Soluble ICAM-1 Levels Research Articles

247-OR: Positive Effects of Bariatric Surgery Are Associated with Attenuation of Cellular Senescence

Bariatric surgery represents the most efficient approach to treatment of obesity; however, the detailed mechanism of its positive metabolic effect is still not fully understood. Cellular senescence arrests the cell cycle in damaged cells thus preventing further spreading of the damage. Persistence of senescent cells especially in adipose tissue can, however, contribute to the development of a number of chronic diseases including obesity and its complications. Reduction of adipose tissue after bariatric surgery can therefore reduce the number of senescent cells and their negative effects on organism. 17 patients with obesity (2nd grade and higher) scheduled for bariatric surgery (sleeve gastrectomy) were included into the study. Subcutaneous (SAT) adipose tissue and plasma were collected during and 6 months after surgery. The analysis of samples included RT-qPCR (mRNA transcription in SAT) and ELISA or Luminex for detection of hormones and proteins from plasma. Our results show that bariatric surgery reduces the amount of senescent cells in adipose tissue, which results in the decrease of oxidative stress and inflammation, partially also by reduced recruitment of pro-inflammatory macrophages. In addition, we detected lower plasma levels of soluble E-selectin and ICAM-1, molecules enhancing cardiovascular damage known to be produced by senescent cells, as well as decreased expression of ACE2, whose increased expression was detected in senescent cells. Importantly, we also observed decreased expression of ADAM17 responsible for producing a soluble form of ACE2, a newly identified predictor of cardiovascular damage. In conclusion, reduction of senescent cells in adipose tissue after bariatric surgery contributes to improvement of inflammation and metabolic parameters in patients with obesity and decreases the risk of cardiovascular complications. Disclosure S.Stemberkova hubackova: None. T.Havrlantova: None. I.Simonik: None. M.Mraz: None. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. Funding Czech Health Science Foundation (NU22-01-00096); Programme EXCELES (LX22NPO5104); Czech Ministry of Health (IKEM, IN00023001)

Genetically determined deficiency of ANGPTL3 does not alter HDL ability to preserve endothelial homeostasis

Individuals with loss-of-function mutations in the ANGPTL3 gene express a rare lipid phenotype called Familial Combined Hypolipidemia (FHBL2). FHBL2 individuals show reduced plasma concentrations of total cholesterol and triglycerides as well as of lipoprotein particles, including HDL. This feature is particularly remarkable in homozygotes in whom ANGPTL3 in blood is completely absent. ANGPTL3 acts as a circulating inhibitor of LPL and EL and it is thought that EL hyperactivity is the cause of plasma HDL reduction in FHBL2. Nevertheless, the consequences of ANGTPL3 deficiency on HDL functionality have been poorly explored. In this report, HDL isolated from homozygous and heterozygous FHBL2 individuals were evaluated for their ability to preserve endothelial homeostasis as compared to control HDL. It was found that only the complete absence of ANGPTL3 alters HDL subclass distribution, as homozygous, but not heterozygous, carriers have reduced content of large and increased content of small HDL with no alterations in HDL2 and HDL3 size. The plasma content of preβ-HDL was reduced in carriers and showed a positive correlation with plasma ANGPTL3 levels. Changes in composition did not however alter the functionality of FHBL2 HDL, as particles isolated from carriers retained their capacity to promote NO production and to inhibit VCAM-1 expression in endothelial cells. Furthermore, no significant changes in circulating levels of soluble ICAM-1 and E-selectin were detected in carriers. These results indicate that changes in HDL composition associated with the partial or complete absence of ANGPTL3 did not alter some of the potentially anti-atherogenic functions of these lipoproteins.

Brain capillary obstruction during neurotoxicity in a mouse model of anti-CD19 chimeric antigen receptor T-cell therapy.

