Intracellular Adhesion Molecule-1 Levels Research Articles

Role of Hydrogen Sulfide in the Development of Atherosclerotic Lesions in Apolipoprotein E Knockout Mice

We explored the effect of hydrogen sulfide (H(2)S) on atherosclerotic progression, particularly on intracellular adhesion molecule-1 (ICAM-1) in apolipoprotein-E knockout (apoE(-/-)) mice and human umbilical vein endothelial cells (HUVECs). ApoE(-/-) mice were treated with sodium hydrosulfide (NaHS) or DL-propargylglycine (PPG); HUVECs were pretreated with NaHS. Compared with control mice, apoE(-/-) mice showed decreased plasma H(2)S level and aortic H(2)S production but increased plasma ICAM-1 and aortic ICAM-1 protein and mRNA. Compared with apoE(-/-) mice, apoE(-/-)+NaHS mice showed increased plasma H(2)S level, but decreased size of atherosclerotic plaque and plasma and aortic ICAM-1 levels, whereas apoE(-/-)+PPG mice showed decreased plasma H(2)S level but enlarged plaque size and increased plasma and aortic ICAM-1 levels. NaHS suppressed ICAM-1 expression in tumor necrosis factor (TNF)-alpha-treated HUVECs. NaHS inhibited IkappaB degradation and NF-kappaB nuclear translocation in HUVECs treated with TNF-alpha. The vascular CSE/H(2)S pathway was disturbed in apoE(-/-) mice. H(2)S exerted an antiatherogenic effect and inhibited ICAM-1 expression in apoE(-/-) mice. H(2)S inhibited ICAM-1 expression in TNF-alpha-induced HUVECs via the NF-kappaB pathway.

The effect of simvastatin on the serum monocyte chemoattractant protein-1 and intracellular adhesion molecule-1 levels in diabetic rats

Objective This study aimed to observe the effect of simvastatin on the serum monocyte chemoattractant protein-1 (MCP-1) and intracellular adhesion molecule-1 (ICAM-1) levels and to probe its protective mechanisms on macroangiopathy in diabetic rats. Methods Twenty-four Wistar rats were randomly assigned to a normal control group (Group A, n=8), and STZ-induced diabetic group (Group B, n=8), or a simvastatin-treated diabetic group (Group C, n=8). Rats in Group C were treated with simvastatin (20 mg kg −1 day −1) 1 week after the establishment of the diabetic model. Groups A and B were treated with corresponding sodium chloride. Peripheral blood glucose was tested weekly; serum MCP-1, ICAM-1, and HbA1c levels were tested at the eighth week. Results At the second, fourth, and eighth week, peripheral blood glucose levels in Group B were similar to those of Group C, which were much higher than those of Group A. Serum MCP-1 and ICAM-1 levels in Groups B and C were higher than those of Group A ( P<.01), and serum MCP-1 and ICAM-1 levels in Group C were lower than those of Group B ( P<.01); HbA1c was not significantly different between Group C and Group B. Conclusion Simvastatin has the effect of anti-inflammation, which may play some protection against the progress of atherosclerosis in diabetic rats.

Globular adiponectin induces adhesion molecule expression through the sphingosine kinase pathway in vascular endothelial cells

The signaling pathways that couple adiponectin receptors to functional, particularly inflammatory, responses have remained elusive. We report here that globular adiponectin induces endothelial cell activation, as measured by the expression of adhesion proteins such as vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin and MCP-1, through the sphingosine kinase (SKase) signaling pathway. Treatment of human umbilical vein endothelial cells with globular adiponectin resulted in NF-κB activation and increased mRNA levels of VCAM-1, ICAM-1, E-selectin and MCP-1. Sphingosine 1-phosphate (S1P), but not ceramide or sphingosine, was a potent stimulator of adhesion protein expression. As S1P is generated from sphingosine by SKase, we treated cells with siRNA for SKase to silence the effects of S1P in the endothelial cells. Treatment with SKase siRNA inhibited globular adiponectin-induced NF-κB activation and markedly decreased the globular adiponectin-induced mRNA levels of adhesion protein. Thus, we demonstrated that the SKase pathway, through the generation of S1P, is critically involved in mediating globular adiponectin-induced endothelial cell activation.

