Evidence for the regulation of levels of plasma adhesion molecules by proinflammatory cytokines and their soluble receptors in type 1 diabetes

OBJECTIVES: To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes. DESIGN: Cross-sectional study. SETTING: University hospital diabetes clinic. SUBJECTS: A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls. OUTCOME MEASURES: Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease. RESULTS: Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r = 0.41, P = 0.012 and r = 0.31, P = 0.04, respectively). Tumour necrosis factor-alpha soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P = 0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r = 0.39, P = 0.008), triglycerides (r = 0.36, P = 0.02 1) and diastolic blood pressure (r = 0.35; P = 0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r = 0.46, P = 0.002; r = 0.32, P = 0.034) and triglycerides (r = 0.33, P = 0.033; r = 0.29, P = 0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P < 0.001). Neither sE-selectin nor vWF were related to cytokine concentrations. Finally, both TNF-alpha and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P < 0.001). None of these interactions were apparent in control subjects. CONCLUSIONS: (i) IL-6, through effects on sICAM-1, and TNF-alpha via effects on sVCAM-1, may promote vascular adhesion; (ii) plasma levels of TNF-alpha are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.     

The levels of soluble adhesion molecules in diabetic and nondiabetic patients with combined hyperlipoproteinemia and the effect of ciprofibrate therapy

Cell adhesion molecules are thought to play a role in atherosclerosis. Several clinical trials have shown that fibrate treatment leads to a reduction in coronary events, although the mechanisms are not fully understood. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin plasma concentrations were measured in 10 obese dyslipidemic men (group A), in 10 obese dyslipidemic type 2 diabetic men without coronary artery disease (CAD) (group B), and in 10 dyslipidemic type 2 diabetic men with angiographically documented CAD (group C) before and after 12 weeks of treatment with ciprofibrate. Compared with nondiabetic dyslipidemic men, diabetic patients with CAD or without documented CAD had significantly increased levels of sVCAM-1 (512 +/-39 versus 750 +/-139 ng/mL; p<0.0001 and 566 +/-78 ng/mL; p<0.01, respectively) and sE-selectin (54.8 +/-6.9 versus 65.9 +/-8.8 ng/mL; p<0.001 and 62.6 +/-9.4 ng/mL; p=0.056, respectively). The levels of sICAM-1 were similar in all 3 groups. Multivariate analyses showed that the higher sCAM levels in patients occurred independently of lipoprotein levels. Waist circumference as a marker of abdominal adiposity was the only independent predictor of elevated concentrations of all 3 cell adhesion molecules in multivariate analyses. sE-selectin was associated with HbA1C levels (p<0.01) in diabetic men at baseline. After 12 weeks of ciprofibrate therapy, sVCAM-1 levels were reduced by 13.5 +/-2.1%, sICAM-1 levels by 11.8 +/-2.2%, and sE-selectin levels by 17.1 +/-3.5% (p<0.01 for all) with the greatest sE-selectin reduction in the diabetic subgroups (p<0.001). There was no correlation between the lowering of soluble adhesion molecules and the magnitude of lipid-lowering effect. An increased level of circulating adhesion molecules may be a mechanism by which dyslipidemia and/or diabetes mellitus promotes atherogenesis, and treatment with ciprofibrate may alter vascular cell activation.     

Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes

To investigate the relationships between serum concentrations of soluble adhesion molecules and hyperglycemia, insulin resistance, or other conventional risk factors in type 2 diabetes, we measured soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), insulin sensitivity, and conventional risk factors in 150 Japanese type 2 diabetic patients without apparent diabetic macroangiopathy. High serum concentrations of sVCAM-1 and sE-selectin were observed in patients with type 2 diabetes. Serum concentrations of soluble adhesion molecules were not significantly influenced by sex, hypertension, dyslipidemia, or microangiopathy. Spearman correlation showed that sVCAM-1 concentrations correlated significantly with fasting plasma glucose (FPG), fasting C-peptide, and insulin sensitivity [K index of the insulin tolerance test (K(ITT))] (rho=0.19,0.23, and -0.23, respectively). Soluble E-selectin concentrations correlated significantly with body mass index (BMI), FPG, fasting C-peptide, insulin sensitivity, and triglyceride (rho=0.33,0.42,0.26,-0.48, and 0.29, respectively). Multiple regression analysis showed that FPG, fasting C-peptide, and total cholesterol were independent factors that correlated with sVCAM-1 levels. BMI, FPG, and insulin sensitivity were independent factors that correlated with sE-selectin levels. Serum concentrations of sE-selectin significantly increased associated with clustering of conventional risk factors those obesity, hypertension, dyslipidemia, and current smoking (P<0.01). Thus, sVCAM-1 and sE-selectin levels are related to both hyperglycemia and insulin resistance. Soluble E-selectin levels may be related to obesity, hyperglycemia, and insulin resistance and may reflect the presence of a multiple risk factor clustering syndrome.     

