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.     

Soluble vascular cell adhesion molecule-1 (sVCAM-1) is an independent prognostic marker in Hodgkin's disease

Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1, sCD106) were significantly elevated in patients with Hodgkin's disease (HD) (n = 101) compared to controls (n = 31) (P < 0.0001). sVCAM-1 correlated with histology, stage, B-symptoms, and prognostic markers (sICAM-1, sCD30, sIL-2R, LDH). sVCAM-1, sICAM-1 and sCD30 added independent prognostic information for both disease-free and overall survival. 14 biopsies from 13 patients with HD were immunostained for VCAM-1 and ICAM-1. The vascular endothelium stained positive for VCAM-1 in 10/12 evaluable biopsies and for ICAM-1 in all evaluable biopsies. A stromal expression of both adhesion molecules precluded a precise evaluation of HRS-cells. This led us to investigate VCAM-1 (and ICAM-1) expression in six Hodgkin cell lines (HDLM-2, L428, L540, L591, DEV, KM-H2). Two cell lines stained positive for VCAM-1 (HDLM-2, L591). All cell lines stained positive for ICAM-1. sVCAM-1 is a new prognostic marker in HD; its predictive power equals or surpasses that of sCD30 and sICAM-1. Furthermore, two Hodgkin cell lines stained positive for VCAM-1. This indicates that VCAM-1 may be expressed by some HD tumour cells in vivo.     

Elevated serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) closely reflect tumour burden in chronic B-lymphocytic leukaemia

The present study is the first to report elevated serum levels of soluble (s)VCAM-1 in B-cell chronic lymphocytic leukaemia (B-CLL). A large cohort of 106 untreated patients was studied. sVCAM-1 was compared to known prognostic serum markers (soluble (s)ICAM-1; lactate dehydrogenase, LDH; sCD23; thymidine kinase, TK; β2microglobulin, β2m). The serum levels of sVCAM-1 reflected tumour burden as expressed by Binet/Rai stages more closely than any other marker. sVCAM-1 also reflected the kinetics of the disease as revealed by lymphocyte doubling time. sVCAM-1 was the only one of the studied markers which showed elevated levels in smouldering disease compared to controls. sVCAM-1, sICAM-1 and sCD23 (but not LDH, TK, β2m) separated smouldering from non-smouldering B-CLL. Only sICAM-1, sCD23 and TK added independent prognostic information for survival to that of stage and lymphocyte doubling time.
The expression of both adhesion molecules was examined in lymph node and splenic specimens. VCAM-1 and ICAM-1 were overexpressed by vascular endothelium and stroma, but the intensity of expression correlated poorly with serum levels of the soluble molecules.
In conclusion, serum levels of sVCAM-1 correlated with tumour burden and other prognostic markers in B-CLL. VCAM-1 was overexpressed in tumour tissue as was ICAM-1. sVCAM-1 could prove a valuable marker in younger early-stage patients eligible for therapeutic trials.     

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.     

可溶性血管细胞黏附分子-1与2型糖尿病及其并发症的相关性研究

目的探讨血清可溶性血管细胞黏附分子-1(sVCAM-1)与2型糖尿病及其并发症的关系.方法采用酶联免疫吸附法测定61例合并高血压和微血管并发症的糖尿病患者及36例正常人血清中sVCAM-1水平.结果2型糖尿病患者的sVCAM-1水平[(973.25±73.38)μg/L]明显高于非糖尿病患者[(230.45±12.47)μg/L],P＜0.001.合并高血压患者sVCAM-1[(1263.99±87.00)μg/L]较微血管病变者[(726.57±95.40)μg/L]增高更明显(P＜0.001).结论sVCAM-1参与了糖尿病血管并发症的发生和发展.     

Plasma levels of soluble vascular adhesion molecule-1 and cholesterol oxidation product in type 2 diabetic patients with nephropathy.