Membrane-type 1-Matrix Metalloproteinase Regulates Intracellular Adhesion Molecule-1 (ICAM-1)-mediated Monocyte Transmigration

We examined the mechanism regulating intercellular cell adhesion molecule-1 (ICAM-1)-dependent monocyte transendothelial migration. Monocyte migration through endothelial cells expressing ICAM-1 alone was comparable to that of tumor necrosis factor-alpha-treated cells. Transmigration was reduced in ICAM-1 lacking the cytoplasmic tail and in tyrosine to alanine substitutions at Tyr-485 and Tyr-474. Tissue inhibitors of matrix metalloproteinases (TIMPs) -2 and -3 blocked transmigration, whereas TIMP-1 was ineffective. This profile suggested a role for membrane-type matrix metalloproteinases (MT-MMPs) in transmigration. Inhibitory antibodies and small interference RNA directed against MT1-MMP blocked transmigration, whereas overexpression of MT1-MMP in endothelial cells or monocytes promoted transmigration. MT1-MMP mediated the ectodomain cleavage of ICAM-1 that was blocked by TIMP-2 and -3. Overexpression of MT1-MMP rescued function in ICAM-1Y485A, and to a lesser extent in the cytoplasmic tail-deleted ICAM-1. In a binding assay, wild-type ICAM-1 bound to purified MT1-MMP while ICAM-1 mutants bound poorly. MT1-MMP co-localized with ICAM-1 at distinct structures in endothelial cells. MT1-MMP localization with cells expressing ICAM-1 mutations was reduced and diffused. These results indicate that the cytoplasmic tail of ICAM-1 regulates leukocyte transmigration through MT1-MMP interaction.

Smoking Is Associated With Epicardial Coronary Endothelial Dysfunction and Elevated White Blood Cell Count in Patients With Chest Pain and Early Coronary Artery Disease

Smoking is a major risk factor for cardiovascular events. One of the potential mechanisms may be related to both coronary endothelial dysfunction and increased inflammatory response. The present study was designed to test the hypothesis that smoking is associated with epicardial coronary endothelial dysfunction and inflammation. Coronary endothelial function in response to acetylcholine was assessed in 881 patients (115 current smokers and 766 nonsmokers, including 314 previous smokers). Smokers were significantly younger than nonsmokers (43+/-1 versus 51+/-1 years, P<0.0001), had more epicardial vasoconstriction in response to intracoronary acetylcholine (-19+/-2% versus -14+/-1% change in coronary artery diameter, P=0.03), and were more likely than nonsmokers to have epicardial endothelial dysfunction (46% versus 35%, P=0.005), but their microvascular endothelial function was intact. Smokers had higher white blood cell counts than nonsmokers (7.7+/-0.2 versus 6.6+/-0.1x10(9)/L, P<0.0001), higher myeloperoxidase (156+/-19 versus 89+/-8 ng/mL), higher lipoprotein-associated phospholipase A2 (242+/-12 versus 215+/-5 ng/mL), and higher levels of intracellular adhesion molecule (283+/-14 versus 252+/-5 ng/mL). There were no differences in the levels of C-reactive protein, fibrinogen, or vascular cell adhesion molecule between the groups. Young smokers are characterized by epicardial coronary endothelial dysfunction, preserved microvascular endothelial function, and increased levels of inflammatory biomarkers and oxidative stress. The present study provides further information regarding the potential mechanisms by which smoking contributes to cardiovascular events.

