Soluble Intercellular Cell Adhesion Molecule-1 Research Articles

The markers of inflammation and endothelial dysfunction in correlation with glycated haemoglobin are present in type 2 diabetes mellitus patients but not in their relatives

The aim of this study is to test several biomarkers of inflammation, of endothelial dysfunction, glycated haemoglobin, and their reflection in arterial dilatation, in patients with type 2 diabetes mellitus and in their relatives, in order to demonstrate if relatives present markers as a form of precocious indicators of diabetes mellitus. Individuals between 30 and 55 years of age and without clinical arterial disease were divided in three groups: type 2 diabetes mellitus patients without complications (12 men and 18 women); first degree relatives of type 2 diabetes mellitus (14 men and 20 women); and control individuals (9 men and 16 women). Body composition was measured with a bioelectrical impedance analyzer and endothelial function with an eco-Doppler device. We determined glucose, insulin, C-peptide, glycated haemoglobin, fibrinogen, E-selectin, P-selectin, soluble intercellular cell adhesion molecule-1 (ICAM-1), soluble vascular cell adhesion molecule-1 (VCAM-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) in plasma. We also studied endothelium independent dilatation and endothelium dependent dilatation. ICAM-1 and VCAM-1 were significantly higher in the diabetic group (237.5+/-43.4 and 692.5+/-168.6 ng/l) than in controls (197.4+/-51.2 and 573.5+/-121.1 ng/l, p=0.011 and 0.013, respectively), but were not higher in the family group (224.5+/-45.2 and 599.8+/-150.4 ng/l). CRP was higher in the diabetic group (3.35+/-3.27 mg/l) than in the other groups (1.28+/-1.29 and 1.61+/-1.54 mg/l, p=0.002) and correlated with glycated haemoglobin. The non-endothelium mediated dilatation was lesser in the diabetic group than in the family group (17.3+/-6.1 vs. 24+/-8, p=0.029) and controls. In conclusion patients with uncomplicated type 2 diabetes, but not their relatives, have biochemical markers of sub-clinical inflammation in relationship with glycated haemoglobin and dysfunction of the endothelial cells markers. In these patients endothelium independent dilatation is more affected than endothelium dependent dilatation.

Platelet and endothelial activity in comorbid major depression and coronary artery disease patients treated with citalopram: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial (CREATE) biomarker sub-study

Major depression is an independent risk factor for increased morbidity and mortality in patients with coronary artery disease (CAD). Increased platelet activity and vascular endothelial dysfunction are possible pathways through which depression may increase cardiovascular risk. Citalopram exhibits strong selective inhibition of human platelet activation, but little is known about its effects on vascular endothelium. We assessed whether treatment of depressed CAD patients with citalopram alters platelet/endothelial biomarkers. The study was performed within the framework of the CREATE trial. We assessed the effect of citalopram on P-selectin, beta-thromboglobulin (betaTG), soluble intercellular cell adhesion molecule-1 (sICAM-1), and total nitric oxide (tNO). Plasma samples were obtained at baseline and week 12 from subjects randomized to citalopram 20-40 mg daily (n = 36), or placebo (n = 21). Anticoagulants, aspirin, and clopidogrel were permitted. Treatment with citalopram was associated with greater increase in tNO over 12 weeks compared to placebo (P = 0.005). There were no differences for the other biomarkers such as P-selectin (P = 0.70), betaTG (P = 0.46) and ICAM (P = 0.59). Treatment with citalopram for 12 weeks in depressed CAD patients is associated with enhanced production of nitric oxide despite the co-administration of commonly prescribed anti-platelet regimens including aspirin and clopidogrel. Clinical implications of these findings are unclear, but improved endothelial function is implied by the increased NO production, suggesting that citalopram may be of particular benefit for patients with comorbid depression and vascular disease including CAD, stroke, peripheral artery disease, and diabetes.