Relationship between insulin resistance, soluble adhesion molecules, and mononuclear cell binding in healthy volunteers.

The relationship between insulin resistance, soluble adhesion molecules E-selectin (sE-selectin), intracellular adhesion molecule-1 (sICAM-1), and vascular adhesion molecule-1 (sVCAM-1), mononuclear cell binding to cultured endothelium, and lipoprotein concentrations were evaluated in 28 healthy, nondiabetic, and normotensive individuals. The mean (+/-SEM) lipid and lipoprotein concentrations were within the normal rage: cholesterol (199 +/- 18 mg/dL); triglyceride (128 +/- 12 mg/dL); low-density cholesterol (127 +/- 8 mg/dL; and high-density cholesterol (47 +/- 3 mg/dL). The results indicated that degree of insulin resistance was significantly correlated with concentrations of sE-selectin (r = 0.54, P < 0.005), sICAM-1 (r = 0.67, P < 0.001), and sVCAM-1 (r = 0.41, P < 0.05). Furthermore, the relationship between insulin resistance and both sE-selectin and sI-CAM-1 remained statistically significant when adjusted for differences in age, gender, body mass index, and all measures of lipoprotein concentrations. Finally, mononuclear cell binding correlated significantly with concentrations of sE-selectin (r = 0.54, P < 0.005) and sICAM-1 (r = 0.47, P < 0.01). These findings raise the possibility that previously described relationships between soluble adhesion molecules in patients with hypertension, type 2 diabetes, and dyslipidemia may be due to the presence of insulin resistance in these clinical syndromes and suggests that insulin resistance may predispose individuals to coronary heart disease by activation of cellular adhesion molecules.     

The effect of cigarette smoking on soluble adhesion molecules in middle-aged patients with Type 2 diabetes mellitus.

AIMS: To investigate the effect of smoking on soluble adhesion molecules in middle-aged diabetic patients. METHODS: One hundred out-patients with Type 2 diabetes and 100 age- and sex-matched non-diabetic subjects without clinical macrovascular disease were selected. Soluble serum levels of adhesion molecules were analysed using enzyme immunoassay. Carotid atherosclerosis was assessed using an ultrasound system. RESULTS: When compared with non-diabetic subjects, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and sE-selectin were found at significantly high levels in diabetic patients and significantly higher levels of sICAM-1, sE-selectin, and sP-selectin were observed in current smokers than never-smokers among diabetic or non-diabetic subjects, respectively. The combined, but not enhanced, effects of diabetes mellitus and smoking were observed in sICAM-1 and sE-selectin levels. Additionally, levels of sICAM-1 (P < 0.05) and sE-selectin (P < 0.01), but not sP-selectin, were high in ex-smokers when compared with never-smokers among diabetic patients. Diabetic smokers were also found to have marked carotid atherosclerosis, which was related to increased levels of sICAM-1. CONCLUSIONS: Our present study shows that levels of adhesion molecules were higher in diabetic smokers than diabetic non-smokers or non-diabetic smokers, and that cessation after chronic smoking did not restore the levels of sICAM-1 and sE-selectin, though sP-selectin levels were restored. These data suggest a possible mechanism for accelerated atherosclerosis induced by smoking in patients with diabetes.     