Bevacizumab: the evidence for its clinical potential in the treatment of nonsmall cell lung cancer

Lung cancer is the leading cause of cancer-related mortality. Platinum-based chemotherapy is the usual first-line treatment for advanced nonsmall cell lung cancer (NSCLC), although an efficacy plateau has been reached with this approach. Bevacizumab is a recombinant, humanized, monoclonal antibody to vascular endothelial growth factor, which inhibits tumor angiogenesis and is being evaluated as a different mechanism to improve outcomes in patients with stage IIIB/stage IV (metastatic) NSCLC. To review the emerging evidence for the potential use of bevacizumab in stage IIIB/IV NSCLC. Adding bevacizumab to carboplatin plus paclitaxel improves response rates and significantly prolongs time to disease progression, which translates into a significant extension of overall survival (median 2.3 months in one key study). Low levels of intracellular adhesion molecule-1 are associated with better response. Preliminary evidence suggests that combining bevacizumab with erlotinib could improve outcomes in patients relapsing following platinum-based chemotherapy. Episodes of bleeding (particularly pulmonary hemorrhage) are the predominant adverse events associated with bevacizumab, probably a result of tumor disintegration. There is limited evidence that the high acquisition cost of bevacizumab unfavorably affects assessment of its cost effectiveness, although there are few other treatment options in these patients with poor prognosis. The encouraging results obtained with bevacizumab in patients with NSCLC are leading to its adoption in some treatment guidelines. Emerging evidence indicates improved outcomes when bevacizumab is added to carboplatin/paclitaxel in previously untreated patients with NSCLC, and when used with erlotinib in patients who have relapsed following platinum-based chemotherapy.

Age and dose sensitivities in the 2-butoxyethanol F344 rat model of hemolytic anemia and disseminated thrombosis

In hemolytic disorders, such as sickle cell disease and β-thalassemia, the mechanisms of thrombosis are poorly understood. Appropriate animal models would increase the understanding of the pathophysiology of thrombosis. We previously reported that rats exposed to 2-butoxyethanol (2-BE) developed hemolytic anemia and disseminated thrombosis resembling sickle cell disease and β-thalassemia. To characterize our model further, we investigated age- and dose-related differences in sensitivity to 2-BE. We exposed groups of 6- and 12-week-old F344 rats (5 animals/group) to 62.5, 125, and 250 mg/kg/day of 2-BE for up to 4 days. Blood was collected on days 2–4 for complete blood count and measurement of intracellular adhesion molecule-1 (ICAM-1). Histopathological evaluation was performed to find evidence of disseminated thrombosis. The maximum hemolytic response, resulting in decreased erythrocyte count and higher mean cell volume (MCV) occurred in the 12-week-old rats treated with the highest dose of 2-BE (250 mg/kg, p<0.0001). The highest increase in ICAM-1 levels occurred in the 12-week-old rats treated with 125 and 250 mg/kg 2-BE ( p<0.0001). No intravascular thrombi were noted in the 6-week-old 2-BE-treated animals. The majority of intravascular thrombi occurred in the 12-week-old rats treated with 250 mg/kg 2-BE. Because our findings show age- and dose-related sensitivities, we suggest that 12-week-old rats and doses of 250 mg/kg be used in the 2-BE model.

PROTECTION AGAINST PSEUDOMONAS AERUGINOSA PNEUMONIA AND SEPSIS-INDUCED LUNG INJURY BY OVEREXPRESSION of β-DEFENSIN-2 IN RATS

Beta-defensin-2 (BD-2), a small cationic antimicrobial peptide, was first described to be an inducible defensin at the epithelial surfaces. In vitro studies have demonstrated that it may play a pivotal role in the anti-inflammatory immune response in addition to its antimicrobial activity. The purpose of this study was to evaluate the effect of overexpression of BD-2 on lung injury to crudely investigate whether the function of BD-2 in the lung attributed to both antimicrobial action and modulation of the immune response. Recombinant adenovirus carrying an expression cassette of rat BD-2 or control adenovirus carrying empty vector was administered intratracheally to Sprague-Dawley rats 48 h before performing acute lung injury, which was induced either by Pseudomonas aeruginosa infection or by cecal ligation and double puncture (2CLP). In vivo antimicrobial activity of BD-2, histological changes of the lungs in both infectious and 2CLP models, pulmonary intracellular adhesion molecule-1 protein level, as well as the 7-day survival rate in the latter model were determined. Amounts of the P. aeruginosa in the lung with BD-2 overexpression were significantly lower compared with that in controls (2.87+/-0.76x10(4) colony-forming units [CFU]/mL vs. 2.49+/-0.74x10(6) CFU/mL, P<0.05). Overexpression of BD-2 reduced alveolar damage, interstitial edema, and infiltration of neutrophils in both models. Furthermore, in the 2CLP model, recombinant BD-2 not only significantly decreased protein levels of intracellular adhesion molecule-1 in lung tissue at 24, 36, and 72 h after 2CLP (P<0.05), but also significantly improved the survival of rats (P<0.05). The CFU of abdominal bacteria was comparable to that in the control rats (P>0.05). Therefore, overexpression of BD-2 protects against P. aeruginosa pneumonia and 2CLP-induced lung injury based on its antimicrobial and anti-inflammatory activities, respectively. Modulating the expression level of BD-2 may serve as an approach to attenuate lung injury.

