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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cognate interactions between human adult microglia and activated T lymphocytes induce the production of inflammatory cytokines. Since this interaction can occur in a non-antigen-dependent manner, it is relevant to a variety of CNS diseases where activated T cells, regardless of specificities, come into contact with microglia; these disorders include multiple sclerosis, trauma, stroke and Alzheimer's disease. A model cell line would facilitate studies of the engagement between T cells and human adult microglia, since the latter are difficult to obtain in substantial quantity or frequency. This study shows that the PMA/IFN gamma-treated U937 cell line shows similarities to microglia in its interaction with activated T lymphocytes, in that the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-10 and IL-12 is induced. Morphological features and mechanisms of cytokine production resemble those observed in microglia--T cell co-cultures since CTLA-4 and CD40--CD40L blockades reduce TNF-alpha and IL-10 levels, while anti-CD23 inhibits IL-10 only in U937--T cell interactions. We propose that PMA/IFN gamma-treated U937 cells can serve as a model of human adult microglia to study cytokine generation in response to interactions with activated T cells.
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PMID:Cytokine production consequent to T cell--microglia interaction: the PMA/IFN gamma-treated U937 cells display similarities to human microglia. 1127 68

The onset of cerebral ischaemia triggers a cascade of proinflammatory molecular and cellular events. Clinical studies suggest that the strength of this acute response is important in early and late clinical outcomes, early clinical worsening, and extent of brain damage. Variables that are predictors of adverse stroke outcome include erythrocyte sedimentation rate, and levels of C-reactive protein (CRP), interleukin-6, tumour necrosis factor-alpha and intercellular adhesion molecule-1. Current data indicate that inflammation serves to fuel atherosclerosis and can act as the link between atherosclerosis and atherothrombosis. Growing evidence indicates that platelets act as prominent players in the inflammatory component of these disease processes. Thus, upon activation, platelets release a series of cytokines and growth factors and express CD40 ligand, which interacts with the CD40 receptor on other major cell types involved in atherosclerosis/atherothrombosis. In healthy volunteers, CD40L expression in platelets is not significantly inhibited by acetylsalicylic acid (ASA) alone, but is inhibited after treatment with the ADP-receptor antagonist clopidogrel or with clopidogrel plus ASA. Of a range of potential inflammatory biomarkers that have been reported in the literature, the best studied is CRP. Such biomarkers may have clinical utility for refined identification of patients at high risk for atherothrombosis in different arterial beds and for monitoring of therapeutic agents in clinical trials.
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PMID:Role of inflammation in stroke and atherothrombosis. 1473 Feb 51

Atherosclerosis is the major cause of cardiovascular disease. Hypercholesterolaemia, hypertension and cigarette smoking are the common risk factors for atherosclerosis. These risk factors unite behind a convergence of mechanism, involving oxidation and inflammation in the artery wall that, with time, gives rise to characteristic fatty-fibrous lesions. Physical trauma and inflammation produce lesion rupture, which can lead to clinical events such as heart attack and stroke, or resolve with plaque growth. Disease progression is marked by the inflammatory indicator CRP (C-reactive protein). Early indicators of heart attack are the inflammatory marker CD40, and the cardiac myofilament protein troponin. Coronary atherosclerosis is the common cause of heart failure (HF). Disordered calcium signalling to the myofilaments occurs in HF and in cardiomyopathy. Enhanced calcium signalling suppresses HF. Neuro-humoral and biomechanical processes, as seen in hypertension, produce cardiac hypertrophy, which predisposes to HF through apoptosis. Although in humans cardiac damage produces permanent loss of cells, because the heart cannot regenerate, developments in stem cell technology suggest that help is at hand.
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PMID:Pathophysiology and biochemistry of cardiovascular disease. 1517 70