Soluble adhesion molecules are not involved in the development of retinopathy in type 2 diabetic patients

Abstract. Raised serum levels of adhesion molecules are believed to reflect endothelial activation and may contribute to the development of diabetic vascular complications. The aim of this study was to clarify the association between soluble adhesion molecules levels and retinopathy in type 2 diabetic patients. Levels of soluble Eselectin, ICAM-1 and VCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 47 type 2 diabetic patients classified in two subgroups according to the presence (n=34) or absence (n=13) of retinopathy as determined by fundus ophthalmoscopy; 22 control subjects were also studied. Soluble E-selectin levels were significantly elevated in both diabetic subgroups compared to control subjects (p<0.01), while no significant difference was found in sICAM-1 and sVCAM-1 levels. However, sE-selectin, sICAM-1 and sVCAM-1 levels were comparable in diabetic subgroups. The progression of retinopathy was not associated with an increase in soluble adhesion molecules levels. Stepwise multiple regression analysis revealed that only diabetes duration and microalbuminuria were independent determinants of retinopathy (p<0.01). Our results confirm the contribution of endothelial activation in the development of diabetic complications as indicated by increased levels of soluble adhesion molecules. However, a direct implication of adhesion molecules in the pathogenesis or progression of type 2 diabetic retinopathy cannot be supported.     

Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with Type 1 diabetes mellitus with microalbuminuria and overt nephropathy.

AIMS: Elevated urinary albumin excretion is associated with macrovascular atherosclerotic complications in Type 1 diabetes mellitus. Adhesion molecules mediate leucocyte adhesion to the endothelium early in the atherosclerotic process. The present study tests the hypothesis that microalbuminuria and diabetic nephropathy are associated with elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1, soluble intercellular adhesion molecule (sICAM)-1, and soluble E-selectin (sE-selectin) aiming to illustrate factors of potential pathogenetic relevance for the excess cardiovascular disease in diabetic patients with renal complications. METHODS: Soluble adhesion molecule concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in healthy controls (n = 16) and in 59 Type 1 diabetic patients: group 1-patients with normoalbuminuria (n = 16); group 2-patients with microalbuminuria (n = 15); group 3-patients with macroalbuminuria and normal serum creatinine (n = 15), group 4-patients with macroalbuminuria and moderately elevated serum creatinine (n = 13). RESULTS: Plasma concentrations of sVCAM-1 and sICAM-1 were similar in healthy controls and normoalbuminuric Type 1 diabetic patients, but the concentrations were increased by the presence of microalbuminuria and overt nephropathy (P < 0.001 and P < 0.0001, ANOVA). Concentrations of sE-selectin did not differ between diabetic patients and controls. CONCLUSIONS: Plasma concentration of sICAM-1 is elevated in Type 1 diabetic patients with microalbuminuria and the concentrations of sICAM-1 as well as sVCAM-1 are elevated in patients with macroalbuminuria and normal s-creatinine. The elevated plasma concentrations of these soluble adhesion molecule concentrations in patients with renal complication can be of pathogenetic importance for the development of atherosclerosis and plasma soluble adhesion molecule concentrations may provide additional information on cardiovascular risk.     

Serum levels of soluble adhesion molecules in stem cell transplantation-related complications.

To assess the involvement of vascular endothelial cell activation and damage in stem cell transplantation (SCT)-related complications, such as acute and chronic GVHD and thrombotic microangiopathy (TMA), we investigated the changes in serum levels of soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin (sE-selectin) in SCT. The soluble form of intercellular adhesion molecule-1 (sICAM-1) was also analyzed. In patients with acute GVHD (grades II-IV), serum levels of sE-selectin and sICAM-1 increased around onset of GVHD (day 30). While the increase of sE-selectin levels was transient, sICAM-1 levels remained high until day 60. In patients with extensive chronic GVHD, sVCAM-1 as well as sE-selectin levels significantly increased. The appearance of clinical symptoms was preceded by elevations of sVCAM-1 and sE-selectin levels on day 60, and sICAM-1 levels on days 30 and 60. For the analysis of TMA, to exclude the influence of GVHD, serum levels were measured in auto-SCT patients. Around the onset of TMA, sVCAM-1 and sE-selectin levels significantly increased in patients with TMA without an increase of sICAM-1 levels. These findings support the notion that activation and injury of endothelium are commonly involved in the pathogenesis of acute and chronic GVHD and TMA.     