Elevation of monocyte-derived microparticles in patients with diabetic retinopathy

Diabetic retinopathy is associated with microvascular damage and capillary occlusions which are common features of the microangiopathy in diabetes. Monocyte-derived microparticles (MDMPs) are released from activated monocytes and enhance the procoagulant activity, and also activate adhesion reactions. These are key events in the development of capillary occlusion. The MDMPs level in the blood, and platelet activation markers (platelet-derived microparticles (PDMPs), CD62P and CD63) were measured by flow cytometry in 72 diabetic patients. The plasma levels of intracellular adhesion molecule-1 (ICAM-1) and P-selectin were analyzed by ELISA. The level of MDMPs was significantly correlated with the levels of PDMPs ( r = 0.52, P < 0.001), CD62P ( r = 0.37, P = 0.001), CD63 ( r = 0.31 and P = 0.007), P-selectin ( r = 0.38, P = 0.001), and ICAM-1 ( r = 0.31, P = 0.009). The MDMPs level increased with the progression of the diabetic retinopathy: 81 ± 14/10 4 platelets (plts) in patients without retinopathy ( n = 10); 88 ± 8/10 4 plts with mild or moderate non-proliferative diabetic retinopathy (NPDR, n = 12); 95 ± 8/10 4 plts with severe NPDR ( n = 24); and 112 ± 9/10 4 plts with proliferative diabetic retinopathy (PDR) ( n = 26). The MDMPs level in patients with areas of capillary occlusion (123 ± 10/10 4 plts, n = 25) was significantly higher than that in patients without areas of capillary occlusion (84 ± 5/10 4 plts, n = 25; P = 0.0008). These correlations suggest that increased levels of MDMPs may accelerate the progression of diabetic retinopathy.

Dietary glutamine supplementation reduces cellular adhesion molecule expression and tissue myeloperoxidase activity in mice with gut-derived sepsis

Objectives This study investigated the effects of glutamine (Gln) on plasma intracellular adhesion molecule-1 levels and leukocyte integrin (CD11a/CD18 and CD11b/CD18) expressions in gut-derived sepsis. Myeloperoxidase (MPO) activities in organs were also analyzed to identify the extent of tissue injury resulting from neutrophil infiltration. Methods Mice were randomly assigned to a normal group (NC), a control group, or a Gln group. The NC group was fed standard chow diet; the control group was fed a common semipurified diet; and the Gln group received a diet in which part of the casein was replaced by Gln, which provided 25% of total amino acid nitrogen. After 3 wk, sepsis was induced by cecal ligation and puncture (CLP) in the control and Gln groups. Mice in the experimental groups were killed at 0, 6, 12, and 24 h after CLP. Mice in the NC group were killed when CLP was performed. Blood and organ samples were collected for further analysis. Results Plasma intracellular adhesion molecule-1 levels were significantly lower in the Gln group than in the control group at 6, 12, and 24 h after CLP. Expressions of lymphocyte CD11a/CD18 were significantly higher, whereas polymorphonuclear lymphocyte expressions of CD11b/CD18 were lower in the Gln group than in the corresponding control group at 6 and 12 h after CLP. In comparisons of MPO activities in various organs, the Gln group had lower MPO activities at 6 and 12 h in the lung, at 6, 12, and 24 h in the liver, at 12 and 24 h in the kidneys, and at 12 h in the intestine than those in the control group. Conclusions Results of this study demonstrate that a Gln-supplemented enteral diet increased lymphocyte CD11a/CD18 expressions, whereas neutrophil CD11b/CD18 expressions, circulating intracellular adhesion molecule-1 levels, and MPO activities in various organs decreased with gut-derived sepsis. These findings suggest that, under septic conditions, Gln administration may enhance lymphocyte function, attenuate interactions between polymorphonuclear lymphocytes and endothelium, and thus may decrease neutrophil infiltration into tissues.