Immunotherapy for haematologic malignancies with CD19-directed chimeric antigen receptor T cells has been highly successful at eradicating cancer but is associated with acute neurotoxicity in ∼40% of patients. This neurotoxicity correlates with systemic cytokine release syndrome, endothelial activation and disruption of endothelial integrity, but it remains unclear how these mechanisms interact and how they lead to neurologic dysfunction. We hypothesized that dysfunction of the neurovascular unit is a key step in the development of neurotoxicity. To recapitulate the interaction of the intact immune system with the blood–brain barrier, we first developed an immunocompetent mouse model of chimeric antigen receptor T-cell treatment-associated neurotoxicity. We treated wild-type mice with cyclophosphamide lymphodepletion followed by escalating doses of murine CD19-directed chimeric antigen receptor T cells. Within 3–5 days after chimeric antigen receptor T-cell infusion, these mice developed systemic cytokine release and abnormal behaviour as measured by daily neurologic screening exams and open-field testing. Histologic examination revealed widespread brain haemorrhages, diffuse extravascular immunoglobulin deposition, loss of capillary pericyte coverage and increased prevalence of string capillaries. To measure any associated changes in cerebral microvascular blood flow, we performed in vivo two-photon imaging through thinned-skull cranial windows. Unexpectedly, we found that 11.9% of cortical capillaries were plugged by Day 6 after chimeric antigen receptor T-cell treatment, compared to 1.1% in controls treated with mock transduced T cells. The capillary plugs comprised CD45+ leucocytes, a subset of which were CD3+ T cells. Plugging of this severity is expected to compromise cerebral perfusion. Indeed, we found widely distributed patchy hypoxia by hypoxyprobe immunolabelling. Increased serum levels of soluble ICAM-1 and VCAM-1 support a putative mechanism of increased leucocyte–endothelial adhesion. These data reveal that brain capillary obstruction may cause sufficient microvascular compromise to explain the clinical phenotype of chimeric antigen receptor T-cell neurotoxicity. The translational impact of this finding is strengthened by the fact that our mouse model closely approximates the kinetics and histologic findings of the chimeric antigen receptor T-cell neurotoxicity syndrome seen in human patients. This new link between systemic immune activation and neurovascular unit injury may be amenable to therapeutic intervention.

Porcine scabies induces marked apoptosis, increased pro‐inflammatory cytokines IL‐1, TNF‐α and shedding of ICAM‐1

Scabies is one of the leading causes of morbidity in pigs worldwide. Limited data are available regarding the role of immune reactions in the development of porcine scabies. The aim of this study was to investigate key pro-inflammatory cytokines (IL-1, TNF-α), soluble variant of adhesion molecule ICAM-1 and mite-mediated apoptosis of peripheral leukocytes in 20 pigs with scabies, in addition to 10healthy controls. The pigs with at least three typical clinical signs and found positive for Sarcoptes scabiei var. suis in microscopy were recruited for the present study. IL-1 acted as the major pro-inflammatory cytokine as serum IL-1 concentrations showed significantly (p<.05) higher levels (7-fold increase) in cases than in controls. The minor cytokine TNF-α was 4-fold higher during scabies, and its mean serum concentration was significantly increased (p<.05) in cases when compared to healthy controls. Soluble ICAM-1levels were significantly higher (p<.05) in all the pigs of infested group compared with the controls. The percentage of apoptotic and necrotic leukocytes was found to be significantly higher (p<.05) in scabies positive pigs as compared to the healthy controls. It is concluded that systemic elevation in pro-inflammatory cytokines IL-1 and TNF-α, shedding of soluble ICAM-1 variant in peripheral blood and increased rate of host-cell apoptosis in peripheral leukocytes might be implicated in the immunopathology of naturally acquired porcine scabies.

Identification of IL-18 and Soluble Cell Adhesion Molecules in the Gingival Crevicular Fluid as Novel Biomarkers of Psoriasis.

Psoriasis is a chronic immunoinflammatory skin disease. Although its diagnosis is clinical, differences in the appearance and severity of lesions pose a challenge for clinicians worldwide. The use of accessible biomarkers for psoriasis could aid in the early diagnosis and treatment of the disease. To date, evidence on the analysis of gingival crevicular fluid (GCF) molecules as novel, accessible, and reliable biomarkers for psoriasis is limited. This cross-sectional study compared the GCF levels of IL-18, soluble (s)ICAM-1, and sE-selectin in psoriatic patients (n = 42) and healthy controls (n = 39). Individuals with psoriasis not undergoing treatment and healthy individuals were included independent of periodontal status. GCF samples were collected, and a multiplex bead immunoassay was performed to quantify the levels of the target molecules. Psoriatic patients presented higher concentrations of IL-18 and lower concentrations of sE-selectin compared to controls (p < 0.05). No differences were found in the levels of sICAM-1 between the two groups (p > 0.05). Psoriasis was associated with IL-18 and E-selectin levels regardless of periodontal status, age, and smoking habit (p < 0.05). The areas under the receiver operating characteristic curve (ROC) for IL-18 and sE-selectin were 0.77 and 0.68, respectively. In conclusion, IL-18 and sE-selectin levels in the GCF could be promising biomarker for psoriasis.