Circulating adhesion molecules in sera of asthmatic children

Infiltration of cells into the lung in asthma is regulated by several expressions of cell adhesion molecules (CAMs) on cells present in the airways, and may play a role in the pathogenesis of bronchial asthma. We sought to evaluate the role of serum concentrations of the soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in the control of disease activity in acute asthma. Circulating levels of sICAM-1, sVCAM-1, and sE-selectin in sera from 15 normal control subjects and from 20 allergic asthmatic children with acute exacerbations who had returned to stable condition were determined by using commercially available enzyme-linked immunosorbent assay kits. The mean concentration of serum sICAM-1 levels was significantly higher during an acute exacerbation of asthmatic children than in those with stable asthma (19.41 +/- 10.65 ng/mL vs. 13.46 +/- 5.44 ng/mL; P < 0.001) or in control subjects (9.83 +/- 2.02 ng/mL; P < 0.001). For sVCAM-1 and sE-selectin, the mean serum concentration of sVCAM-1 was slightly higher in children during an acute exacerbation asthma than when stable. However, the differences did not reach statistical significance. The mean serum concentrations of sVCAM-1 and sE-selectin in acute asthma or stable asthma were significantly higher than in control subjects. This study provides further evidence that serum concentrations of sICAM-1, sVCAM-1, and sE-selectin are increased in acute asthma. These findings further confirm that leukocyte endothelial adhesion plays a role in inflammatory airway disease.     

康复运动对心衰患者血浆可溶性粘附分子水平的影响

目的:通过观察充血性心力衰竭(CHF)患者运动训练前、后血浆可溶性细胞间粘附分子-1(sICAM-1)、血管细胞粘附分子-1(sVCAM-1)和E-选择素(sE-selectin)水平的变化,探讨其临床意义。方法:用ELISA法检测23例CHF患者6 min步行运动试验前、后血浆sICAM-1、sVCAM-1、sE-selectin水平,并以20例健康体检者作为对照,18例患者运动训练一个月后进行了随访。结果:CHF患者基础状态血浆sICAM-1、sVCAM-1和sE-selectin水平显著高于对照组(P<0.05-<0.01),且sICAM-1、sVCAM-1水平与心功能密切相关(P<0.05);运动后即刻sICAM-1、sVCAM-1水平较运动前升高(P<0.05),而sE-selectin水平运动前、后无显著性差异;康复训练一月后,无论基础状态还是运动后,sICAM-1、sVCAM-1水平较前次实验明显降低(P<0.05),而sE-selectin水平无显著性变化。结论:CHF患者血浆可溶性粘附分子水平较正常升高,6 min步行运动试验升高CHF患者血浆sICAM-1、sVCAM-1水平,接近日常生活活动强度的运动训练可降低该二者水平。     

Severe malaria in Cameroonian children: correlation between plasma levels of three soluble inducible adhesion molecules and TNF-alpha

Plasma levels of three soluble inducible adhesion molecules, namely: intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and endothelial leucocyte adhesion molecule-1 (sELAM-1) or sE-selectin and the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha) were measured in well-defined clinical groups of children with severe and uncomplicated malaria. The goal of the study was to investigate the role of these molecules in immunopathogenic processes associated with severe malaria in Cameroonian children. Results showed significantly increased plasma concentrations of sICAM-1, sVCAM-1 and sE-selectin in children with severe malaria compared to those with uncomplicated malaria and healthy children (P<0.001). TNF-alpha levels increased significantly in children with severe malaria, approximately 2-folds compared to those with uncomplicated malaria and about 3-folds compared to healthy children (P<0.001). More importantly, levels of TNF-alpha strongly correlated with those of the three adhesion molecules and were significantly associated with increased risk of death (P=0.03). In addition, children who died from severe malaria showed higher mean levels of all measured factors compared to those who recovered, with significant differences observed with sICAM-1 (P<0.001) and sE-selectin (P=0.002). Furthermore, children with severe malarial anemia relative to those without, showed significantly elevated levels of the three soluble molecules; and sICAM-1 was significantly associated with increased risk of severe anemia. Taken together, these results confirm the role of TNF-alpha and the three adhesion molecules in pathogenic processes associated with severe malaria in children, and suggest an association between sICAM-1 and severe malarial anemia.     

