Introduction
Delirium is a frequent and serious complication of cardiac surgery. However, the knowledge regarding pathogenesis of postoperative delirium is limited.
Objectives
To investigate whether ...increased levels of monocyte chemoattractant protein-1 (MCP-1) and hyper-sensitive C-Reactive Protein (hsCRP) are associated with postoperative delirium in cardiac surgery patients.
Methods
Patients were examined and screened for major depressive disorder (MDD) and cognitive impairment one day preoperatively, using the Mini International Neuropsychiatric Interview and The Mini-Mental State Examination Test. Blood samples were collected pre- and postoperatively for hsCRP and chemokine levels. Following surgical interventions, the Confusion Assessment Method for the Intensive Care Unit and the Memorial Delirium Assessment Scale with the cut-off score 10 were used to diagnose delirium.
Results
Postoperative delirium screening was found positive in 34% (61 of 177) of patients. Both, pre- and postoperative hsCRP, and preoperative MCP-1 levels were associated with postoperative delirium in univariate comparisons; p=0.001; p=0.0004; p < 0.001, respectively. However, according to a multivariate stepwise logistic regression analysis only MCP-1 concentration raised before surgery was independently associated with postoperative delirium, and related to advancing age of participants (Spearman’s Rank Correlation 0.192; p=0.0103). According to ROC analysis, the most optimal cut-off for MCP-1 concentration in predicting the development of delirium was 371.81 ng/ml with sensitivity of 77.0% and specificity of 58.6%.
Conclusions
The present study suggests that raised preoperative MCP-1 concentration is independently associated with delirium after cardiac surgery. Preoperative monitoring of pro-inflammatory markers combined with regular surveillance may be helpful in the prediction and early detection of postoperative delirium in this patient group.
Introduction
Coronary-artery bypass graft (CABG) surgery is known to improve cardiac function and decrease mortality, albeit, this method of treatment is associated with a high risk of postoperative ...delirium. The pathophysiology of delirium after cardiac surgery is largely unknown.
Objectives
To investigate whether oxidative stress reflected by decreased preoperative and postoperative plasma antioxidant capacity (AC) is independently associated with delirium after cardiac surgery. Furthermore, to assess whether the association between AC and the level of soluble receptor for advanced glycation end-products (sRAGE) exists.
Methods
The patients were examined 1 day preoperatively with the Mini International Neuropsychiatric Interview and MMSE test to screen for depression, anxiety disorders, and for cognitive impairment, respectively. Blood samples for AC and sRAGE levels were collected both preopertively and postoperatively. The CAM ICU and MDAS were used within the first 5 days postoperatively to screen for a diagnosis of delirium.
Results
Postoperative delirium developed in 34% (61 of 177) of participants. Multivariate stepwise logistic regression analysis revealed that patients with low baseline AC are at significantly increased risk of developing delirium. Moreover, preoperative AC levels were inversly correlated with postoperative sRAGE concentrations (Spearman’s Rank Correlation -0.198; p<0.05). The most optimal cutoff values of the preoperative and postoperative AC that predict the development of delirium were 1.720 mM and 1.893 mM, respectively.
Conclusions
Decreased plasma AC levels are associated with delirium after cardiac surgery and inversly correlated with post-surgery sRAGE concentration. This may be an important pathophysiological consideration in the increased risk of postoperative delirium seen in cardiac surgery patients.
Despite the absence of endogenous chitin in humans, chitinases are present in the serum of healthy subjects and their levels are increased in a variety of chronic inflammatory conditions. It has been ...shown that chitotriosidase and structurally related chitinase-like protein-YKL-40 contribute to the pathogenesis of COPD. However, details regarding the relation of their systemic and local airways levels remain unknown.
To examine peripheral blood and sputum chitotriosidase and YKL-40 expression in smokers and patients with COPD.
Forty patients with COPD, 20 healthy smokers and 10 healthy never-smokers were studied. Serum and induced sputum chitotriosidase protein and activity levels, YKL-40 concentrations, and their gene expression in sputum cells and peripheral blood mononuclear cells (PBMC) were evaluated.
Both chitotriosidase protein levels and activity were higher in sputum obtained from COPD subjects compared to healthy never-smokers (
<0.05 and
<0.01, respectively). A similar pattern was observed for PBMC chitotriosidase mRNA expression (
<0.001). YKL-40 serum concentrations were elevated in healthy smokers and COPD subjects compared to healthy never-smokers (
<0.001 and
<0.01, respectively). In sputum, YKL-40 levels were increased in COPD compared to healthy never-smokers (
<0.01). PBMC YKL-40 mRNA expression was increased in COPD and healthy smokers compared to healthy never-smokers (
<0.0001). No associations were found between chitotriosidase or YKL-40 peripheral blood levels and sputum levels.
Our results demonstrate that chitotriosidase and YKL-40 are overexpressed in peripheral blood and airways in both healthy smokers and COPD subjects which may indicate smoking-related activation of macrophages, neutrophils, and epithelial cells.