Elevated concentrations of retinol-binding protein-4 (RBP-4) in gestational diabetes mellitus: Negative correlation with soluble vascular cell adhesion molecule-1 (sVCAM-1)

Background. Retinol-binding protein-4 (RBP-4) may increase insulin resistance (IR) in animals, with elevated levels reported in humans with obesity and type 2 diabetes. There are, however, few data on concentrations of RBP-4 in gestational diabetes mellitus (GDM).Methods. We measured fasting serum levels of RBP-4, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in 50 women at 28 weeks of gestation, divided according to the results of a 50 g glucose challenge test (GCT) and a 75 g oral glucose tolerance test (OGTT): (1) controls (n = 20), normal responses to both GCT and OGTT; (2) intermediate group (IG) (n = 15): false positive GCT, but normal OGTT; and (3) GDM group (n = 15), both GCT and OGTT abnormal. IR was assessed by homeostasis model assessment (HOMA-IR) and by insulin resistance index (IRI) based on glycemia and insulinemia during OGTT.Results. All groups were matched for age and body mass index (BMI). RBP-4 levels (μg/ml, mean±standard deviation) were higher in women with GDM vs. controls (53.9 ± 17.9 vs. 29.7 ± 13.9, p ≤ 0.001), with a trend towards higher RBP-4 in GDM compared with IG (38.0 ± 19.3, p = 0.07). There was no significant correlation between RBP-4 and age, BMI, insulin, IRI or HOMA-IR, but there was a moderate, significant negative correlation between RBP-4 and sVCAM-1 (r2 = 0.20, p = 0.001).Conclusions. RBP-4 levels are elevated in women with GDM, but do not correlate with IR indices and correlate negatively with sVCAM-1. The physiological significance of RBP-4 rise in women with GDM remains to be elucidated.

Premature compared with late onset of coronary artery disease: young patients show a severe defect in fibrinolytic response to venous occlusion

Inflammatory processes play a role in the onset of acute cardiovascular events associated with activation of the coagulation system whereas the fibrinolytic system may prevent local thrombus formation. We compared 25 patients with premature coronary artery disease (CAD) (first ST-elevation myocardial infarction, < 55 years old) with 25 sex-matched patients older than 55 years at their first myocardial infarction. Six months after the acute event, patients with late onset of CAD showed a significantly higher increase of tissue-type plasminogen activator activity during venous occlusion compared with patients with premature CAD (P < 0.005). Prothrombin fragment 1+2 was higher in patients with late-onset CAD (P < 0.05), whereas the inflammatory markers C-reactive protein and soluble intercellular cell adhesion molecule-1 were not different in both groups. A multivariate analysis including cardiovascular risk factors showed that the tissue-type plasminogen activator response to venous occlusion was independently associated with patient age at onset of first ST-elevation myocardial infarction. Although in our series high age was associated with a prothrombotic state, a high fibrinolytic capacity might have some beneficial effect and contribute to a delayed onset of adverse cardiovascular events in these patients.

Elevation of E-Selectin Concentrations may Correlate with Potential Endothelial Dysfunction in Individuals with Hypopituitarism During Therapy with Growth Hormone

Increased mortality due to cardiovascular disease has been described in adult patients with untreated growth hormone (GH) deficiency. GH replacement therapy has been demonstrate to improve vascular reactivity and reverses early atherosclerotic changes in GH deficient adults. The objective of this study was the assessment of fibrinolytic markers, soluble adhesion molecules, inflammatory cytokines and endothelial function in hypopituitary adults with GH deficiency and with GH replacement therapy. We studied 20 GH deficient patients, 10 men and 10 women (aged, 43.4 +/- 8.4 years) under GH replacement therapy compared with a control group matched for age and body mass index, 9 men and 16 women. All subjects, patients and controls, were life-long non-smokers, normotensive and non-diabetic. The following variables were recorded: anthropometrical and body composition variables, serum concentrations of glucose, insulin and C-peptide; thrombin anti-thrombin fragments and fibrin degradation product D-dimer that were determined by an enzyme-linked-immunosorbent assay (ELISA); IGF-I by radioimmunoassay; C-reactive protein by highly sensitive immunonephelometry; E-selectine, P-selectine, soluble intercellular cell adhesion molecule-1, soluble vascular cell adhesion molecule-1, interleukin-6 and monocyte chemoattractant protein-1 by ELISA. The assessment of endothelial function in vivo was measured by Doppler. Patients with GH deficiency had higher hip/waist ratio and C-peptide and triglycerides concentrations than controls. Our results demonstrated no difference in fibrinolytic markers among patients and controls. E-selectin concentrations were higher in patients than in controls, 22.5+/-11.4 vs. 10.7+/-6.2 microg/L, p = 0.0001. P-selectin, soluble intercellular cell adhesion molecule-1, soluble vascular cell adhesion molecule-1, interleukin-6, monocyte chemoattractant protein-1 and C-reactive protein were similar in the 2 groups. Vascular reactivity and carotid intima-media thickness were also similar in patients and controls. In this study we have demonstrated in adults with GH deficiency under GH substitution elevation of E-selectin concentrations that may correlate with potential endothelial dysfunction suggesting that the protective effect of GH in these patients may be enhancing other mechanisms.