Flavonoid treatment in patients with healed venous ulcer: flow cytometry analysis suggests increased CD11b expression on neutrophil granulocytes in the circulation

The objective was to determine the activation of white blood cells (WBCs) and endothelial cells in patients with healed venous ulcer and the influence of the standing position and of treatment with flavonoids. Ten patients with a healed venous ulcer were treated with flavonoid substance (90% diosmin), 1000 mg three times daily for 30 days. Blood samples were taken from arm and dorsal foot veins before and after standing for 30 minutes. Blood sampling was performed before treatment, after three days, one month and three months. The activation of WBCs was determined by measuring adhesion molecule CD11b and CD18 expression on the surface of granulocytes and monocytes. In addition, interleukin 6 (IL-6), IL-8, soluble E-selectin (sE-selectin), sL-selectin and sICAM-1 levels in serum were quantified. The results showed that standing did not influence any of the measured parameters significantly. Expression of CD11b adhesion molecules on granulocytes was significantly up-regulated (p = 0.044) after treatment with flavonoids for one month, but this increase was not significant (p = 0.056) two months after the treatment period compared with the baseline level. The expression of CD18 remained unchanged. Baseline expression of CD11b or CD18 on monocytes did not change significantly during the study period. Neither was any significant change observed in the levels of IL-6, IL-8 or the soluble adhesion molecules. It was concluded that flavonoid treatment for 30 days increased the expression of CD11b adhesion molecules on circulating granulocytes. No general effect on the inflammatory process could be observed as assessed by levels of cytokines and soluble adhesion molecules. Possible explanations for these findings could be that a decreased number of primed granulocytes leave the circulation due to a changed WBC/endothelial cell interaction or that flavonoids have a direct effect on granulocytes. Further studies are needed to clarify the mode of action of flavonoids in chronic venous disease.     

Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis

BACKGROUND: Cell adhesion molecules and endothelial growth factors have an important role in the infiltrating of rheumatoid synovium with mononuclear cells, leading to the initiation and progression of the disease. OBJECTIVE: To investigate whether the serum profile of soluble adhesion molecules and of vascular endothelial growth factor (VEGF) is associated with the histological appearance of rheumatoid arthritis (RA). METHODS: Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and VEGF were assessed by enzyme linked immunosorbent assay (ELISA) in 40 patients with RA and 32 patients with osteoarthritis (OA). RESULTS: Histological analysis of synovium specimens distinguished two types of rheumatoid synovitis. Twenty four RA samples presented diffuse infiltrates of mononuclear cells without any further microanatomical organisation, whereas in the remaining 16 samples lymphocytic follicles with germinal centre-like structures were identified. In comparison with patients with OA, constituting a control group, higher serum concentrations of sICAM-1 (p<0.001), sVCAM-1 (p<0.001), sE-selectin (p<0.01), and VEGF (p<0.001) were detected in patients with RA. Raised concentrations of sICAM-1, sVCAM-1, and VEGF dominated in the serum of patients with RA with follicular synovitis compared with those with diffuse synovitis (p<0.01 for all comparisons). The serum concentrations of sICAM-1, sVCAM-1, and VEGF correlated with markers of disease activity such as the erythrocyte sedimentation rate and C reactive protein levels. Furthermore, the clinical data analysed in our study indicated that patients with RA with follicular synovitis tend to have more severe disease. CONCLUSIONS: The distinct histological appearances of rheumatoid synovitis associated with different serum profiles of sICAM-1, sVCAM-1, and VEGF reflect varied clinical activity of the disease and confirm RA heterogeneity. Patients with different histological forms of synovitis may respond differently to the treatment regimens.     

Circulating E-selectin,vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in men with coronary artery disease assessed by angiography and disturbances of carbohydrate metabolism