PAI-1 is a multifunctional protein stimulated by infectious agents and its activation is mediated by inflammatory cytokines such as TNFα. Recent studies demonstrate that natriuretic peptides, ...particularly C-type (CNP), can affect PAI-1 expression in bovine aortic smooth muscle cells and rat aortic endothelial cells. We have previously shown that CNP inhibits both basal and TNFα induced expression of PAI-1 in human endothelial cells. Herein, we describe mechanism by which CNP modulates signaling engaged in controlling PAI-1 expression in human endothelial cells. To examine which pathway initiated by TNFα is influenced, we tested kinase activity of MAP, PI3K/AKT and involvement of cGMP in endothelial cells exposed to CNP. CNP significantly increased cGMP level in endothelial cells. Its analogue, 8-Br-cGMP alone had no effect but significantly inhibited TNFα induced expression of PAI-1. Similarly, CNP and the inhibitors of ERK1/2 (PD098059) and PI3K (LY294002) attenuated PAI-1 expression induced by TNFα. CNP almost abolished TNFα induced phosphorylation of ERK1/2 but did not affect JNK phosphorylation, indicating that its effect on ERK1/2 was specific. These data suggest that CNP might function as the natural defense of vascular wall against cytokine induced PAI-1 release through its ability to inactivate PI3K/AKT and MEK/ERK pathways.
Angiogenesis, new blood vessel formation, is a multistep process, precisely regulated by pro-angiogenic cytokines, which stimulate endothelial cells to migrate, proliferate and differentiate to form ...new capillary microvessels. Excessive vascular development and blood vessel remodeling appears in psoriasis, rheumatoid arthritis, diabetic retinopathy and solid tumors formation. Thalidomide α-(
N-phthalimido)-glutarimide is known to be a potent inhibitor of angiogenesis, but the mechanism of its inhibitory action remains unclear. The aim of the study was to investigate the potential influence of thalidomide on the several steps of angiogenesis, using in vitro models. We have evaluated the effect of thalidomide on VEGF secretion, cell migration, adhesion as well as in capillary formation of human endothelial cell line EA.hy 926. Thalidomide at the concentrations of 0.01 μM and 10 μM inhibited VEGF secretion into supernatants, decreased the number of formed capillary tubes and increased cell adhesion to collagen. Administration of thalidomide at the concentration of 0.01 μM increased cell migration, while at 10 μM, it decreased cell migration. Thalidomide in concentrations from 0.1 μM to 10 μM did not change cell proliferation of 72-h cell cultures. We conclude that anti-angiogenic action of thalidomide is due to direct inhibitory action on VEGF secretion and capillary microvessel formation as well as immunomodulatory influence on EA.hy 926 cells migration and adhesion.
Proteome analysis of human umbilical endothelial cells was performed to identify proteins that are modified during vascular endothelial cell growth factor (VEGF)‐induced transition from the quiescent ...into the proliferating‐migrative phenotype. Subtractive analysis of two‐dimensional gel patterns of human endothelial cells, before and after stimulation with VEGF165, revealed differences in 85 protein spots. All proteins were identified by peptide sequencing and peptide mass fingerprinting using an electrospray spectrometer. The proteins identified were members of specific families including Ca2+‐binding proteins, fatty‐acid binding proteins, structural proteins, and chaperones. Remarkably, there was a massive activation of cellular machinery for both protein synthesis and protein degradation. Thus, among up‐regulated proteins there were members of all groups of heat shock proteins (HSPs; HSP 27, HSP 60, HSP 70p5, HSP 70p8, HSP 90, and HSP 96) and some other proteins showing either chaperone activity or which participate in assembly of multimolecular structures (TCP‐1, desmoplakins, junction plakoglobin, GRP 94, thioredoxin related protein, and peptidylprolyl isomerase). The increased expression of HSPs was confirmed at the mRNA level at different stages of treatment with VEGF. Similarly, components of the proteolytic machinery for the degradation of misfolded proteins (ER‐60, cathepsin D, proteasome subunits, and protease inhibitor 6) were also up‐regulated. On the other hand, changes in the expression of structural proteins (T‐plastin, vimentin, α tubulin, actin, and myosin) could account, at least in part, for the different morphologies displayed by migrating endothelial cells. In summary, our data show that VEGF levels similar to those during physiological stresses induce a number of genes and multiple endogenous pathways seem to be engaged in restoring cellular homeostasis. To ensure cell survival, the molecular chaperones (the heat shock family of stress proteins) are highly up‐regulated providing protein‐folding machinery to repair or degrade misfolded proteins.
Plasma concentrations of natriuretic peptides increase in some pathological conditions, but very little is known about the effect of these vasodilator peptides on the regulation of the blood ...coagulation system. The fundamental role in the regulation of fibrinolysis is played by plasminogen activator inhibitor type 1 (PAI-1). Recent studies demonstrate that natriuretic peptides can modulate PAI-1 expression in bovine aortic smooth muscle cells and rat aortic endothelial cells. In this report, we tested the effect of natriuretic peptides on PAI-1 expression in the human endothelial cell line (EA.hy 926). For this purpose, we treated the cell cultures with ANP, BNP and CNP, and modulation of PAI-1 synthesis was evaluated. We compared the effect of natriuretic peptides on synthesis and release of PAI-1 in unstimulated cells, and after activation with tumour necrosis factor alpha (TNFalpha). Natriuretic peptides abolished TNFalpha - induced upregulation of PAI-1 expression at both the PAI-1 mRNA and the antigen levels. The inhibitory efficiency was higher in the case of CNP when compared to that produced by ANP and BNP, particularly when TNFalpha-stimulated cells were used. We observed an inhibition of stimulatory effect of TNFalpha on PAI-1 expression also at the level of the PAI-1 promoter in cells transfected with a PAI-1 promoter fragment (+71 to -800). The PAI-1 promoter activity was markedly inhibited by C-type natriuretic peptide, already at a very low (0.001 micro M) concentration of the peptide.
PDF