ICAM-1 Cross-Linking Stimulates Endothelial Glutathione Synthesis

What mechanisms regulate endothelial glutathione (GSH) during inflammation? Addressing this question is critical in understanding mechanisms leading to endothelial dysfunction and cardiovascular disease. Herein, the authors show data that support the hypothesis that the intercellular cell adhesion molecule-1 (ICAM-1) regulates GSH. Ligating either constitutive or induced ICAM-1 on the endothelial surface, or exposing endothelial cells to soluble ICAM-1, increases GSH concentrations. ICAM-1 is important in mediating leukocyte adhesion and modulates endothelial signaling pathways important in controlling transmigration. The present data underscore a novel function for ICAM-1 in modulating GSH metabolism and raise the hypothesis that this adhesion molecule controls endothelial redox status under basal and inflammatory conditions.

Longitudinal Assessment of Maternal Endothelial Function and Markers of Inflammation and Placental Function throughout Pregnancy in Lean and Obese Mothers

Obesity in pregnancy is increasing and is a risk factor for metabolic pathology such as preeclampsia. In the nonpregnant, obesity is associated with dyslipidemia, vascular dysfunction, and low-grade chronic inflammation. Our aim was to measure microvascular endothelial function in lean and obese pregnant women at intervals throughout their pregnancies and at 4 months after delivery. Plasma markers of endothelial function, inflammation, and placental function and their association with microvascular function were also assessed. Women in the 1st trimester of pregnancy were recruited, 30 with a body mass index (BMI) less than 30 kg/m(2) and 30 with a BMI more than or equal to 30 kg/m(2) matched for age, parity, and smoking status. In vivo endothelial-dependent and -independent microvascular function was measured using laser Doppler imaging in the 1st, 2nd, and 3rd trimesters of pregnancy and at 4 months postnatal. Plasma markers of endothelial activation [soluble intercellular cell adhesion molecule-1 (sVCAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF), and plasminogen activator inhibitor (PAI)-1], inflammation (IL-6, TNFalpha, C-reactive protein, and IL-10), and placental function (PAI-1/PAI-2 ratio) were also assessed at each time point. The pattern of improving endothelial function during pregnancy was the same for lean and obese, but endothelial-dependent vasodilation was significantly lower (P < 0.05) in the obese women at each trimester (51, 41, and 39%, respectively). In the postpartum period, the improvement in endothelial-dependent vasodilation persisted in the lean women but declined to near 1st trimester levels in the obese (lean/obese difference, 115%; P < 0.01). There was a small but significant difference in endothelial-independent vasodilation between the two groups, lean response being greater than obese (P = 0.021), and response declined in both groups in the postpartum period. In multivariate analysis, time of sampling had the most impact on endothelial-independent function [18.5% (adjusted sum of squares expressed as a percentage of total means squared), P < 0.001 for sodium nitroprusside response; 9.8%, P < 0.001 for acetylcholine response], and obesity had the most impact on endothelial-dependent microvascular function (1.7%, P = 0.046 for sodium nitroprusside response; 19.3%, P < 0.001 for acetylcholine response). Time of sampling (11.2%, P < 0.001), IL-6 (4.0%, P = 0.002), and IL-10 (2.4%, P = 0.018) were significant independent contributors to variation in endothelial-dependent microvascular function. When obesity was entered into the model, the association with IL-6 and IL-10 was no longer significant, and obesity explained 6.8% (P < 0.001) of the variability in endothelial-dependent microvascular function. In the 1st trimester, obese women had a significantly higher PAI-1/PAI-2 ratio [obese median (interquartile range), 0.87 (0.54-1.21) vs. lean 0.30 (0.21-0.47), P < 0.001), reflecting the lower PAI-2 levels in obese pregnant women. In a multivariate analysis, 1st trimester BMI (7.6%, P = 0.012), IL-10 (8.2%, P < 0.001), and sVCAM-1 (0.73%, P = 0.007) contributed to the 1st trimester PAI-1/PAI-2 ratio. Obese mothers have a lower endothelium-dependent and -independent vasodilation when compared with lean counterparts. There was a higher PAI-1/ PAI-2 ratio in the 1st trimester in obese women, which improved later in pregnancy. Obese pregnancy is associated with chronic preexisting endothelial activation and impairment of endothelial function secondary to increased production of inflammatory T-helper cells-2 cytokines.