It is hypothesized that adhesion molecules could be an early predictor of coronary artery disease. Therefore we investigated the relationship between the concentrations of soluble forms of adhesion molecules and disturbances of glucose metabolism in 78 men referred for coronary angiography but with no previous history of diabetes. The group consisted of 78 men (mean age, 47.6 +/- 7.0 years; mean body mass index [BMI], 28.4 +/- 3.24 with the symptoms of angina pectoris and positive exercise test. All subjects were given a standard oral glucose tolerance test (OGTT) with glucose and insulin estimations. Fasting plasma concentrations of the soluble (s) forms of E-selectin, intercellular adhesion cell molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and HbA(1c) were also measured. According to the OGTT, 10.2% of the patients (n = 8) fulfilled the criteria for type 2 diabetes mellitus and 44.9% (n = 35) for impaired glucose tolerance (IGT). The highest concentrations of sE-selectin were observed in patients with type 2 diabetes mellitus and were significantly higher in comparison to the group with normal glucose tolerance and IGT. The concentration of sVCAM-1 increased with the progression of disturbances of glucose metabolism and remained the highest in type 2 diabetic patients. sICAM-1 concentration was not significantly different. sE-selectin concentration correlated significantly with fasting glucose (r = 0.23, P =.041), postload glucose (r = 0.39, P =.001), and postload insulin (r = 0.28, P =.023). sVCAM-1 was significantly related to the postload glucose concentration (r = 0.30, P =.009). A significant correlation between sICAM-1 concentration and postload insulin was also observed (r = 0.27, P =.025). This would suggest that hyperglycemia increases sE-selectin and sVCAM-1 in plasma, which reflects excessive formation of atherosclerotic plaques in patients with disturbances of glucose metabolism.     

Inflammatory markers and IL-6 polymorphism in peripheral arterial disease with and without diabetes mellitus

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis, recognized as an inflammatory disease of the vessel wall, probably accelerated by diabetes mellitus (DM). Elevated interleukin (IL)-6 levels have been associated with increased cardiovascular morbidity and a common polymorphism has been identified in the promoter region of the IL-6 gene. The aim of this prospective study was to investigate inflammatory mediators in PAD patients (+/- DM) and to investigate a possible relationship to the IL-6 gene polymorphism. Five groups of patients (DM, intermittent claudication +/- DM, critical limb ischemia (CLI) +/- DM) and a control group of 20 individuals each were included. Hemoglobin, high sensitive C-reactive protein (hsCRP), creatinine, blood lipids, white blood cells (WBC); CD11b/CD18; vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1), sE-selectin, sP-selectin; IL-6, IL-8, tumour necrosis factor (TNF)alpha, sTNFalpha-R1 and sTNFalpha-R2 were analysed. The IL-6 gene polymorphism was determined in all groups and also compared with 200 healthy controls from a larger study of blood donors. In a multiple regression analysis, adjusted for gender, smoking and age, the effect of CLI was significantly (p < 0.05) associated with elevated levels of the WBC count, hsCRP, proinflammatory cytokines (IL-6, TNFalpha-R1-2) and endothelial (sICAM, sVCAM) and WBC (CD11b gran) markers. The effect of less advanced PAD (intermittent claudication) was related to an increased concentration of sVCAM-1 and the number of monocytes and granulocytes. DM or leg ulcers were not significantly related to any of the markers. No significant difference in frequency of the various IL-6 genotypes was found between the groups or when compared with the group of 200 blood donors (p> 0.3). Activation of cytokines, endothelial cells and WBC was related to the Fontaine stage of PAD but not to the presence of DM or ulcers. No association was found between the polymorphism in the IL-6 promoter region and PAD.     

Elevated soluble cellular adhesion molecules in subjects with low HDL-cholesterol

The purpose of this study was to investigate whether the expression of cellular adhesion molecules (CAMs) is enhanced in individuals with low HDL cholesterol (HDL-C). Plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sE-selectin) were measured in subjects with low (below the 10th percentile for the Italian population), average, or high (above the 90th percentile) HDL-C. Average sICAM-1 and sE-selectin levels were significantly higher in two groups of 65 individuals with low HDL levels, either hyperlipidemic (320.5+/-16.0 and 61.4+/-3.5 ng/mL) or normolipidemic (309.6+/-13.0 and 60.0+/-2.7 ng/mL), than in subjects with average HDL levels, either hyperlipidemic (267.0+/-10.1 and 50.4+/-2.8 ng/mL) or normolipidemic (257.9+/-5.4 and 51.1+/-2.4 ng/mL), or with high HDL levels (254.8+/-10.2 and 52.5+/-3.2 ng/mL). No significant difference was found in the plasma sVCAM-1 concentration. HDL-C was inversely correlated with sICAM-1 and sE-selectin in the low-HDL subjects (r(2)=0.087 and 0.035, P=0.0007 and 0.033, respectively), but not in individuals with normal or elevated HDL-C (r(2)=0.012 and 0.006). A fenofibrate-induced increase of HDL-C in 20 low-HDL subjects was associated with a significant reduction of plasma sICAM-1 and sE-selectin concentrations. An increased CAMs expression may be a mechanism by which a low plasma HDL level promotes atherogenesis and causes acute atherothrombotic events.     

