UMLS:C0042384 - FACTA Search

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Query: UMLS:C0042384 (vasculitis)
20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In ANCA-associated vasculitis the activation of primed leucocytes by autoantibodies with subsequent release of proteases such as myeloperoxidase (MPO), proteinase 3 (PR3) and elastase is thought to play an important pathogenetic role. Whether these proteases contribute to the vascular lesions by stimulating the procoagulant activity of these cells is unknown. Tissue factor (TF) expression and activity were investigated in human umbilical vein endothelial cells after stimulation with MPO, PR3 and elastase. TF activity was measured using a one-stage clotting assay. Polyclonal antibodies to TF were used to prove specificity. TF mRNA was detected by reverse transcriptase-polymerase chain reaction. PR3 and elastase led to a significant increase in TF mRNA expression and increased activity. The stimulation was not mediated by IL-1. The stimulatory effect of PR3 did not depend on its proteolytic activity (no inhibition by alpha-1-antitrypsin), whereas the effect of elastase was blocked by alpha-1-antitrypsin. MPO had no effect on TF activity. These results show that PR3 and elastase stimulate TF expression in human endothelial cells. In ANCA-associated vasculitis the increased release of proteases may contribute to the development of microthrombi and consecutive necrosis.
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PMID:Endothelial tissue factor stimulation by proteinase 3 and elastase. 1173 80

Despite an increasing incidence of acute sensorineural hearing loss, the pathogenesis of this disease remains uncertain. While viral infection of the stria vascularis, organ of Corti or spiral ganglion cells is discussed in the American literature, a vascular genesis with resulting impaired perfusion of the inner ear is favoured by European investigators. Although both hypotheses are supported by different therapeutic strategies to regain normal hearing, the influence of spontaneous remission remains unclear. This study aims at combining these seemingly opposing concepts with the assumption of an immunologically mediated vasculitis with consequent cochlear hypoperfusion. We already know from other organs that during viral vasculitis circulating immunoglobulins are deposited perivascularly, which leads to a local decrease in perfusion and tissue hypoxia. Also in autoimmune diseases, perivasculitis is common with the endothelium playing a major role at the initial stages of the disease. These endothelial cells promote vasculitis by secreting pro-inflammatory cytokines like IL-1, IL-6 or TNF-alpha in addition to the expression of adhesion molecules. Due to the persistence of these immunopathological mechanisms stenosis or atresia with ischaemic necrosis results. To examine whether this pathomechanism is also important in inner ear dysfunction, the immunological response after stimulation of the cochlear endothelium of guinea pigs was determined. In addition, the influence of corticosteroids on this immune cascade was examined.
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PMID:Pharmacological influence on inner ear endothelial cells in relation to the pathogenesis of sensorineural hearing loss. 1188 64

Vasculitis, inflammation of the vessel wall, can be observed in acute and chronic inflammatory processes, in vascular rejection of allogeneic transplants and can be encountered as primary vasculitis of arterial, arteriolar, capillary and venular vessels. Although the numerous forms of vasculitis and their associations with different diseases result in a multitude of etiologic and pathogenetic factors there are pathogenetic factors common to several vasculitides. These include innate immunity factors, transcription factors such as NFkB, endothelial cytoprotective agents such as NO and anti-neutrophilic cytoplasmic auto-antibodies (ANCA). ANCA may be directed against several antigens, in the majority of cases against proteinase 3 and myeloperoxidase. The complex of proteinase 3 and ANCA leads to an increased expression of CD18, CD14 and an elevated synthesis of cytokines and chemokines such as interleukin 1, interleukin 8 in monocytes. In granulocytes generation of reactive oxygen species is found in addition. In both cells apoptosis finally occurs. ANCA may also bind to a surface glycoprotein (gp130) expressed on glomerular and peritubular endothelia in the kidney. Thus the activation of granulocytes, monocytes and endothelial cells by ANCA may be a critical step in the initiation phases of vasculitis. NO is cytoprotective for endothelial cells in small concentrations. Our group has shown in detailed studies that inhibition of endothelial NO synthase is detrimental and enhancement of activity of endothelial NO synthase is beneficial for allogeneic solid organ transplants. The transcription factor complex NFkB is a key regulatory transcription factor for the expression of genes and proteins associated with acute inflammatory processes and endothelialitis. Inhibition of NFkB activity by a decoy-oligonucleotide prevented activation of endothelial calls in reperfusion injury and vascular rejection. The complement system probably plays an essential role in the initiation and propagation phases of vasculitis. Specifically the pneumococcal C-polysaccharide-reactive protein (CRP), synthesized after trauma and infection, can potently activate the complement cascade which leads to an activation of endothelial cells with increased expression of adhesion molecules. The 4 shortly described pathogenetic mechanisms of vasculitis seem to be important and common factors for the generation and maintenance of vascular inflammation; nevertheless these factors are only part of the spectrum of different humoral and cellular responses in vasculitis. The described experimental investigations on endothelial damage and endothelialitis may lead to new therapeutic strategies in vasculitis.
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PMID:[Vasculitis--aspect of cellular and molecular pathogenesis]. 1189 91