A Pilot Pharmacokinetic and Antiangiogenic Biomarker Study of Celecoxib and Low-dose Metronomic Vinblastine or Cyclophosphamide in Pediatric Recurrent Solid Tumors

Tumor vasculature is a reasonable target for cancer therapy and lower more frequent doses of traditional chemotherapeutics [low-dose metronomic (LDM) chemotherapy] has been shown to have antiangiogenic efficacy. This study evaluated the safety and pharmacokinetics of celecoxib and LDM vinblastine or cyclophosphamide in children with recurrent, refractory solid tumors. We also investigated whether a subset of circulating plasma proteins are surrogate markers of angiogenic activity. Thirty-three children were enrolled in this pilot study and received celecoxib (250 mg/m(2) PO b.i.d.) and either vinblastine (1 mg/m(2) IV 3 x /wk) or cyclophosphamide (30 mg/m(2) PO daily) continually. Celecoxib alone and with LDM chemotherapy was well tolerated and plasma concentrations were consistent with those shown to have antiangiogenic activity. Four patients (13%) had durable stable disease (28 to 78 wk) although no complete or partial responses were observed. The surrogate markers measured (vascular endothelial growth factor, basic fibroblast growth factor, soluble vascular cell adhesion molecule, soluble intercellular cell adhesion molecule, endostatin, and thrombospondin-1) were highly variable and no statistically significant relationship between them and disease progression or maintenance of stable disease was observed. We concluded that this regimen is well tolerated hence supporting the use of this form of therapy in pediatric patients. However, future studies should include more homogenous patient populations and focus on validating surrogate markers to monitor treatment activity.

Effects of selective LDL apheresis on plasma concentrations of ICAM-1, VCAM-1 and P-selectin in diabetic patients with arteriosclerosis obliterans and receiving maintenance hemodialysis

BackgroundArteriosclerosis obliterans (ASO) is a serious complication in patients with end-stage renal disease (ESRD) caused by diabetic nephropathy. Adsorption of low-density lipoprotein (LDL) has been performed to treat ASO. While efficacy of this treatment has been reported in limb ischemia, the mechanism underlying the benefit remains unclear. We investigated how LDL adsorption affected soluble adhesion molecules; P-selectin, an endothelial and platelet activation marker; inflammatory cytokines such as interleukin (IL)-1β, IL-6 and tissue necrosis factor (TNF)-α; and lipids in serum. MethodsSelective LDL adsorption by dextran sulfate columns (LDL apheresis) was performed weekly for 10 weeks to treat eight hemodialysis patients with ASO, ESRD, and type 2 diabetes mellitus. Serum was sampled before and immediately after apheresis. ResultsLDL apheresis was performed safely. After LDL apheresis lipid concentrations were significantly reduced and clinical findings, such as Fontaine's classification and ankle brachial pressure index values, were improved. Pretreatment concentrations of soluble intercellular and vascular cell adhesion molecules (sICAM-1 and sVCAM-1) and also P-selectin were higher in patients than healthy controls. After apheresis these decreased, especially P-selectin. IL-1β, IL-6, and TNF-α concentrations before apheresis were similar to those in controls and were unaffected by treatment. ConclusionEffectiveness of LDL apheresis against ASO may involve decreased endothelial cell and platelet activation.