Persistent Hyperactivation of Endothelial Cells in Patients with Alcoholic Hepatitis.

Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up-regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM-1, VCAM-1, and VEGF-A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkerswith and without AH. ELISA and multiplex immunoassays were used to measure soluble EC activationmarkers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6-month follow-up, and 18 AH patients and 25 HDC at 12-month follow-up. At baseline, the 4 soluble markers were significantly up-regulated in AH patients compared with HDC and HC, whereas only sVCAM-1 was elevated in HDC relative to HC. At follow-ups, plasma levels of CD146, VCAM-1, and VEGF-A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several solubleinflammatory factors. The levels of soluble CD146, ICAM-1, VCAM-1, and VEGF-A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities.

Lower Interferon Regulatory Factor-8 Expression in Peripheral Myeloid Cells Tracks With Adverse Central Nervous System Outcomes in Treated HIV Infection.

Cognitive dysfunction persists in 30–50% of chronically HIV-infected individuals despite combination antiretroviral therapy (ART). Although monocytes are implicated in poor cognitive performance, distinct biological mechanisms associated with cognitive dysfunction in HIV infection are unclear. We previously showed that a regulatory region of the interferon regulatory factor-8 (IRF8) gene is hyper-methylated in HIV-infected individuals with cognitive impairment compared to those with normal cognition. Here, we investigated IRF-8 protein expression and assessed relationships with multiple parameters associated with brain health. Intracellular IRF-8 expression was measured in cryopreserved peripheral blood mononuclear cells from chronically HIV-infected individuals on ART using flow cytometry. Neuropsychological performance was assessed by generating domain-specific standardized (NPZ) scores, with a global score defined by aggregating individual domain scores. Regional brain volumes were obtained by magnetic resonance imaging and soluble inflammatory factors were assessed by immunosorbent assays. Non-parametric analyses were conducted and statistical significance was defined as p < 0.05. Twenty aviremic (HIV RNA<50 copies/ml) participants, 84% male, median age 51 [interquartile range (IQR) 46, 55], median CD4 count 548 [439, 700] were evaluated. IRF-8 expression was highest in plasmacytoid dendritic cells (pDCs). Assessing cognitive function, lower IRF-8 density in classical monocytes significantly correlated with worse NPZ_learning memory (LM; rho = 0.556) and NPZ_working memory (WM; rho = 0.612) scores, in intermediate monocytes with worse NPZ_LM (rho = 0.532) scores, and in non-classical monocytes, lower IRF-8 correlated with worse global NPZ (rho = 0.646), NPZ_LM (rho = 0.536), NPZ_WM (rho = 0.647), and NPZ_executive function (rho = 0.605) scores. In myeloid DCs (mDCs) lower IRF-8 correlated with worse NPZ_WM (rho = 0.48) scores and in pDCs with worse NPZ_WM (rho = 0.561) scores. Declines in IRF-8 in classical monocytes significantly correlated with smaller hippocampal volume (rho = 0.573) and in intermediate and non-classical monocytes with smaller cerebral white matter volume (rho = 0.509 and rho = 0.473, respectively). IRF-8 density in DCs did not significantly correlate with brain volumes. Among biomarkers tested, higher soluble ICAM-1 levels significantly correlated with higher IRF-8 in all monocyte and DC subsets. These data may implicate IRF-8 as a novel transcription factor in the neuropathophysiology of brain abnormalities in treated HIV and serve as a potential therapeutic target to decrease the burden of cognitive dysfunction in this population.

Luteolin suppresses inflammation through inhibiting cAMP-phosphodiesterases activity and expression of adhesion molecules in microvascular endothelial cells.