Functional impairment of the vascular endothelium is an early event in the development of atherosclerosis, and soluble adhesion molecules in plasma are regarded as an indicator of the endothelial damage in diabetes mellitus. We compared the soluble vascular adhesion molecule levels in the patients with diabetic nephropathy in concerning with plasma 7-ketocholesterol levels, which is major cholesterol auto-oxidation products. Average value of plasma VCAM-1 in 31 patients with type 2 diabetes mellitus was 297.6+/-10.2 ng/ml (mean+/-SE), and the value was significantly higher than that in 8 age-matched healthy controls (231.9+/-15.0 ng/ml). Among the 31 diabetic patients, the group with macroalbuminuria (n = 8) had the higher levels of plasma VCAM-1 (349.5+/-26.0 ng/ml) than the levels in the group with normoalbuminuria (n=15; 280.6+/-12.3 ng/ml). The levels of plasma 7-ketocholesterol in diabetes (26.9+/-1.5 ng/ml) or the patients with macroalbuminuria (31.4+/-3.3 ng/ml) were significantly higher than the control (22.5+/-1.8 ng/ml). The level of soluble VCAM-1 showed significant correlation between the values of 7-ketocholesterol (r=0.42, p=0.024), TC (r=0.42, p=0.014) and LDL-C (r=0.38, p=0.044). However no correlation was demonstrated with HbA1c nor creatinine level. We conclude that soluble VCAM-1 in plasma may be an indicator of oxidative stress and vascular injury in diabetic nephropathy.     

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.     

Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and von Willebrand factor levels and increases nitric oxide concentrations in hypercholesterolemic patients

Up-regulation of vascular cell adhesion molecule-1 (VCAM-1) and reduced nitric oxide (NO) availability represent early characteristics of atherosclerosis. To evaluate whether the antioxidant vitamin E affected the circulating levels of soluble VCAM-1 (sVCAM-1) and the plasma metabolite of NO (nitrite+nitrate) in hypercholesterolemic patients, either vitamin E (either 400 IU or 800 IU/d for 8 wk) or placebo were randomly, double-blindly given to 36 hypercholesterolemic patients and 22 age- and sex-matched controls. At baseline hypercholesterolemic patients showed higher plasma sVCAM-1 (microg.liter(-1)) (591.2 +/- 132.5 vs. 505.0 +/- 65.6, P < 0.007) and lower NO metabolite (microM) levels (15.9 +/- 3.4 vs. 29.2 +/- 5.1, P < 0.0001) than controls. In hypercholesterolemic patients, 8 wk vitamin E (but not placebo) treatment significantly decreased circulating sVCAM-1 levels (400 IU: -148.9 +/- 84.6, P < 0.009; 800 IU: -204.0 +/- 75.7, P < 0.0001; placebo: -4.7 +/- 22.6, NS), whereas it increased NO metabolite concentrations (400 IU: +4.0 +/- 1.7, P < 0.02; 800 IU: +5.5 +/- 0.8, P < 0.0001; placebo: +0.1 +/- 1.1, NS) without affecting circulating low- density lipoprotein levels. Changes in both plasma sVCAM-1 and NO metabolite levels showed a trend to significantly correlate (r = -0.515, P = 0.010; and r = 0.435, P = 0.034, respectively) with changes in vitamin E concentrations induced by vitamin E supplementation. In conclusion, isolated hypercholesterolemia both increased circulating sVCAM-1 and reduced NO metabolite concentrations. Vitamin E supplementation counteracts these alterations, thus representing a potential tool for endothelial protection in hypercholesterolemic patients.     