Peripheral fibrinolytic markers, soluble adhesion molecules, inflammatory cytokines and endothelial function in hypopituitary adults with growth hormone deficiency

Increased mortality due to cardiovascular disease has been described in adult patients with untreated GH deficiency (GHD). GH replacement has been demonstrate to improve vascular reactivity and reverse early atherosclerotic changes in adults with GHD. Assessment of fibrinolytic markers, soluble adhesion molecules, inflammatory cytokines and endothelial function in hypopituitary adults with GHD at baseline and 1 year after GH replacement therapy. We studied 10 patients with GHD (five men and five women; aged 45.6 +/- 10.4 years) at baseline and 1 year after GH replacement therapy compared with a control group (nine men and 16 women) matched for age and body mass index (BMI). All subjects, patients and controls, were life-long nonsmokers, normotensive and nondiabetic. The following variables were recorded: anthropometric and body composition variables, serum concentrations of glucose, insulin and C-peptide; thrombin anti-thrombin (TAT) fragments and fibrin degradation product D-dimer, which were determined by an enzyme-linked immunosorbent assay (ELISA); IGF-I by radioimmunoassay (RIA); C-reactive protein (CRP) by highly sensitive immunonephelometry; E-selectin, P-selectin, soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) by ELISA. The assessment of endothelial function in vivo was measured with a Doppler device. Patients with GHD without GH substitution had higher hip/waist ratio and body fat than controls. Insulin, C-peptide and triglyceride concentrations were also higher. Our results demonstrated no difference in fibrinogen and in TAT fragment concentrations among patients and controls. E-selectin concentrations were higher in patients than in controls (26.1 +/- 11 vs. 10.7 +/- 6.2 microg/l, P = 0.0001). P-selectin, sICAM-1, sVCAM-1, IL-6, MCP-1 and CRP were similar in the two groups. Vascular reactivity and carotid intima-media thickness (IMT) were also similar in patients and controls. After 1 year of GH treatment we found no changes in biochemical parameters, fibrinolytic markers, soluble adhesion molecules, inflammatory cytokines and endothelial function. Adults with GHD show some subtle changes in soluble adhesion molecules but our data suggest no beneficial effects of GH over these markers in relationship to endothelial function. Factors other than GH treatment, such as differences in age, degree of obesity, the presence of diabetes mellitus and arterial hypertension or tobacco consumption, could explain the observed increase in markers of vascular risk in GH-deficient patients.

Pharmacokinetics and Anti-asthmatic Potential of Non-parenterally Administered Recombinant Human Interleukin-1 Receptor Antagonist in Animal Models

The objectives of this study were to define the pharmacokinetics of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) and its effects on allergic asthma, cell adhesion molecules, and upper respiratory tract following non-parenteral administration in animals. Pharmacokinetics and immunomodulating effects of rhIL-1ra were investigated in Sprague-Dawley rats and asthmatic guinea pigs, respectively. Effects on the upper respiratory tract following the applications of rhIL-1ra were investigated on the ex vivo nasal mucosa of Sprague-Dawley rats and in situ in the upper palate of Chinese toads. Absolute bioavailabilities after intratracheal and intranasal administrations of rhIL-1ra were 94.3% and 24.8%, respectively. After administration of rhIL-1ra solution as ultrasonic spraying, the asthmatic symptom in guinea pigs was obviously attenuated. The plasma soluble intercellular cell adhesion molecule (sICAM-1) and P-selectin levels in asthmatic guinea pigs were each dose-dependently reduced with the increase of rhIL-1ra dose. The rhIL-1ra solution after administration via the airway seemed to have no impact on the integrity of nasal mucosa and mucocilia clearance in the upper respiratory tract. The present study provides evidence that rhIL-1ra effectively suppresses allergen-induced asthmatic symptoms through spraying, which corresponds to nasal and pulmonary absorption or both, and the efficacy is associated with downregulation of sICAM-1 and P-selectin expressions.

Inflammatory Mediator Release in Normal Bronchial Smooth Muscle Cells is Altered by Pregnant Maternal and Fetal Plasma Independent of Asthma