Luteolin, an anti-inflammatory ingredient found in the Chinese herb Folium perillae, can inhibit not only the cyclic adenosine monophosphate (cAMP)-phosphodiesterases (PDEs) activity of neutrophils, but also the expression of lymphocyte function-associated antigen-1 in neutrophils, both of which result in a decrease in the adhesion between neutrophils and microvascular endothelial cells. However, the effect of luteolin on the cAMP-PDEs activity and expression of adhesion molecules in endothelial cells are not clear. In the present study, primary rat pulmonary microvascular endothelial cells and a lipopolysaccharide-induced rat acute pneumonia model were used to explore the role of luteolin on cAMP-PDEs activity, expression of adhesion molecules, and leukocyte infiltration. We demonstrate that rat pulmonary microvascular endothelial cells expressed high levels of cAMP-PDEs, specifically PDE4, and further luteolin exhibited dose-dependent inhibition on the activity of cAMP-PDEs or PDE4 in endothelial cells. Luteolin also had a significant inhibitory effect on the expression of vascular cell adhesion molecule (VCAM)-1, but not intracellular cell adhesion molecule (ICAM)-1 in microvascular endothelial cells. Further, we show that luteolin decreased the levels of soluble ICAM-1 (sICAM-1), but not soluble E-selectin in the serum of rats subjected to acute pneumonia. We also show that luteolin treatment decreased the wet/dry weight ratio of lung tissue and reduced the total number of serum leukocytes in a dose-dependent manner in a rat acute pneumonia model. In conclusion, these results demonstrate that luteolin suppresses inflammation, at least in part, through inhibiting both cAMP-PDEs or PDE4 activity and the expression of VCAM-1 (in vitro) and sICAM-1 (in vivo) in endothelial cells.

Serological inflammatory factors as biomarkers for anatomic response in diabetic macular edema treated with anti-VEGF

PurposeTo study the relationship between systemic pro-inflammatory factors and macular structural response to intravitreal bevacizumab for diabetic macular edema (DME). MethodsProspective study including 30 cases with DME, treated with bevacizumab and a minimum follow-up of 6 months. All cases underwent baseline laboratory testing for cardiovascular risk (high sensitivity C-reactive protein (hsCRP), homocystein), dyslipidemia, renal dysfunction and glucose control. Serum levels of VEGF, soluble ICAM-1, MCP-1 and TNF-α were assessed by enzyme-linked immunosorbent assay kits. Significant associations between systemic factors and quantitative and qualitative spectral-domain optical coherence macular features were analyzed. ResultsA mean of 4.82 ± 0.56 intravitreal injections was performed, resulting in significant improvement of central foveal thickness (CFT) (p < 0.001). A significant association with third month CFT decrease <10% was found for hsCRP (3.33 ± 2.01 vs 1.39 ± 1.15 mg/l, p = 0.007) and ICAM1 (975.54 ± 265.49 vs 727.07 ± 336.09 pg/ml, p = 0.012). ROC curve analysis indicated hsCRP and ICAM1 as significant biomarkers for 3rd month reduced anatomic response (area under the curve (AUC) = 0.807, p = 0.009 for hsCRP; AUC = 0.788, p = 0.014 for ICAM1). ROC curve analysis revealed hsCRP as a significant biomarker for 6th month CFT decrease <10% (AUC = 0.903, p < 0.001, cutoff value = 1.81 mg/l). A significant association with 6th month CFT decrease ≥25% was found for serum MCP1 (244.69 ± 49.34 pg/ml vs 319.24 ± 94.88 pg/ml, p = 0.017) and serum VEGF (90.84 ± 37.33 vs 58.28 ± 25.19 pg/ml, p = 0.027). The combined model of serum VEGF and LDL-cholesterol was found to be predictive of 6th month hard exudate severity (p = 0.001, r2 = 0.463). ConclusionsIncreased levels of hsCRP and ICAM1 were found to be significant biomarkers for early reduced anatomic response to anti-VEGF treatment. Cases with higher serum levels of such factors had increased CFT values, despite treatment, suggesting inner blood-retinal barrier breakdown that is not adequately responsive to anti-VEGF monotherapy.

Microrna 221 Expression By Leukocytes Strongly Correlates with the Clinical Severity of Sickle Cell Disease