14: Dynamic changes in plasma ICAM and VWF levels in primary graft dysfunction after lung transplantation

The role of upregulation in intracellular adhesion molecule (ICAM) in the pathogenesis of experimental lung injury has been recognized, and Von Willebrand Factor antigen (VWF) has been suggested as a marker of acute lung injury. We hypothesized that plasma levels of ICAM and VWF levels would be elevated in PGD after lung transplant.

DIETARY ARGININE ENHANCES ADHESION MOLECULE AND T HELPER 2 CYTOKINE EXPRESSION IN MICE WITH GUT-DERIVED SEPSIS

This study investigated the effects of arginine (Arg) on cellular adhesion molecules and intracellular Th1/Th2 cytokine expressions in mice with polymicrobial sepsis. Myeloperoxidase activity in organs was also analyzed to identify the extent of tissue injury resulting from neutrophil infiltration. Mice were randomly assigned to a normal group (NC), a control group, or an Arg group. The NC group was fed a standard chow diet. The control group was fed a common semipurified diet, and in the Arg group, part of the casein was replaced by Arg, which provided 2% of the total calories. After 3 weeks, sepsis was induced by cecal ligation and puncture (CLP) in the control and Arg groups. Mice in the experimental groups were sacrificed at 0, 6, 12, and 24 h after CLP, whereas mice in the NC group were sacrificed when the CLP was performed. Blood and organ samples were immediately collected for further analysis. Results showed that compared with the control group, plasma intracellular adhesion molecule-1 levels were significantly higher in the Arg group 12 and 24 h after CLP. Lymphocyte interferon-gamma expression in the Arg groups was significantly lower, whereas interleukin (IL)-4 expression was higher than the control group at various time points after CLP. The expression of lymphocyte CD11a/CD18 was significantly higher in the Arg group 6, 12, and 24 h after CLP than those of the corresponding control group and the NC group. PMN expressions of CD11b/CD18 in the Arg groups were higher than those in the control group at 12 and 24 h after CLP. The Arg group had higher IL-6 levels at 6 and 12 h in the kidney and intestine and 12 h in the lung after CLP. Higher myeloperoxidase activities were observed in the Arg groups at 24 h after CLP than those in the control group in various organs. These findings suggest that pretreatment with an Arg-supplemented diet enhances adhesion molecule and inflammatory cytokine expression during sepsis, which may aggravate the inflammatory reaction and increase neutrophil infiltration into tissues. In addition, Arg supplementation reduced intracellular interferon-gamma and enhanced IL-4 expression. This change may promote the Th2-type response and suppress the cellular immune response in gut-derived sepsis.

Vascular Endothelial Growth Factor And Soluble Adhesion Molecules As A Diagnostic Markers For Spontaneous Bacterial Peritonitis In Cirrhotic Liver Disease