The understanding of the pathophysiology governing atherosclerosis supports a prominent role for inflammation pathways in plaque initiation and progression that result in stroke and myocardial infarction. Elevated levels of inflammatory markers in the blood, such as C-reactive protein and CD40 ligand/CD40, in concert with increased expression of adhesion molecules, chemokines, cytokines, matrix metalloproteinases (MMP), and inflammatory cells in the plaque, characterize the symptomatic atherothrombotic state. Advances in predictive capabilities of vascular events using a number of these biomarkers are beginning to remodel our clinical practice in the use of medications such as statins and angiotensin receptor blockers for stroke prevention. Although the general inflammatory features of atherosclerosis are becoming widely recognized, factors resulting in individual variability in plaque formation and instability remain poorly defined. Emerging literature points toward several acquired and innate susceptibility factors in the immune pathways that may provide insight into why many plaques rapidly evolve from a "stable" to an "unstable" or symptomatic state. First, exposure of plaque memory T-lymphocytes to infectious or endogenous antigens may result in rapid clonal expansion of T-cell variable beta chain subtypes and stimulate macrophages to release MMPs, causing plaque destabilization. The effects of infectious agents can further be influenced by an individual's major histocompatibility complex class II molecule profiles, which can affect susceptibility to specific organisms. Second, functional polymorphisms of genes that regulate the immune pathway can predispose patients to a more robust inflammatory expression after risk factor exposure. Identification of a susceptibility gene profile and immunologic mediators that promote T-cell activation provides a unique opportunity for early identification of stroke risk and targets for future therapy.
Stroke 2004 Nov
PMID:Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation. 1547 6

Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported during the last few years in patients with systemic lupus erythematosus (SLE). Studies found relative risks of 5 to 7 for myocardial infarction in SLE patients. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS, in addition prolonged glucocorticoid therapy and long duration of SLE seem to be of importance. The disease SLE per se is an independent risk factor. The current pathogenic hypothesis for atherosclerosis involves an inflammatory response, autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), CD40/CD40 ligand interactions, and bacterial or viral infections responsible for an immune response. The determination of classic and new risk factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis. Therapeutic strategies, including early risk factor intervention and effective control of inflammation, are essential to reduce morbidity and mortality and should be incorporated into the management of connective tissue disease with the goal of protecting patients against atherosclerosis.
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PMID:[Accelerated atherosclerosis in rheumatic systemic diseases as an example of systemic lupus erythematosus--what is the consequence?]. 1590 83

Atherosclerosis (AT) is a metabolic, systemic inflammatory/immune disease characterized by lipoproteins metabolism alteration that leads to immune/inflammatory system activation with the consequent proliferation of smooth-muscle cells, narrowing arteries and atheroma formation. Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombophilic state and circulating antiphospholipid antibodies (aPL) including anti beta2-GPI. Experimental studies and human observations suggest that APS is associated with AT. In fact, innate and adaptive immune responses participate in the pathogenesis of both diseases. Anti-oxLDL, anti-aPL, anti beta2GPI, anti-HSP antibodies, among others, has been found in patients with APS and AT. Endothelial dysfunctions, oxidative stress, increase of cell adhesion molecules, active platelets, are common findings in both diseases. Macrophages, dendritic cells, T-cell activation, CD40-CD40 ligand interaction, are considered as pathogenic mechanism of AT and APS. Premature AT may be the first symptom of APS. Thrombophilia, aPL antibodies, and APS may be present in patients with premature AT. An association between AT and venous thrombosis (a clinical hallmark of APS) has been proposed in unselected patients with deep venous thrombosis of the legs without symptomatic AT. Asymptomatic AT, defined in terms of carotid intima media thickness and lumen diameter decrease, was observed in patients with APS. Premenopausal female patients with PAPS have a higher prevalence of cerebrovascular disease in comparison with male patients. Accelerated AT and hormones could be the explanation of these findings. High levels of aCLs, significantly predict the risk of future ischemic stroke in women but not in men. AT is one of the main features of systemic APS and offer opportunities for new treatment strategies.
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PMID:Systemic antiphospholipid syndrome and atherosclerosis. 1791 89

Microglial cells are the innate immune cells of the central nervous system and quickly respond to injury by proliferation, cytokine release, and increased cell surface antigen expression. Thrombin is a multifunctional serine proteinase, which has the capability to activate microglial cells. Here, we report that pharmaceutical-grade thrombin dose-dependently increases the expression of CD40 in N9 microglial cells. This effect is blocked by a thrombin inhibitor, mimicked by thrombin receptor-activating peptide and modified by mitogen-activated protein kinase pathway inhibitors. Thrombin-induced CD40 regulation might play a role in diseases with breakdown of the blood-brain barrier such as multiple sclerosis or stroke.
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PMID:Thrombin regulates CD40 expression in microglial cells. 1841 52