Serum level of soluble vascular cell adhesion molecule in patients with hepatocellular carcinoma and its association with severity of liver disease

Background. VCAM-1 (soluble vascular cell adhesion molecule-1) plays a role in liver angiogenesis. Hepatocellular carcinoma (HCC) has important angiogenic activity, so expression of VCAM-1 may be pathogenic. Aim. To assess the association between serum VCAM-1 (sVCAM-1) levels and features of tumour and liver disease in patients with and without HCC, and to study the influence of HCC treatment on sVCAM-1 levels.Material and methods. Concentrations in peripheral (sVCAM-1-P) and hepatic (sVCAM-1-H) veins were analysed using ELISA in 134 consecutive patients with chronic liver disease between May 2004 and February 2006, who underwent a splanchnic haemodynamic study. Of these patients, 58 had HCC.Results. sVCAM-1-P and sVCAM-1-H were well correlated in both groups. No association was found between sVCAM-1-H and tumour features. No differences were observed in sVCAM-1-H between HCC and non-HCC cirrhotic patients. There was a significant linear association between Child-Pugh stage and sVCAM-1-H in HCC-patients (Child-Pugh A [2,485 ± 1,294 ng/mL] vs. Child-Pugh B [3,408 ± 1,338 ng/mL] vs. Child-Pugh C [4,096 ± 862 ng/ mL]; p = 0.007). Seven non-cirrhotic HCC patients had a significantly lower sVCAM-1-H than cirrhotic HCC patients. Treatment of HCC leads to an increase in sVCAM-1-H levels although this was not associated with the necrosis response to treatment.Conclusions. sVCAM-1 levels are more closely associated with the severity of underlying liver disease than with the presence of HCC. sVCAM-1 levels are not associated with tumour features or invasiveness; therefore, sVCAM-1 does not seem to play an important role in the angiogenic processes of HCC.     

血管黏附分子在大肠癌组织中的表达及意义

目的 探讨血管黏附分子(VCAM-1)在大肠癌发生、发展中的作用.方法 用免疫组化SABC法检测65例大肠癌、16例大肠息肉和4例癌旁组织中VCAM-1的表达,酶联免疫吸附试验检测20例健康人、40 例大肠癌患者外周血可溶性VCAM-1(sVCAM-1)水平,分析VCAM-1 表达与大肠癌病理特征的关系.结果 大肠癌组织中VCAM-1阳性率明显高于大肠息肉和癌旁组织(P均<0.01),VCAM-1表达与大肠癌的侵袭深度及淋巴结转移相关.大肠癌患者外周血清sVCAM-1水平高于健康人(P<0.01),其中有淋巴结转移者明显高于无淋巴结转移者(P<0.01).结论 VCAM-1可促进大肠癌的发生、发展;sVCAM-1有望成为大肠癌早期诊断及判断转移的指标.     

Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) are elevated in advanced stages of non-Hodgkin's lymphomas

Abstract: The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in 116 patients with non-Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule-1 (sICAM-1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM-1 levels in NHL patients were not significantly different from the levels of healthy controls (n = 31). However, sVCAM-1 was elevated in advanced stage disease, i.e. stages III + IV. Elevated serum levels of sVCAM-1 were associated with significantly poorer disease-free (p = 0.024) and overall (p = 0.02) survival. sVCAM-1 correlated poorly with other known prognostic variables (LDH, sTK and β₂m) and with sICAM-1. None of the tested markers added prognostic information for disease-free survival independently of Ann Arbor stage and B-symptoms. The expression of VCAM-1 and ICAM-1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.     

Relationship between circulating vascular cell adhesion molecule-1 and microvascular complications in Type 2 diabetes mellitus

The soluble form of the vascular cell adhesion molecule-1 (VCAM-1) is detectable in human sera and is elevated in diabetic patients, with unknown clinical significance. In the present study, the relationship between serum soluble VCAM-1 and diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) was evaluated in 95 Japanese patients with Type 2 diabetes mellitus (DM). Serum soluble VCAM-1 concentration was higher in patients with more advanced stages of retinopathy as well as nephropathy. There was a significant correlation between soluble VCAM-1 and log₁₀ (urinary albumin excretion) in 69 patients with normal serum creatinine levels (r = 0.51, p<0.0001) and a significant correlation between soluble VCAM-1 and log₁₀ (serum creatinine) in all the patients (r = 0.83, p<0.0001). Soluble VCAM-1 concentration was also elevated in patients with neuropathy. There was a significant correlation between soluble VCAM-1 concentration and the number of microvascular complications (r = 0.59, p<0.0001). However, multivariate regression analysis revealed that only diabetic nephropathy, was associated with the soluble VCAM-1 concentration. The elevation of circulating VCAM-1 level in diabetic nephropathy may result from underlying systemic endothelial dysfunction, increased VCAM-1 production in damaged renal tubular or glomerular epithelial cells and/or decreased renal clearance of this molecule, depending on the stage of nephropathy. © 1998 John Wiley & Sons, Ltd.     

Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) are elevated in advanced stages of non-Hodgkin's lymphomas

The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in 116 patients with non-Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule-1 (sICAM-1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM-1 levels in NHL patients were not significantly different from the levels of healthy controls (n = 31). However, sVCAM-1 was elevated in advanced stage disease, i.e. stages III + IV. Elevated serum levels of sVCAM-1 were associated with significantly poorer disease-free (p = 0.024) and overall (p = 0.02) survival. sVCAM-1 correlated poorly with other known prognostic variables (LDH, sTK and beta 2m) and with sICAM-1. None of the tested markers added prognostic information for disease-free survival independently of Ann Arbor stage and B-symptoms. The expression of VCAM-1 and ICAM-1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.     

Soluble vascular cell adhesion molecule-1 and soluble E-selectin are associated with micro- and macrovascular complications in Type 1 diabetic patients

OBJECTIVE: There are no large studies in Type 1 diabetic patients that have examined the relation between soluble adhesion molecules and micro- and macrovascular outcomes, although the risks of such complications are high. Therefore, the main objective is to examine the relationship between soluble (s) vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin and retinopathy, albuminuria, and cardiovascular disease (CVD) in Type 1 diabetic patients. METHODS: Cross-sectional data on 540 Type 1 diabetic patients, with a mean age of 40 years and diabetes duration of 22 years, from the EURODIAB Prospective Complications Study (PCS) were analysed. Retinopathy was assessed by centrally graded retinal photographs. Albumin excretion rate (AER) was used to define micro- and macroalbuminuria. CVD was defined as having physician diagnosed myocardial infarction (MI), stroke, coronary artery bypass graft (CABG) or angina, or Minnesota coded ischaemic electrocardiograms (ECGs). RESULTS: Unadjusted, there was a positive relationship between sVCAM-1 and sE-selectin with nonproliferative and proliferative retinopathy, micro- and macroalbuminuria, and CVD. After adjustment for age, sex, duration of diabetes, systolic blood pressure (BP), LDL-cholesterol, fasting triglycerides (TGs), smoking, body mass index (BMI), and glycated haemoglobin, as well as other complications, the strongest significant associations were shown between sVCAM-1 and macroalbuminuria, with an odds ratio of 1.83 (1.33-2.53) for every 100 ng/ml increase in sVCAM-1. CONCLUSIONS: In this large sample of Type 1 diabetic patients, it was shown that sVCAM-1 and sE-selectin have positive associations with retinopathy, albuminuria, and CVD. This suggests that adhesion molecules are important in the pathogenesis of vascular complications in Type 1 diabetes.     

Effects of the prostaglandin I2 analogue,beraprost sodium,on vascular cell adhesion molecule-1 expression in human vascular endothelial cells and circulating vascular cell adhesion molecule-1 level in patients with type 2 diabetes mellitus