Spontaneous bacterial peritonitis (SBP) is a frequent and severe complication in cirrhotic patients with ascites that usually results in renal failure and death despite the efficacy of the current antibiotic therapy. The aim of this study was determine serum and ascitic fluid of soluble-L selectin (s-L Selectin), intracellular adhesion molecule-1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1) and vascular endothelial growth factor (VEGF) in cirrhotic patients, and to search for a relationship between them and SBP. This study was performed on 30 cirrhotic patients with SBP. Their ages ranged (from 38- 55 years) with mean of (32 + 5.5), 30 cirrhotic patients with non-infected ascites; their ages ranged (from 30-52 years) with mean of (35 + 6.5). This group considered as cirrhotic control group and 20 healthy control subjects their ages ranged (from 28-55 years) with mean of (30 + 7.5). Serum and ascitic fluid of adhesion molecules as well as VEGF levels were significantly higher in cirrhotic patients with SBP as well as cirrhotic patients with non-infected ascites as compared to healthy control group. There were significant increase in serum and ascitic fluid level of leukocyte, PMN and ICAM-1 in SBP as compared to cirrhotic with non-infected ascites. There was non-significant decrease in serum and AF level of VEGF in cirrhotic control group as compared to SBP group. The ascitic fluid PMN and s-L Selectin were higher in culture positive SBP patients particularly in those with gram positive isolates, where these are non-significant increase in serum and ascitic fluid level of VEGF in culture positive SBP than culture negative cases. Positive correlation was found between serum and ascitic fluid level of ICAM-1 in SBP and non-infected cirrhotic group. Also, positive correlation was found between VEGF levels in serum ascetic fluid levels in both cirrhotic groups (SBP and non-infected cirrhotic group). These data suggest that: Significant elevated level of VEGF in both SBP and non infected cirrhotic patient may have pathophsiological consequences of local regulation of vascular tone and endothelial permeability, significant elevated level of adhesion molecules in both SBP and non-infected cirrhotic patients are due to inflammatory response and endothelial cell activation. Serum and ascetic fluid of ICAM-1 can be used as useful marker for diagnosis of SBP and for monitoring the treatment of cirrhotic patients.

Access to exercise and its relation to cardiovascular health and gene expression in laboratory animals

The interaction between genes and environment can influence cardiovascular disease (CVD). This 16 month study investigated if genes associated with cardiovascular (CV) regulation were expressed differently in animals having: 1) no access to physical activity or exercise (SED), 2) access to hour-long, twice weekly activity (PA), and 3) access every-other-day to a running wheel (EX). Out of 31,000 genes, a CV subset comprising 44 genes was investigated. Ten genes from this subset were expressed differently in EX compared with SED, and 34 genes were expressed differently in PA compared with SED ( p < 0.05). Total cholesterol (70 ± 8 vs. 101 ± 9 mg dl − 1 ), triglycerides (104 ± 8 vs. 127 ± 4 mg dl − 1 ), resting systolic blood pressure (130 ± 3 vs. 141 ± 3 mmHg), mean arterial pressure (110 ± 2 vs. 120 ± 2 mmHg) and heart rate (380 ± 6 vs. 405 ± 9 beats min − 1 ) were lower in EX compared with SED ( p < 0.05), but intracellular adhesion molecule levels did not differ among groups. Mean gene expressions for Gja1, Fdft1, Edn1, Cd36, and Hmgb2 differed in animals according to access to physical activity. These genes play roles in heart rate, cholesterol biosynthesis, blood pressure, cell adhesion, and transcription and neurogenesis regulation, respectively. In conclusion, a total of 44 CV genes were expressed differently in SED compared to PA and EX; and SED showed more physiological evidence of CVD.

Porphyromonas gingivalis strain-dependent activation of human endothelial cells.

Porphyromonas gingivalis is an important bacterium involved in periodontal diseases. Colonization by periodontopathogens has been associated with severe local inflammatory reactions in the connective tissue. In this study we characterized P. gingivalis-mediated infection and activation of human umbilical vein endothelial cells by using two strains of different virulence capacities, strains ATCC 53977 and DSMZ 20709. Both strains were able to adhere to and infect endothelial cells with an infection rate of 0.48% for ATCC 53977 and 0.007% for DSMZ 20709. The triggering of two signal transduction pathways in P. gingivalis-infected endothelial cells was demonstrated for both strains, with a rapid increase of p38 mitogen-activated protein kinase phosphorylation and a more delayed degradation of IkappaBalpha, followed by nuclear translocation of NF-kappaB. In addition, both strains induced enhanced expression of endothelial adhesion molecules E-selectin and intracellular adhesion molecule 1 (ICAM-1). Target cell activation was independent of bacterial fimbriae expression since the fimA knockout strain A7436 DeltafimA induced the same level of ICAM-1 as the corresponding wild type (A7436-WT). Thus, two P. gingivalis strains, ATCC 53799 and DSMZ 20709, infect endothelial cells and trigger signaling cascades leading to endothelial activation, which in turn may result in or promote severe local and systemic inflammation.