Studies have shown that pregnancy can alter the pathophysiology of a pre-existing maternal disease such as asthma. However, the mechanisms that alter maternal asthma during pregnancy are presently unknown. Previous work has demonstrated that human bronchial smooth muscle (BSM) cells produce inflammatory factors in response to nonpregnant, atopic plasma. The aim of this study was to determine whether circulating pregnancy-derived factors in maternal and fetal plasma can stimulate inflammatory mediator release in BSM cells in the presence and absence of maternal asthma. Cultured human BSM cells were exposed to maternal and fetal plasma from normal pregnancies and pregnancies complicated by asthma. Inflammatory mediator release was determined by enzyme-linked immunosorbent assay (ELISA). Both maternal and fetal plasma from asthmatic and nonasthmatic individuals significantly increased production of interleukin (IL)-6 (ANOVA, P<0.001), regulated upon activation, normal T-cell expressed and secreted (RANTES) (ANOVA, P<0.01), and soluble intercellular cell-adhesion molecule-1 (sICAM-1) (ANOVA, P<0.01). There was no difference in inflammatory mediator release in response to asthma and nonasthmatic plasma. Eotaxin release was increased by pregnant asthmatic plasma (ANOVA, P<0.05). The results of this study suggest that circulating pregnancy-related factors can activate asthma-associated mediators in BSM cells. This change in BSM function may be one mechanism that contributes to increased asthma severity during pregnancy.

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.

Soluble cell adhesion molecules s-VCAM-1 and s-ICAM-1 in subjects with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH) is the most common familial hyperlipidemia with a high risk for early atherosclerosis. The aim of this study was to compare levels of soluble intercellular cell adhesion molecule 1 (s-ICAM-1) and soluble vascular cell adhesion molecule 1 (s-VCAM-1) in asymptomatic members of FCH families with healthy controls and to determine the relation between s-ICAM-1, s-VCAM-1 and risk factors accompanying FCH. We also investigated the association between adhesion molecules and the intima-media thickness (IMT) of the common carotid artery, a recognized morphological marker of early atherosclerosis. 82 members of 29 FCH families were divided into the 2 groups: HL (probands and hyperlipidemic first-degree relatives, n = 47) and NL (normolipidemic first-degree relatives, n = 35). The control groups--HL-C (n = 20) and NL-C (n = 20)--consisted of sex- and age-matched healthy individuals. Hyperlipidemic members had significantly higher concentration of s-ICAM-1 (633.7 +/- 169.6 ng/ml versus 546.2 +/- 155.9 ng/ml, p < 0.05). The elevation of s-VCAM-1 was not significant (880.8 +/- 202.9 ng/ml versus 826.5 +/- 174.6 ng/ml, N.S.). Levels of s-ICAM-1 and of s-VCAM-1 in normolipidemic relatives were not significantly different from the control group (530.8 +/- 113.9 ng/ml versus 530.0 +/- 101.0 ng/ml and 860.2 +/- 265.7 ng/ml versus 822.1 +/- 197.0 ng/ml respectively). There was a significant correlation between s-ICAM-1 and apoB (r = 0.42; p < 0.01) in hyperlipidemic subjects and between s-ICAM-1 and proinsulin (r = 0.54; p < 0.01) in normolipidemic subjects. S-ICAM-1 correlated with IMT (r = 0.32; p < 0.05) in all members of FCH families. The increase of s-ICAM-1 in asymptomatic hyperlipidemic members of FCH families reflects their high cardiovascular risk. The positive association between s-ICAM-1 and IMT could indicate s-ICAM-1 as a potential predictor of atherosclerosis manifestation.

Diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction

Endothelial dysfunction is one of the mechanisms linked to an increased risk of cardiovascular disease. We assessed the association between several diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction. Diet-quality scores on the Healthy Eating Index (HEI), Alternate Healthy Eating Index (AHEI), Diet Quality Index Revised (DQI-R), Recommended Food Score (RFS), and the alternate Mediterranean Diet Index (aMED) were calculated by using a food-frequency questionnaire that was administered in 1990 to 690 women in the Nurses' Health Study (ages 43-69 y, no cardiovascular disease or diabetes). Blood collection was completed in the same year. We used regression analysis to assess the associations between these diet-quality scores and plasma concentrations of C-reactive protein, interleukin 6, E-selectin, soluble intercellular cell adhesion molecule 1, and soluble vascular cell adhesion molecule 1. The various diet-quality scores were significantly correlated with each other; correlation coefficients ranged from 0.56 to 0.80 (all P values < 0.0001). After adjustment for age, body mass index, alcohol intake, physical activity, smoking status, and energy intake, the HEI and DQI-R were not significantly associated with any of the biomarkers, whereas the AHEI and aMED scores were associated with significantly lower concentrations of most biomarkers. The RFS was significantly associated with a lower concentration of E-selectin only. C-reactive protein concentrations were 30% (P < 0.05) and 24% (P < 0.05) lower in the top than in the bottom quintile of the AHEI and of the aMED, respectively Higher AHEI and aMED scores were associated with lower concentrations of biomarkers of inflammation and endothelial dysfunction and therefore may be useful as guidelines for reducing the risk of diseases involving such biological pathways.