Introduction The severity of sickle cell disease (SCD) increases with absolute neutrophil count (ANC, Eur J Haematol. 1998; 60: 267-8) and expression of adhesion molecules by leukocytes (Eur J Haematol. 2002; 69: 135 -144.). Intercellular adhesion molecule 1 (ICAM 1) on vascular endothelium mediates leukocyte adherence to the blood vessel wall. This contributes to vaso-occlusion, the main mechanism of tissue damage in SCD. Micro-RNA 221 (MIR 221) regulates the gene for ICAM-1 (J Cell Science 2011; 124, 999-1006). How the severity of SCD relates with expression of MIR 221 was evaluated in this study.Methods Following IRB approval and informed consent by appropriate persons, 25 healthy HbAA control persons and 73 HbSS patients (45M, 28F; age 2-18 yrs) were consecutively enrolled from University of Nigeria Teaching Hospital, Enugu. Patients who had blood transfusion in the previous 3 months were excluded. Information from medical records and clinical assessment was used to determine the SCD Severity Score according to the system previously validated by Cameron et al (J Nat Med Assoc. 1983; 75: 483-7). This system assigns scores to age at which the first symptom of SCD occurred, number of hospital admissions due to SCD per year, number of painful episodes per year, type of sickle cell crisis, number of major organ complications of SCD, pneumococcal sepsis, and the degree of failure to thrive assessed with patient's height and weight percentiles. A total score up to 4 indicates mild, 5-8 moderate, and 9-21 severe SCD.Absolute neutrophil count (ANC) and Hb level were determined with an automated blood analyser, plasma level of soluble ICAM-1 (sICAM-1) by enzyme-linked immunosorbent assay (ELISA), and expression of MIR 221 in leukocytes by polymerase chain reaction with fluorescent probes to enable quantification. To obtain a composite picture of the relationship between study parameters, 4mls of venous blood from each patient was analysed during vaso-occlusive crisis; and 4 weeks after the crisis had resolved (steady state). To help evaluate the degree of resolution of the crisis and the level of inflammation in each patient, the concentration of C-reactive protein was measured by ELISA in blood samples taken during crisis and steady state. The GraphPad Prism statistical package version 5.03 was used for data analyses. Following D'Agostino and Pearson's Omnibus normality test which showed that the values of MIR 221expression, sICAM 1 concentration, and ANC did not have a normal (Gaussian) distribution, median values and non-parametric tests were used for statistical analyses of these data.Results Based on Cameron Severity Scores, 25 patients had mild, 36 moderate and 12 severe SCD. The mean severity score for all patients was 5.85± 2.31. Median leukocyte MIR-221 of 3,092 copies/5ul of cDNA in steady state was comparable to 3,764 copies/5ul of cDNA in crisis (p = 0.6, Table 1). Both values were significantly higher than the median leukocyte MIR221 of 1428 copies/5ul of cDNA in healthy HbAA controls; P<0.0001. The quantity of MIR221 in leukocytes in mild SCD (median 3092 copies/5ul of cDNA) was significantly different from that in moderate disease (median 4004 copies/5ul of CDNA) which, in turn, differed significantly from that in severe SCD (median 5587 copies/5ul of cDNA, p< 0.05, Kruskal-Wallis Test). Spearman’s correlation coefficient (Rho) between the Cameron Severity Scores in patients with severe SCD and the quantity of MIR 221 in leukocytes during steady state was high at 0.72 (Table 2). The quantity of MIR 221 in leukocytes during steady state emerged as a stronger correlate of SCD severity than ANC (Table 3). As crisis resolved and steady state returned, the inflammatory markers C-reactive protein (Kruskal-Wallis test, p=0.0003) and ANC (Wilcoxon matched pairs test; p<0.0001) reduced.Conclusions The strong correlation between severity of SCD and the quantity of leukocyte MIR 221 in steady state suggests that leukocyte MIR 221 is a candidate biomarker for assessing the severity of SCD. The quantity of MIR 221 in leukocytes, unlike ANC, did not change significantly from crisis to steady state in this study; and could be a more consistent and stronger index of SCD severity than absolute neutrophil count. As a regulator of the gene for ICAM 1 which contributes to leukocyte adhesion and organ damage, the role of MIR 221 in SCD deserves further studies in view of the potential benefit of anti-adhesion therapy. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Parkin regulates lipopolysaccharide-induced proinflammatory responses in acute lung injury