Beraprost sodium is an orally active prostaglandin (PG)I(2) analogue, which has antiplatelet and vasodilating properties. In this study, we investigated the effects of beraprost on the expression of vascular cell adhesion molecule-1 (VCAM-1), one of the key molecules involved in atherosclerosis, in cultured vascular endothelial cells. In addition, we examined the effects of beraprost on circulating VCAM-1 level and atherosclerosis progression in patients with type 2 diabetes mellitus. Beraprost significantly decreased tumor necrosis factor-alpha (TNF-alpha)-induced VCAM-1 expression in human vascular endothelial cells. Beraprost also repressed human monocytoid U937 cell adhesion to the vascular endothelial cells. Twenty-five patients with type 2 diabetes mellitus who had atherosclerotic change of carotid arteries were enrolled for an open prospective study: 11 patients received beraprost for 3 years, while the other 14 did not. The 3-year changes of circulating VCAM-1 level, as well as those of carotid arterial intima-media thickness (IMT) were significantly lower in the patients receiving the beraprost treatment than that in the patients without the treatment. Thus, beraprost had an ability to repress the expression of VCAM-1 in human vascular endothelial cells. In addition, beraprost lowered circulating VCAM-1 level and prevented the increase of carotid IMT in patients with type 2 diabetes mellitus. Considering that circulating VCAM-1 and IMT are predictive of future vascular events, beraprost may have a beneficial effect on progression of atherosclerosis in diabetic patients.     

2型糖尿病合并糖尿病肾病脂联素水平变化及与血管内皮功能的关系

目的探讨糖尿病肾病患者血清脂联素水平的变化,及与血管内皮功能的关系。方法 50例无明显临床大血管并发症的2型糖尿病患者,按24 h尿白蛋白排出量分为正常白蛋白尿组、微量白蛋白尿组及大量白蛋白尿组。检测血清脂联素、可溶性血管细胞黏附分子1、生物化学指标、肱动脉内皮依赖性舒张功能(FMD)、含服硝酸甘油后肱动脉内皮依赖性舒张功能(NID)、心脏结构参数及颈动脉内膜-中膜厚度。结果大量白蛋白尿组脂联素水平是正常白蛋白尿组的4倍,是微量白蛋白尿组的2倍(P<0.01和P<0.05)。微量白蛋白尿组脂联素水平比正常白蛋白尿组升高(P<0.05)。脂联素/血肌酐在三组中有同样的变化(均P<0.05)。大量白蛋白尿组和微量白蛋白尿组可溶性血管细胞黏附分子1均高于正常白蛋白尿组(P<0.01和P<0.05)。大量白蛋白尿组FMD、NID随脂联素水平的增加而下降(P<0.05)。颈动脉内膜-中膜厚度在三组间无统计学差异。脂联素与可溶性血管细胞黏附分子1、24 h尿白蛋白排出量、血肌酐、左心室后壁厚度、内膜-中膜厚度呈正相关(r值分别为0.338、0.704、0.470、0.331、0.324,P<0.05),与FMD、NID呈显著负相关(r值为-0.397、-0.413,P<0.01)。结论糖尿病肾病伴随高脂联素血症,且与血管内皮功能损害密切相关。脂联素可作为糖尿病肾病患者早期血管内皮功能障碍的预测指标。     

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.     

Elevated plasma sVCAM-1 levels in children with sickle cell disease: impact of chronic transfusion therapy

Vascular cell adhesion molecule-1 (VCAM-1) has been implicated as being important in the pathophysiology of acute pain episodes (APE) and acute chest syndrome (ACS) of sickle cell disease (SCD). The frequency of these episodes is reduced by chronic transfusion therapy. The impact of chronic transfusion therapy on VCAM-1 expression is unknown. Soluble VCAM-1 (sVCAM-1) levels were measured in plasma using an ELISA assay (R&D Systems) in 61 patients with SCD (age range 1.5-20 years) and 12 normal controls (2.5-14 years). SCD patients included 20 with ACS, 14 with APE, 12 at well-child visits, and 15 receiving chronic transfusion therapy. Asymptomatic SCD patients had higher sVCAM-1 levels compared to normal subjects (P < 0.001). Levels of sVCAM-1 were further elevated during ACS (P < 0.001) and APE (P = 0.072) and returned to the asymptomatic range on resolution. Levels were significantly lower in transfused patients (P = 0.003) compared to asymptomatic SCD patients. Our findings of increased VCAM-1 expression during ACS and perhaps APE offer a rationale for therapeutic use of cytokine and other VCAM-1 modulators. The reduction of sVCAM-1 levels observed in our transfused SCD patients offers insight into the mechanism of the protective effect of transfusion against ACS and APE and possibly stroke.     