Mechanism of topical glucocorticoid treatment of hay fever: IL-5 and eosinophil activation during natural allergen exposure are suppressed, but IL-4, IL-6, and IgE antibody production are unaffected

Background: Allergic rhinitis is traditionally defined as an IgE- and mast cell–mediated hypersensitivity reaction. Allergen challenge models suggest that cytokines and eosinophil mediators may also play roles. However, the causal relationship among inflammatory cells, their products, and patients’ symptoms during natural allergen exposure has not been established. Objective: We sought to elucidate the mechanisms of seasonal allergic rhinitis and the beneficial effects of topical glucocorticoids. Methods: Thirty patients with ragweed-induced hay fever and a strongly positive serologic test response for ragweed IgE antibody received budesonide nasal spray or placebo in a randomized, parallel, double-blind study. Nasal wash fluids and sera were collected before and during the hay fever season. The levels of inflammatory mediators and allergen-specific immunoglobulins were measured by immunoassay. The activation markers on blood eosinophils were quantitated by flow cytometry. Results: Compared with placebo-treated patients, budesonide-treated patients had strikingly reduced symptoms. In the placebo group, nasal symptoms correlated with nasal lavage fluid eosinophil-derived neurotoxin and IL-5 levels. At the season peak, the budesonide-treated group had significantly lower nasal fluid eosinophil-derived neurotoxin, IL-5, and soluble intracellular adhesion molecule-1 levels. In the treated group eosinophil expression of CD11b was suppressed at the season peak. In contrast, levels of IL-4 and IL-6 in nasal fluid and the seasonal increases in serum ragweed-specific IgE and nasal fluid IgA antibodies did not differ between groups. Conclusion: Eosinophilic inflammation plays a critical role in seasonal allergic rhinitis symptoms. One of the therapeutic effects of glucocorticoids is to suppress this inflammation. (J Allergy Clin Immunol 2000;106:521-9.)

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

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

Plasma soluble intercellular adhesion molecule-1 levels in coronary circulation in patients with unstable angina

It has been suggested that active inflammation plays an important role in the pathogenesis of acute coronary syndromes, including unstable angina. Intracellular adhesion molecule-1 (ICAM-1) is a major ligand on the endothelial cells for adherence of the activated polymorphonuclear leukocytes. Recently, it has been demonstrated that the soluble form of ICAM-1 has been detected in human serum and has been increased in many other inflammatory or autoimmune disorders. To evaluate the involvement of ICAM-1 in unstable angina, we examined plasma soluble ICAM-1 (sICAM-1) levels in coronary circulation. The plasma sICAM-1 levels in the coronary sinus and aortic root were simultaneously examined in 20 patients with unstable angina, 19 patients with stable exertional angina, and 16 control subjects. The plasma levels of sICAM-1 were measured by enzyme-linked immunosorbent assay. The mean plasma sICAM-1 levels (nanograms per milliliter) both in the coronary sinus and aortic root were significantly higher (p <0.01) in patients with unstable angina than in those with stable exertional angina and in control subjects (217 ± 14 vs 126 ± 8; 120 ± 10 in the coronary sinus, 202 ± 13 vs 125 ± 9; 123 ± 10 in the aortic root). Furthermore, the mean value was higher in the coronary sinus than in the aortic root in patients with unstable angina. There were no significant differences in the values between in the coronary sinus and aortic root in patients with stable exertional angina and control subjects. Thus, sICAM-1 release is increased, especially in coronary circulation in unstable angina.

Increased release of the soluble form of the adhesion molecules L-selectin and ICAM-1 but not E-selectin during attacks of angina pectoris.