The acute respiratory distress syndrome (ARDS) is a serious condition resulting from direct or indirect lung injury that is associated with high mortality and morbidity. A key biological event in the pathogenesis of the acute lung injury (ALI) that causes acute respiratory distress syndrome is activation of the lung endothelium cells (ECs), which is triggered by a variety of inflammatory insults leading to barrier disruption and excessive accumulation of neutrophils. Recently, we demonstrated that imatinib protects against lipopolysaccharide (LPS)-induced EC activation by inhibiting c-Abl kinase. In the present study, we explored the role of parkin, a novel c-Abl substrate, in ALI. Parkin is an E3 ubiquitin ligase originally characterized in the pathogenesis of Parkinson disease; however, its potential role in acute inflammatory processes and lung EC function remains largely unknown. Using parkin deficient (PARK2-/-) mice, we now demonstrate that parkin mediates LPS-induced ALI. After LPS, PARK2-/- mice have reduced total protein and cell levels in bronchoalveolar lavage (BAL) compared to wild type. Moreover, in LPS-treated PARK2-/- lungs, the sequestration and activation of neutrophils and release of inflammatory cytokines (interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α]) are significantly reduced. The BAL levels of soluble VCAM-1 and ICAM-1 are also decreased in LPS-treated PARK2-/- mice compared to wild type. In cultured human lung endothelial cells, downregulation of parkin by small interfering RNA decreases LPS-induced VCAM-1 expression, IL-8 and IL-6 secretion, and NF-kB phosphorylation. These results suggest a previously unidentified role of parkin in mediating endotoxin-induced endothelial proinflammatory signaling and indicate that it may play a critical role in acute inflammation.

Hypoglycemia and the predisposition to cardiovascular disease: Is the pro-inflammatory-pro-coagulant diathesis a plausible explanation?

Hypoglycemia and the predisposition to cardiovascular disease: Is the pro-inflammatory-pro-coagulant diathesis a plausible explanation?

Alterations in adhesion molecules, pro-inflammatory cytokines and cell-derived microparticles contribute to intima-media thickness and symptoms in postmenopausal women.

Menopause, the cessation of menses, occurs with estrogens decline, low-grade inflammation, and impaired endothelial function, contributing to atherosclerotic risk. Intima-media thickness (IMT) is an early subclinical biomarker of atherosclerosis. Inflammation may have a role on symptoms: hot flashes, anxiety, and depressive mood, which also are related to endothelial dysfunction, increased IMT and cardiovascular risk. In this study we compared several inflammatory markers in early vs. late postmenopausal women and studied the association of IMT and symptoms with these markers in the full sample. In a cross-sectional design including 60 women (53.1±4.4 years old) at early and late postmenopause, we evaluated the expression of CD62L, ICAM-1, PSGL-1, CD11b, CD11c, and IL-8R on PBMC by flow cytometry. Serum soluble ICAM-1, sVCAM-1, sCD62E, sCD62P, CXCL8, IL-1β, IL-6, and TNF-α levels were quantified by ELISA. Plasma levels of microparticles (MPs) were determined by FACS. Finally, carotid intima-media thickness (IMT) was measured by ultrasound. We observed that ICAM-1 expression by lymphocytes and serum sVCAM-1 levels were augmented at late postmenopause. Late postmenopause women with severe hot flashes had increased expression of CD62L and IL-8R on neutrophils. By multivariate analysis, the carotid IMT was strongly associated with membrane-bound TNF-α, CD11b expression, Annexin V+ CD3+ MPs, LPS-induced NO production, HDL-cholesterol and age. Depressive mood was associated negatively with PSGL-1 and positively with LPS-induced NO. Finally, Log(AMH) levels were associated with carotid IMT, IL-8R expression and time since menopause. IMT and depressive mood were the main clinical features related to vascular inflammation. Aging, hormonal changes and obesity were also related to endothelial dysfunction. These findings provide further evidence for a link between estrogen deficiency and low-grade inflammation in endothelial impairment in mature women.

Impact of a high energy diet on obesity-associated immune biomarkers in Sprague Dawley rats (MUC2P.929)

Abstract A trial was designed to examine effects of a high energy diet on obesity-associated biomarkers in Sprague-Dawley (SD) rats. Male rats (n = 176) were fed an AIN93G high-energy diet containing 16% dietary fat for 2 weeks, and segregated into obese-prone and obese-resistant phenotypes. Necropsies of animals displaying the highest (n = 10) and those displaying the lowest weight gain (n = 10) were conducted to examine potential differences in the concentration of immune biomarkers. Adipose, mucosal (ileum, ileal Peyer’s patches, cecum, proximal and distal colon), mesenteric lymph nodes (mln) and systemic (serum, liver, spleen) tissues were comparatively analyzed for cytokine or adipokine profiles. Obese rats had higher levels of leptin (P = 0.0001) and IL-22 (P = 0.059) in the distal colon and higher levels of IL-10 (P = 0.032) and TNF-α (P = 0.016) in the proximal colon compared to their obese-resistant counterparts. In obese-resistant rats, higher levels of CINC-2αβ (P = 0.048) occurred in mesenteric adipose tissue along with higher levels of soluble ICAM-1 (P = 0.018) in the mln. These findings suggest a high energy diet imparted differential effects on mucosal cytokine and adipokine production in colonic and mesenteric tissue between obese-prone and obese-resistant SD rats. Elevated levels of pro-inflammatory and regulatory cytokines are evident as little as 2 weeks after the initiation of a high-energy diet.