Soluble thrombomodulin and vascular adhesion molecule-1 are associated to leptin plasma levels in obese women

Recent studies have suggested that leptin, a plasma protein secreted by adipocytes, may play a role in artherothrombosis. In this study, we tested the hypothesis that leptin contributes to in vivo endothelial dysfunction in obese subjects. A cross-sectional comparison of plasma leptin, soluble thrombomodulin (sTM) and soluble vascular adhesion molecule-1 (VCAM-1) was carried out in 35 obese women (age 48+/-13) selected with a body mass index (BMI) > or =30kg/m(2) and 25 normal weight women (age 50+/-11, BMI < 25). An additional study was conducted to determine the short-term effects of weight loss induced by caloric restriction. Plasma levels of leptin, sTM and sVCAM-1 were measured before and after weight loss. Obese women had higher levels of leptin (35+/-22 versus 22+/-19, P<0.01), sTM (4.8+/-1.8 versus 1.9+/-1.5, P<0.001) and sVCAM-1 (726+/-109 versus 583+/-50, P<0.001) than non-obese women. sTM and sVCAM-1 concentrations had a positive correlation with BMI (sTM, r=0.70, P<0.001; sVCAM-1, r=0.60, P<0.001), waist circumference (sTM, r=0.66, P<0.001; sVCAM-1, r=0.37, P<0.01) and leptin levels (sTM, r=0.53, P<0.001; sVCAM-1, r=0.42, P<0.005). At multiple regression analysis leptin predicted sTM and sVCAM-1 independently of obesity measures and other covariates. Twenty-nine obese patients who completed the program of weight reduction showed a significant decrease in leptin, sTM, and sVCAM-1 levels. The magnitude of decrease of sTM and sVCAM-1 was related to the magnitude of reduction in leptin levels. Therefore, our results show that obesity is associated with enhanced levels of atherosclerosis markers. These abnormalities are related to abdominal obesity possibly mediated by leptin levels, and are reversible with weight loss.     

Clinical implication of vascular cell adhesion molecule-1 and very late activation antigen-4 interaction, and matrix metalloproteinase-2 production in patients with liver disease.

OBJECTIVES: To clarify the role of adhesion molecule in liver cell injury. PATIENTS AND METHODS: The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), and the expression of VCAM-1 and its ligand, very late activation antigen-4 (VLA-4), were examined in patients with various liver diseases. In addition, the presence of matrix metalloproteinase-2 (MMP-2) was investigated because the release of MMP-2 is thought to be mediated by VLA-4-positive cells. sVCAM-1 and MMP-2 were measured by ELISA assay, and VCAM-1 and VLA-4 were studied by immuno-histological methods. RESULTS: In acute hepatitis (AH) patients, the serum level of sVCAM-1 was significantly elevated compared with that in other cohorts. VCAM-1 was expressed on sinusoidal lining cells but not on hepatocytes. In patients with chronic liver disease, sVCAM-1 levels rose in concert with the progression of chronic hepatitis (CH), and VCAM-1 was also expressed. VLA-4 was detected in both mononuclear cells and Kupffer cells in AH livers, but mainly in Kupffer cells in patients with CH. In AH patients, MMP-2 levels were similar to those in control subjects, but in CH and liver cirrhosis patients, MMP-2 level was elevated in association with CH progression. CONCLUSIONS: The immune response through the VCAM-1 and VLA-4 pathways is important in hepatocyte injury, especially in AH patients, to attach VLA-4-positive mononuclear cells to VCAM-1-positive sinusoidal lining cells. The distribution of VLA-4-positive cells differs between AH and CH patients. VLA-4-positive Kupffer cells in chronic liver diseases might be involved in the progression of CH, perhaps through the mechanism of upregulation of MMP-2 production.