Leukocytes are recruited into the cerebral microcirculation following an ischemic insult. The leukocyte-endothelial cell adhesion manifested within a few hours after ischemia (followed by reperfusion, I/R) largely reflects an infiltration of neutrophils, while other leukocyte populations appear to dominate the adhesive interactions with the vessel wall at 24 h of reperfusion. The influx of rolling and adherent leukocytes is accompanied by the recruitment of adherent platelets, which likely enhances the cytotoxic potential of the leukocytes to which they are attached. The recruitment of leukocytes and platelets in the postischemic brain is mediated by specific adhesion glycoproteins expressed by the activated blood cells and on cerebral microvascular endothelial cells. This process is also modulated by different signaling pathways (e.g., CD40/CD40L, Notch) and cytokines (e.g., RANTES) that are activated/released following I/R. Some of the known risk factors for cardiovascular disease, including hypercholesterolemia and obesity appear to exacerbate the leukocyte and platelet recruitment elicited by brain I/R. Although lymphocyte-endothelial cell and -platelet interactions in the postischemic cerebral microcirculation have not been evaluated to date, recent evidence in experimental animals implicate both CD4+ and CD8+ T-lymphocytes in the cerebral microvascular dysfunction, inflammation, and tissue injury associated with brain I/R. Evidence implicating regulatory T-cells as cerebroprotective modulators of the inflammatory and tissue injury responses to brain I/R support a continued focus on leukocytes as a target for therapeutic intervention in ischemic stroke.
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PMID:Leukocyte recruitment and ischemic brain injury. 1957 16

Interleukin-6 (IL-6) is produced by neurons, astrocytes, and microglia, and elevated levels of IL-6 within the CNS have been documented in multiple neurological disorders including Alzheimer's disease, stroke, epilepsy, attention deficit disorder, cerebral palsy, and multiple sclerosis. Here, we sought to understand how IL-6 regulates microglial signal transduction and their immune properties. Using highly enriched cultures of neonatal murine microglia we show that IL-6 alone has direct effects on microglia as it activates STAT3 and extracellular signal-regulated kinase pathways in a time- and dose-dependent fashion and it enhances interferon-gamma (IFNgamma)-stimulated IL-12 secretion. However, other immune properties were only weakly modulated by IL-6 when administered without the soluble IL-6 receptor (sIL-6R). For instance, IFNgamma-induced expression of the co-stimulatory molecule, CD40 was dependent on sIL-6R administration. IL-6 with or without sIL-6R did not affect major histocompatability complex class II expression. In granulocyte-macrophage colony-stimulating factor (GMCSF)-induced dendritic cell-like microglia, IL-6/sIL-6R and IFNgamma stimulated an even greater increase in CD40 expression compared with primary microglia. Altogether, our results demonstrate that microglial responses to IL-6 are not simple in that the effects of IL-6 are context-dependent. In particular, the presence or absence of sIL-6R, IFNgamma or GMCSF will alter the type and amplitude of their response.
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PMID:Context-dependent IL-6 potentiation of interferon- gamma-induced IL-12 secretion and CD40 expression in murine microglia. 1971 53

1. CD40 and CD40 ligand (CD40L) have a critical role in the pathophysiology and risk prediction of coronary artery syndrome, including atherothrombosis and atherosclerosis. However, the contribution of the CD40/CD40L dyad, especially the soluble form of CD40L (sCD40L), to the pathophysiology of hypertension and associated organ damage remains unknown. 2. In the present study, serum levels of CD40 and sCD40L were measured in 328 hypertensive patients with varying degrees of organ damage. The data revealed that serum levels of CD40 were significantly greater in patients with severe, but not mild, organ damage compared with patients without any organ damage. There were no significant differences in serum concentrations of sCD40L between patients with no, mild and severe organ damage. Concentrations of soluble CD40 were comparable in patients with mild organ damage that included left ventricular hypertrophy, retinal damage, renal dysfunction and proteinuria. In contrast, concentrations of soluble CD40 were increased significantly in patients with certain forms of severe organ damage, specifically stroke, but not coronary and peripheral artery disease. 3. Collectively, our data indicate that upregulation of the CD40 system in hypertensive patients with certain forms of severe end-organ damage may contribute to the pro-inflammatory, pro-atherogenic and prothrombotic milieu in hypertension.
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PMID:Association between serum levels of soluble CD40/CD40 ligand and organ damage in hypertensive patients. 2045 28


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