Measuring soluble ICAM-1 in African populations.

The level of plasma soluble ICAM-1 (sICAM-1) has been associated with the pathogenesis of several diseases. Previously, a commercial antibody was reported not to recognize an ICAM-1 allele known as ICAM-1kilifi prevalent among African populations. However, that study was based on 19 samples from African Americans of whom 13 had the wild type allele, five heterozygotes and one homozygote. Here, we compare plasma sICAM-1 measures using three different commercial antibodies in samples from Kenyan children genotyped for ICAM-1kilifi allele. We show that two of these antibodies have some degree of deficiency in detecting the ICAM-1kilifi allele. Consideration of the antibody used to measure sICAM-1 is important as up to 30% of the populations in Africa harbour this allele.

Anti-inflammatory Effects of Ischemic Preconditioning on Rat Small Bowel Allografts

IntroductionMinimizing the inflammatory events that follow intestinal transplantation may influence immediate graft function and improve outcome. Ischemic preconditioning (IPc) has been shown to ameliorate early inflammatory responses, and it may also attenuate the potentially damaging inflammation after intestinal transplantation. Herein, we examine the influence of intestinal IPc on inflammatory indices (tissue expression of ICAM-1, CD11a, and CD44 and serum levels of the soluble ICAM-1, sICAM-1) after heterotopic intestinal transplantation. MethodsLewis rats received full-length preconditioned or non-preconditioned Brown Norway intestinal allografts in the absence of immunosuppression. Preconditioned grafts were subjected to 1 cycle of 10 minutes of ischemia-reperfusion. Preconditioned and non-preconditioned isografts acted as controls. Blood was collected on alternate days post-transplant, and graft tissue harvested on sacrifice. ICAM-1, CD44, and CD11a expression was determined by immunohistochemistry, and the area of staining was quantified using image analysis. Serum soluble ICAM-1 levels were determined using an R&D Systems Quantikine enzyme immunoassay. Results(1) IPc ameliorated serum levels of sICAM-1 until severe rejection (day 7) overcame this down-regulation when compared to non-preconditioned allografts (day 3: 34,304 vs 40,479 pg/mL; day 5: 52,441 vs 61,593 pg/mL; day 7: 75,114 vs 73,309 pg/mL; day 9: 72,872 vs 76,314 pg/mL, respectively). (2) ICAM-1 expression was significantly lower in preconditioned allografts (1.02 vs 2.01 mm2). (3) CD44 tissue levels were also found to be lower in preconditioned allografts (0.86 vs 1.13 mm2). (4) There was a significant relationship between tissue ICAM-1 expression and serum levels of soluble ICAM-1 (P < .02). ConclusionsIPc improves inflammatory indices in the early stages following intestinal transplantation, and this might lead to a preserved cellular, architectural, and functional graft status. Furthermore, our results support the use of soluble ICAM-1 as a marker of endothelial activation, and thence of inflammation and developing rejection.

The influence of physical training on endothelial function in patients with stable coronary artery disease.

Endothelial damage is the key factor in the pathophysiology of atherosclerosis. Regular physical activity exerts beneficial direct and indirect effects on, among others, cardiovascular system, locomotor system, lipids, carbohydrate and hormonal balance, maintenance of aproper body weight as well as immunological system. The aim of the study included evaluating the effect of aregular, two-month physical training on endothelial function parameters in patients with stable coronary artery disease. The study involved 61patients after coronary angioplasty, 13women and 48men aged 62.8±8.7years. The control group included 21 subjects aged 63.2±9.7years, 17 of whom had hypertension which was well controlled pharmacologically. Blood for VCAM-1 and ICAM-1 was collected with the subjects remaining for 30min in supine position, through avenous access inserted in the basilica vein. In the patients' group the blood was collected twice, prior to and after aphysical training cycle. In controls the blood was collected once. The investigated groups differ slightly but not in astatistically significant way with regard to the hemodynamic parameters BP 124.4/75.9 vs. 123.4/76.3mmHg, p=ns., HR 66.2±6.8 vs. 68.8±6.3 bpm, p=ns., left ventricular ejection fraction -EF 60.1±7.6 vs. 63.7±5.2 %, p<0.05 and did not differ with regard to the incidence of hypertension or BMI value. The level of soluble ICAM-1 prior to physical training was higher in the investigated group (289.0±97.1 vs. 230.2±47.1ng/mL, p<0.01) and after the training it decreased but remained higher than in control group (252.4±100.8ng/mL, p<0.05. vs. control group). The level of soluble VCAM-1 did not differ initially between the groups, nor did it change significantly after the training. Moderately intense physical training only slightly affects the investigated parameters of the endothelial function in patients with coronary artery disease. Abeneficial effect of training on endothelial function was observed as adecrease of the level of soluble ICAM-1. 8-week, moderately intense physical training is sufficient to cause aclinically significant decrease in arterial blood pressure.