Transcardiac release of soluble adhesion molecules during coronary artery bypass grafting: effects of crystalloid and blood cardioplegia

BACKGROUND: Dysfunction of myocardium as a result of ischemia/reperfusion during coronary artery bypass grafting (CABG) is currently one of the biggest problems in cardiovascular surgery. In previous studies, it has been well established that activated leukocytes and coronary vascular endothelial cells play an important role in the development of cardiac tissue damage during ischemia followed by reperfusion. Interactions between both of these cell types require the expression of adhesion molecules on their surface. In certain conditions, on cell activation, the adhesion proteins may be released from activated cells in soluble form into circulation. The purpose of our study was to establish whether the use of blood cardioplegia modifies plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and soluble L-selectin (sL-selectin) in comparison with crystalloid cardioplegia in patients undergoing CABG. METHODS: Patients undergoing CABG were classified into two groups to receive cold crystalloid cardioplegia (St. Thomas' Hospital) or cold blood cardioplegia (method of Buckberg), followed by a "warm-shot" of the solution. Coronary sinus and arterial blood samples were obtained from 50 patients (42 men and 8 women; age range, 34 to 73 years) before aortic cross-clamping, at the beginning of reperfusion, and after 30 min of reperfusion. Plasma levels of soluble adhesion molecules were measured using sensitive enzyme-linked immunosorbent assays. RESULTS: The transcardiac release of sICAM-1 and sVCAM-1 following myocardial ischemia/reperfusion during CABG was evident in both groups of patients. However, the increase of soluble forms of both of these adhesion proteins was more significant in the group of patients receiving crystalloid cardioplegia. Crystalloid cardioplegia resulted in decreased plasma level of sE-selectin in the coronary sinus blood sample after 30 min of reperfusion. No significant changes in plasma levels of sL-selectin in either group were observed. CONCLUSION: Cardioplegia may affect the release of soluble forms of adhesion molecules from ischemic myocardium and modify endothelium activation in patients undergoing CABG.     

Platelet-endothelial cell adhesion molecule-1 and CD146: soluble levels and in situ expression of cellular adhesion molecules implicated in the cohesion of endothelial cells in idiopathic inflammatory myopathies

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases characterized by chronic inflammation of muscles. We investigated the role of cellular adhesion molecules implicated in the cohesion of endothelial cells in IIM. METHODS: In 22 patients with IIM we investigated plasma concentrations of soluble junctional adhesion molecules [platelet-endothelial cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules [sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial cell interactions. Results were compared to a control group. Muscle biopsy samples from 8 out of 22 IIM patients were studied by immunohistochemistry for tissue expression of these molecules and compared to normal muscle samples. PECAM-1 and CD146 expression was also studied using immunoblots from muscle biopsies from 5 patients and 2 controls. RESULTS: We observed distinct patterns of soluble levels and in situ expression between dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin, sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small group of s-IBM samples, results were similar to PM, but the only significant increase was the level of sPECAM-1. Immunoblots confirmed increased expression of PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the highest expression in PM and IBM samples. CONCLUSION: We observed abnormal increases of soluble levels of adhesion molecules implicated in endothelial cell junctions in PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM (sPECAM-1). We conclude that the distinctly different profiles between PM/s-IBM and DM reflect differences in the pathophysiological background of these diseases.     

