM-1 staining extended into the uninvolved aorta. These expression patterns were highly reproducible in both species. The only difference was that VCAM-1 expression in endothelium over the central portions of lesions was found frequently in rabbits and rarely in mice. The expression of VCAM-1 by arterial endothelium in normal animals may represent a pathogenic mechanism or a phenotypic marker of predisposition to atherogenesis.     

他汀类调脂药物对高脂血症患者黏附分子的影响

目的　探讨他汀类调脂药物对高脂血症患者血清可溶性黏附分子含量及白细胞黏附分子表达的影响。方法　38例高脂血症患者使用他汀类药物治疗8周,观察治疗前后血清可溶性内皮细胞白细胞黏附分子(sELAM)、可溶性细胞间黏附分子-1(sICAM-1)、可溶性血管细胞黏附分子-1(sVCAM-1)水平,白细胞黏附分子L-选择素(L-Selectin)、细胞间黏附分子-1(ICAM-1)、细胞间黏附分子-3(ICAM-3)的表达及血清白细胞介素-1β(IL-1β)、肿瘤坏死因子(TNF)浓度的变化。结果　治疗8周后,高脂血症患者血清sELAM、sICAM-1水平显著下降（P<0.01）,个体sELAM、sICAM-1水平均与血清总胆固醇呈正相关（P<0.005及P<0.01）,与高密度脂蛋白胆固醇呈负相关（P<0.01）,sVCAM-1无明显变化;L-选择素阳性单核细胞、淋巴细胞百分率升高（P<0.05及P<0.01）,ICAM-1阳性单核细胞及淋巴细胞百分率下降（P<0.05及P<0.01）,白细胞ICAM-3平均荧光强度明显下降（P<0.01）;血清IL-1β含量下降,其降低值与L-选择素阳性淋巴细胞百分率上升值及ICAM-3阳性白细胞平均荧光强度下降值明显相关（P<0.01）。结论　他汀类药物降低高脂血症患者血清内皮细胞黏附分子水平,并可调节白细胞黏附分子的表达和细胞因子的生成,其作用可能主要是通过调节血脂而产生。     

Vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 serum level in patients with chest pain and normal coronary arteries (syndrome X)

BACKGROUND: Plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) mediators of leukocyte adhesion to vascular endothelium may implicate in the pathogenesis of the syndrome of chest pain with normal coronary arteries. HYPOTHESIS: We attempted to determine whether markers of endothelial activation are raised in patients with chest pain and normal coronary arteries. METHODS: We measured plasma VCAM-1, ICAM-1 (ng/ ml) in 36 patients (34 men, 2 women, aged 62 +/- 9 years) with stable angina, coronary artery disease (CAD), and a positive response to exercise test; in 21 patients (6 men, 15 women, aged 56 +/- 9 years) with chest pain and normal coronary arteriograms (syndrome X); and in 11 healthy control subjects (8 men, 3 women, aged 49 +/- 14 years). RESULTS: Plasma ICAM-1 levels were significantly higher both in patients with CAD (mean +/- standard error of the mean) (328 +/- 26, p < 0.05), and in syndrome X (362 +/- 22, p < 0.01) than in controls (225 +/- 29). VCAM-1 levels were also higher in syndrome X (656 +/- 42 ng/ml) and in patients with CAD (626 +/- 42 ng/ml) than in controls (551 +/- 60, p = 0.09). CONCLUSIONS: ICAM-1 and VCAM-1 levels are increased both in patients with CAD and with syndrome X compared with control individuals. These findings may suggest the presence of chronic inflammation with involvement of the endothelium in patients with anginal chest pain and normal coronary angiograms.