Myocardial ischemia leads to the activation of neutrophils as well as endothelial cells. The interaction between these cells is dependent on certain adhesion glycoproteins which are expressed on their surface. Adhesion of neutrophils to endothelium, mediated by adhesion molecules, has been shown to result in coronary capillary plugging and impairment of coronary blood flow. In certain conditions, upon cell activation, adhesion proteins may be released in soluble form into the circulating blood. The purpose of our study was to verify whether myocardial ischemia occurring during angina episodes results in the release of the soluble adhesion molecules, L-selectin, E-selectin, and intracellular adhesion molecule-1 (ICAM-1), into the circulation. Plasma samples were collected by venepuncture from 15 patients admitted to the emergency room with chest pain caused by attacks of angina pectoris and 15 patients with noncardiac chest pain. To confirm the diagnosis, all patients underwent an exercise stress test and, if not conclusive, 99mTc MIBI SPECT or coronary arteriography. Another set of plasma samples were taken from each patient in the absence of chest pain. In addition, blood for analysis was obtained from 15 sex-and age-matched healthy subjects. Soluble adhesion molecules plasma levels were measured by standard enzyme-linked immunosorbent assay. In patients with angina pectoris, plasma levels of soluble L-selectin estimated during chest pain were significantly higher than in the control group and decreased in the absence of chest pain. Similarly, the mean concentration of soluble ICAM-1 at the time of angina onset was significantly elevated in the patients in comparison with the control group and remained higher, although not significantly, in the absence of chest pain. In patients with noncardiac chest pain, plasma levels of soluble L-selectin did not differ significantly from those observed in control subjects. In this group of patients, the plasma levels of soluble ICAM-1 estimated during pain onset and in the absence of this symptom were not significantly elevated. On the contrary, the mean values of soluble E-selectin in the patients with ischemic cardiac pain during chest pain and in the absence of this symptom, as well as those in the patients with noncardiac chest pain during or without symptoms, remained unchanged in comparison with the control group. During attacks of angina pectoris an increase in the plasma levels of the soluble adhesion molecules, ICAM-1 and L-selectin, was noted, possibly reflecting activation of neutrophils and endothelial cells during myocardial ischemia. However, E-selectin plasma levels remained unchanged in response to myocardial ischemia.

Progressive vascular damage in hypertension is associated with increased levels of circulating P-selectin.

To assess whether increased shedding of adhesion molecules in plasma provides an index for endothelial damage in hypertension. Three groups of hypertensive patients with increasing severity of vascular damage were studied: 20 essential hypertensives, 21 atherosclerotic, renovascular hypertensives and four malignant hypertensives. Twenty healthy subjects were included as a control group. Levels of P-selectin, E-selectin, intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor in venous blood were measured, using sandwich-type enzyme-linked immunosorbent assay. For essential hypertensives a trend for increased P-selectin and E-selectin values compared with those in controls was observed (159+/-44 versus 132+/-40 ng/ml, P = 0.062 and 40+/-13 versus 34+/-17 ng/ml, P = 0.055, respectively). P-selectin (210+/-84 ng/ml, P = 0.0021) and E-selectin (42+/-12 ng/ml, P = 0.012) levels in renovascular hypertensives were significantly higher than those in healthy controls. There were no significant increases in circulating levels of intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor either in essential hypertensives or in renovascular hypertensives. Marked increases in circulating levels of adhesion molecules and von Willebrand factor relative to those in controls were observed in malignant hypertensives (P-selectin 634+/-332 versus 132+/-40 ng/ml, P = 0.0004; vascular cell adhesion molecule 968+/-187 versus 493+/-139 ng/ml, P = 0.0004; and von Willebrand factor 259+/-75 versus 130+/-72 U/dl, P = 0.016). Progression of vascular damage in essential, renovascular and malignant hypertension is associated with a rise in circulating levels of P-selectins and, to a lesser extent, E-selectins, whereas levels of intracellular adhesion molecule 1, vascular cell adhesion molecule and von Willebrand factor are elevated only in diseases associated with acute severe vascular damage, including malignant hypertension. Our data suggest that selectins may be useful as indicators of vascular damage in hypertension.