Cellular adhesion molecules and their relationship with measures of obesity and metabolic syndrome in a multiethnic population

BACKGROUND: The relationships between adhesion molecules and measures of obesity and metabolic syndrome in different ethnic populations are unclear. OBJECTIVE: Our aim was to study the association between body mass index (BMI), waist-hip ratio (WHR) and the parameters of the metabolic syndrome with four different adhesion molecules, adjusting for potential confounders, in men and women from different ethnic origins. METHODS: Soluble plasma adhesion molecules (sP-selectin, sE-selectin, intracellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were measured in 261 white (120 women), 188 African origin (99 women) and 215 South Asian (99 women) individuals living in South London. All were free from coronary heart disease (CHD), stroke and other cardiovascular disease (CVD), diabetes, drug therapy for hypertension or high lipids, hormone replacement therapy or oral contraceptive pill. RESULTS: sE-selectin levels were positively and significantly associated with both BMI (P < 0.001) and WHR (P < 0.001). There were no major interactions with either sex or ethnicity. The strength of the association between sE-selectin and WHR was not affected by multiple adjustment for age, sex, ethnicity smoking, blood pressure, serum lipids and insulin (P < 0.001), whereas the association with BMI was attenuated by multiple adjustments (P = 0.037). An approximate 2% higher sE-selectin levels would be associated with a 1 unit higher BMI and a 0.01 unit greater WHR. CONCLUSIONS: The relationships between adhesion molecules and conventional measures of obesity are adhesion molecule specific and are strongest between sE-selectin and WHR.     

胃肿瘤患者循环可溶性细胞间粘附分子-1和血管细胞粘附分子-1

AIM To elucidate the biological and clinical significance of sICAM-1 and sVCAM-1 in patients with gastric cancer.METHODS The serum levels of soluble ICAM-1 and VCAM-1 were measured with sandwith enzyme immunoassay.RESULTS In gastric cancer patients, soluble ICAM-1 and VCAM-1 concentrations were significantly elevated in comparision with those of healthy subjects (289.23μg/L±32.69μg/L vs 190.44μ/L±35.92μg/L,1430.88μg/L±421.71μg/L vs 727.24μg/L±157.68μg/L, respectively, P＜0.01). The increment in serum sICAM-1 and sVCAM-1 concentrations correlated well with the staging of gastric cancer. The serum levels of sICAM-1 and sVCAM-1 in patients of Ⅲ-Ⅳ stages were higher than those of Ⅰ-Ⅱ stages (346.60μg/L±92.10μg/L vs 257.54μg/L±32.77μg/L, 1800.60μg/L±510.76μg/L vs 1262.81μg/L±236.73μg/L). The levels of sICAM-1 and sVCAM-1 were correlated significantly (r=0.49,P＜0.01). The sICAM-1 and sVCAM-1 levels correlated positively with alkaline phophatase (r=0.63,0.71,P＜0.001) and white cell count (r=0.52,0.43, P＜0.01); but correlated negatively with serum albumin (r=-0.41, -0.49, P＜0.01).CONCLUSION The measurement of circulating ICAM-1 and VCAM-1 may bring additional prognostic information for patients with gastric cancer in varying stages.INTRODUCTIONTumor growth and metastasis involves a variety of cell-cell and cell-extracellular matrix interactions mediated by cell adhesion molecules. Currently, a number of cell adhesion molecules, such as intercellular adhesion molecules-1 (ICAM-1), vascular cell adhesion molecules-1 (VCAM-1), etc. have been found.ICAM-1 and VCAM-1 are members of the immunoglobulin supergene family which are cytokine-induced glycoproteins (IL-1, TNFα and IFNγ). Both of them have five or seven extracellular immunoglobulin-like domains, a single transmembranous domain and a short cytoplasmic tail[1,2]. The natural ligand of ICAM-1 or VCAM-1 is LFA-1 (CD11a) and Mac-1 (CD11b) or VLA-4, respectively[3]. ICAM-1 is a widely distributed protein on a variety of tissues, and can be detected in many cells such as macrophage, T- and B-cells, or fibroblasts, endothelial and epithelial cells. VCAM-1 is also a widely distributed protein and is constitutively expressed on tissue macrophage, dentritic cells in lymphoid tissue and skin, as well as on bone marrow fibroblasts and epithelial cells. Expression of VCAM-1 is inducible on vascular endothelial cells under pathological conditions[4].Recently, soluble forms of several adhesion molecules including ICAM-1 and VCAM-1 were found in serum of normal donors[5]. Abnormally high levels of them have been described in some solid malignant tumors, leukemia, autoimmune disease, infectious disease, etc.The present study was carried out to measure the circulating levels of sICAM-1 and sVCAM-1 in gastric cancer before treatment was given and to study their correlation with clinical, histological and routine laboratory parameters.