Total antioxidant capacity of the diet is inversely and independently related to plasma concentration of high-sensitivity C-reactive protein in adult Italian subjects

Inflammation, a risk factor for cardiovascular disease, is associated with low plasma levels of antioxidant vitamins. In addition to vitamins, other antioxidants modulate the synthesis of inflammatory markers in vitro and contribute to the total antioxidant capacity (TAC) of a diet. However, the relationship between dietary TAC and markers of inflammation has never been evaluated in vivo. We investigated the relationship between dietary TAC and markers of systemic (high-sensitivity C-reactive protein (hs-CRP), leucocytes) and vascular (soluble intercellular cell adhesion molecule-1) inflammation in 243 non-diabetic subjects. General Linear Model (GLM) analysis showed a significant (P=0.005) inverse relationship between hs-CRP and quartiles of energy-adjusted dietary TAC, even when recognized modulating factors of inflammation, namely alcohol, fibre, vitamin C, alpha-tocopherol, beta-carotene, BMI, waist circumference, HDL-cholesterol, hypertension, insulin sensitivity and plasma beta-carotene, were included in the model as covariates (P=0.004). The relationship was stronger for subjects with hypertension (P=0.013 v. P=0.109 for normotensive individuals). Among dietary factors, TAC was significantly higher (5.3 (sd 3.0) v. 4.9 (sd 2.7) mmol Trolox/d; P=0.026) in subjects with low plasma hs-CRP (range: 0.0-4.1 mg/l) than in subjects with high plasma hs-CRP (range: 4.2-27.8 mg/l). We conclude that dietary TAC is inversely and independently correlated with plasma concentrations of hs-CRP and this could be one of the mechanisms explaining the protective effects against CVD of antioxidant-rich foods such as fruits, whole cereals and red wine. This could be of particular significance for subjects with high blood pressure.

On‐line Hemodiafiltration Does Not Induce Inflammatory Response in End‐stage Renal Disease Patients: Results From a Multicenter Cross‐over Study

On-line hemodiafiltration (HDF) represents the supreme blood purification modality for end-stage renal disease (ESRD) patients. Large-volume infusion of on-line prepared substitution fluid may, however, expose patients to inflammatory contaminants. As a result, on-line HDF might aggravate chronic inflammation, which correlates with malnutrition, cardiovascular disease, and mortality among ESRD patients. In a multicenter cross-over study, 27 ESRD patients were randomly assigned to treatment with on-line HDF and low-flux hemodialysis (HD). After 6 months, patients were crossed to the other treatment modality, and treatment continued for another 6 months. Both on-line HDF and low-flux HD were conducted with polysulfone membranes and ultrapure dialysis fluid. Samples were drawn at the end of each treatment period. Inflammatory parameters were elevated in the study population when compared to healthy controls. Induction of interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor alpha (TNF-alpha) was comparable for on-line HDF and low-flux HD, and there was no intradialytic increase in cytokine production. As a result, interleukin-6 (IL-6) plasma levels did not differ significantly between the two treatment modalities. Similarly, no difference between on-line HDF and low-flux HD was observed for C-reactive protein (CRP) and albumin. Markers of endothelial cell activation (soluble intercellular and vascular cell adhesion molecules sICAM-1 and sVCAM-1) as well as the cardiovascular risk marker cardiac troponin T (cTnT) remained elevated compared to healthy subjects, but showed no difference between the two treatment modalities. On-line HDF, as the most effective renal replacement therapy, does not provoke inflammatory response and is both safe and highly biocompatible.