Endotelial activation and flow-mediated vasodilation in young patients with breast cancer

Endothelial activation and dysfunction may play a significant role in the progression of breast cancer. In our study we examined markers of endothelial activation (soluble ICAM-1, P-selectin, E-selectin) in 98 young patients with breast cancer (< 40 years). In 50 of them (and 20 age-matched controls) we also measured flow mediated vasodilation. Patients with breast cancer had significantly higher serum levels of soluble E-selectin, P-selectin and ICAM-1, P-selectin was higher in patients with larger tumors, node involvement and seemed to be apredictor of poor outcome. We were unable to find significant difference in the parameters of flow mediated vasodilation between patients with breast cancer and healthy subjects, although both peak blood flow (PBF) and flow mediated vasodilation (FMD) seemed to be skewed compared to healthy subjects toward mean and lower levels. Cluster analysis enabled us to distinguish several larger groups of patients with different degree of endothelial activation and function and different outcome. Group of patients with high E-selectin, high ICAM-1 (higher endothelial activation) and low VEGF (putative endothelial damage) had more frequently negative estrogen receptors and had worse outcome compared to the group of patients with lower E-selectin, lower ICAM-1 and mostly positive estrogen receptors. Further studies of larger groups of patients should help to identify the panel of endothelial markers which could help in predicting the outcome of young patients with breast cancer.

High Plasma Levels of Soluble Intercellular Adhesion Molecule (ICAM)-1 Are Associated with Cerebral Malaria

BackgroundCerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM-1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM.Methodology/Principal FindingsPaediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p<0.0037). Median levels of antibodies to CD36-binding VSA were comparable in the two groups at the time of admission and 7 days after treatment was initiated (p>0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups.Conclusions/SignificanceHigh levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies to parasite expressing non-ICAM-1-binding VSAs were not.

The Cytokine and Chemokine Profiles in Patients with Hand, Foot and Mouth Disease of Different Severities in Shanghai, China, 2010

Background and purposeSystemic upregulation of inflammatory cytokines is characteristic of critical severe hand, foot, and mouth disease (HFMD) with pulmonary edema. Thus, immunomodulatory medicines such as steroids, including methylprednisolone, have been proposed to treat patients with severe HFMD in China, because it is postulated that inflammatory cytokines play a role in the development of severe complications. This study is to further investigate the inflammatory response in the relatively mild HFMD patients, and whether steroid treatment has a beneficial effect on the suppression of inflammation in HFMD patients.MethodWe measured the levels of 50 kinds of chemokines, cytokines, growth factors and soluble receptors in serum samples from control patients without HFMD and the HFMD patients with or without prior treatment of intravenous methylprednisolone.ResultsOur present study found that even relatively mild HFMD patients without central nervous system (CNS) complications had elevated serum levels of inflammatory cytokines, including interleukin (IL)-3, IL-6, IL-12p40, and tumor necrosis factor (TNF)-α, which suggested systemic inflammation. In contrast, these patients also have decreased levels of other serum biomarkers, including IL-1Ra, IL-8, IL-16, soluble ICAM-1, CXCL-1, and CCL27. The dysregulation of cytokine and chemokine expression may be involved in CNS complications and unbalanced circulating leukocytes in HFMD patients. Surprisingly, patients treated with methylprednisolone had no difference in the expression levels of HFMD-associated biomarkers instead had slightly increased levels of IL-17A, which was not associated with the occurrence of HFMD.ConclusionWhether steroid treatment has any beneficial effect on the prognosis of HFMD patients requires to be further investigated.