Protocatechuic aldehyde suppresses TNF-α-induced ICAM-1 and VCAM-1 expression in human umbilical vein endothelial cells

Adhesion molecules, which play a crucial role in the development of atherogenesis, are produced by endothelial cells following stimulation with various inflammatory cytokines. The current studies examined the effect of a potent water-soluble antioxidant, protocatechuic aldehyde (derived from the Chinese herb, Salvia miltiorrhiza), on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs) stimulated with tumor necrosis factor-α (TNF-α). Protocatechuic aldehyde appeared to specifically downregulate the TNF-α-induced cell surface expression of vascular adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on HUVECs as well as the release of soluble VCAM-1and ICAM-1 from HUVECs in a dose–response manner at pharmacologically relevant concentrations (0.15–1.35 mM). We also observed a dose-dependent lowering of mRNA expression of VCAM-1 and ICAM-1 in the presence of protocatechuic aldehyde. Furthermore, protocatechuic aldehyde (0.15, 0.45, and 1.35 mM) notably inhibited TNF-α-induced upregulation of U937 cell adhesion to HUVECs to 83.7%, 60.9%, and 40.8%, respectively. A gel shift assay further showed that protocatechuic aldehyde inhibited the TNF-α-activated NF-κB and AP-1 DNA binding activities in a dose-dependent manner. Collectively, these results indicate that protocatechuic aldehyde inhibits TNF-α-stimulated VCAM-1 and ICAM-1expression in HUVECs through a mechanism that involves NF-κB and AP-1.

Inflammatory and redox responses to ischaemia/reperfusion in human skeletal muscle.

The objective of this study was to identify cellular and plasma marker(s) of post-I/R (ischaemia/reperfusion) in patients undergoing elective knee surgery where a tourniquet was used to facilitate a bloodless surgical field. We evaluated the inflammatory and redox response by measuring the mRNA levels of ICAM-1 (intercellular cell-adhesion molecule-1), MnSOD (manganese superoxide dismutase), GST-mu (glutathione transferase-mu) and Cu/ZnSOD (copper/zinc superoxide dismutase) in the operated muscle and blood cells pre-operatively (pre-tourniquet) and at various times after reperfusion (tourniquet release). We also measured plasma concentrations of IL (interleukin)-6, IL-8, sICAM-1 (soluble ICAM-1), IL-1beta and TNF-alpha (tumour necrosis factor-alpha) using ELISA. Our results show a strong induction of MnSOD and GST-mu in granulocytes (but not in mononuclear cells or muscle) after reperfusion (2 and 4 h). There was no change in the mRNA level of Cu/ZnSOD after reperfusion. An up-regulation of membrane ICAM-1 in muscle and a decrease in sICAM-1 in plasma were detected after reperfusion. Plasma IL-6 and IL-8 levels (but not TNF-alpha or IL-1beta) increased significantly over baseline at 2 and 4 h after reperfusion. Elevated expression of ICAM-1 in muscle, MnSOD and GST-mu in granulocytes and increased levels of plasma IL-6 and IL-8 may be considered as phase- and cell-specific markers of post-I/R of skeletal muscle in humans.

Weight loss leads to reductions in inflammatory biomarkers after a very-low-carbohydrate diet and a low-fat diet in overweight men

In recent years, it has become apparent that low-grade vascular inflammation plays a key role in all stages of the pathogenesis of atherosclerosis. Weight loss has been shown to improve blood inflammatory markers; however, it is unknown if weight-loss diets varying in macronutrient composition differentially affect inflammatory responses. The primary purpose of the present study was to compare a very-low-carbohydrate diet and a low-fat weight-loss diet on inflammatory biomarkers in overweight men. In a randomized cross-over design, 15 overweight men (body fat, >25%; body mass index, 34 kg/m2) consumed two experimental weight-loss diets for two consecutive 6-week periods: a very-low-carbohydrate diet (<10% energy via carbohydrate) and a low-fat diet (<30% energy via fat). Both the low-fat and the very-low-carbohydrate diets resulted in significant decreases in absolute concentrations of hsTNF-alpha (high-sensitivity tumour necrosis factor-alpha), hsIL-6 (high-sensitivity interleukin-6), hsCRP (high-sensitivity C-reactive protein) and sICAM-1 (soluble intercellular cell-adhesion molecule-1). There was no significant change in absolute sP-selectin (soluble P-selectin) concentrations after either diet. Normalized inflammatory values represented as the delta change per 1 kg reduction in body mass showed a significant difference between the two diets only for sP-selectin (P<0.05). In summary, energy-restricted low-fat and very-low-carbohydrate diets both significantly decreased several biomarkers of inflammation. These data suggest that, in the short-term, weight loss is primarily the driving force underlying the reductions in most of the inflammatory biomarkers.