Cytokines are a large family of small proteins secreted by leukocytes and having an essential role in mediating the immune function. Many cytokines have multiple cellular sources and targets, as well as many natural inducers and inhibitors. These features and moreover the functional particularities of cytokines (autocrine and paracrine mode of action, overlapped activities, pleiotropic action, functioning as a complex regulatory network, and reciprocal down-regulation of the Th1 and Th2 cytokine groups) hampered the investigation of cytokines' role in autoimmune diseases (ADs). Despite this, the experimental and clinical studies have firmly documented the implication of cytokines in major pathophysiological and pathogenetic mechanisms associated with both the acute (onset and/or recurrence) and the chronic stages of ADs. The enhanced production of cytokines during the acute phase of systemic lupus erythematosus, rheumatoid arthritis and vasculitis has pathogenic effects such as appearance of anti-neutrophil cytoplasmic antibodies, initiation of vascular thrombosis and/or an increased production of autoantigens. The potent proinflammatory cytokines IL-1 and TNFalpha and also IL-8 and IFNalpha,gamma stimulate cells in different tissues to release harmful proteinases and reactive oxygen species, contributing to tissue damage. Some correlations have been found between serum cytokine levels and disease activity in certain systemic ADs. Studies investigating the cytokine pattern in ADs revealed the prevalence of the proinflammatory Th1-type cytokines in the target organ of patients with organ-specific ADs, such as multiple sclerosis and autoimmune thyroid disease, and heterogeneous cytokine profiles in patients with systemic ADs. A lot of factors, including the mechanism of tissue damage, the type of antigen-presenting cells and costimulatory molecules, and also the hormonal status, favor secretion of cytokines of Th1- or Th2-type in these patients. Beneficial effects have been obtained in patients with rheumatoid arthritis and Crohn disease by administering biotechnologically manufactured anti-TNFalpha antibodies or TNFalpha receptors. The risks of these cytokine-targeting therapeutical interventions are also discussed.
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PMID:Cytokine patterns and pathogenicity in autoimmune diseases. 1552 38

We have established an animal model of coronary arteritis which is histopathologically similar to that observed in cases of Kawasaki disease (KD), is a well-known childhood vasculitis syndrome. Coronary arteritis in this mouse model has been induced by intraperitoneal injection of Candida albicans -derived substances (CADS). Arteritis varied by mouse strain with the highest incidence by 71.1% (27/38) found in C3H/HeN mice, but absent in CBA/JN mice (0%, 0/27), suggesting association of genomic background to develop the disease. The present study aims to elucidate the susceptibility loci associated with coronary arteritis by using this animal model. The association of the onset of arteritis with polymorphic microsatellite markers between the two strains was examined using one hundred and fifteen of N1 backcross progeny [(CBAxC3H)F1xC3H]. Based on our analysis, arteritis-susceptibility loci with suggestive linkage were mapped on D1Mit171 and D1Mit245(map position 20.2 cM) on chromosome 1 (P=0.0019). These loci include several kinds of inflammatory cytokine receptors, such as interleukin 1 receptor and tumor necrosis factor receptor. We also found the cytokine response against CADS, levels of inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6 in sera increased within 24 hr after CADS injection. Our results may indicate based on genomics that ligand-receptor interaction between these inflammatory cytokines and the receptors of these cytokines may affect the onset of arteritis.
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PMID:Susceptibility loci to coronary arteritis in animal model of Kawasaki disease induced with Candida albicans -derived substances. 1572 3

During sepsis, endothelial cells are both a source and target of pro-inflammatory cytokines (e.g. IL-1alpha, IL-1beta, TNFalpha and others), which may be detrimental to vascular homeostasis. Our laboratory has demonstrated that Haemophilus somnus, a gram-negative pathogen of cattle that causes sepsis and vasculitis, and its lipooligosaccharide (LOS) induce caspases-3, -8 and -9 activation, and apoptosis of endothelial cells in vitro. In this study, we provide evidence that H. somnus LOS increases IL-1alpha and IL-1beta mRNA expression, and caspase-1 activation in endothelial cells. Addition of a caspase-1 inhibitor (YVAD), or incubation in a high extracellular potassium buffer (150 mM), reduced caspase-1 activation and significantly enhanced H. somnus LOS-mediated caspase-3 activation. Likewise, blocking the IL-1 type 1 receptor by addition of IL-receptor antagonist (IL-1ra) significantly enhanced LOS-mediated caspase-3 activation. Conversely, addition of exogenous recombinant bovine IL-1beta (100 ng/mL) to endothelial cells diminished LOS-mediated apoptosis. IL-1beta has been reported previously to protect numerous cell types from apoptosis by activating PI3 kinase/p-Akt signaling pathways. Addition of selective PI3 kinase inhibitors (e.g. wortmannin and LY294002) significantly enhanced LOS-mediated caspase-3 activation. Exposure of endothelial cells to IL-1beta or LOS increased pAkt protein as assessed by western blot. Overall, these results suggest that signaling through the IL-1 type 1 receptor diminishes H. somnus LOS-mediated apoptosis.
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PMID:Signaling through interleukin-1 type 1 receptor diminishes Haemophilus somnus lipooligosaccharide-mediated apoptosis of endothelial cells. 1612 94

In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1beta (IL-1beta). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGFbeta) is a potent deactivator of PMN and macrophages since TGFbeta suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGFbeta receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGFbeta receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGFbeta was found to impair the expression of L (leucocyte)-selectin on PMN from control mice but not from mice lacking TGFbeta receptor II. L-selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGFbeta signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearance.
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PMID:TGFbeta receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis. 1689 35

Ulinastatin, a trypsin inhibitor, is useful as a first-line or a second-line treatment regimen including alternative therapy for IVIG-resistant or IVIG nonresponder Kawasaki disease (KD) patients. Mechanisms involving protections against tissue organs and endthelial cell and anti-inflammatory effects by ulinastatin, are dependent on the inhibition of PMN-derived elastase, tumor necrosis factor alpha (TNFalpha), and other proinflammatory cytokines/interleukins(IL-1, IL-6, IL-8). Ulinastatin also suppresses the activation of PMN cells, macrophages, and platelets. Although almost no statistical data related to the definitive effect in acute stage of KD, ulinastatin have shown possible effects, but not always, in a part of KD patients. The indications of clinical use include shock and pancreatitis. Off-label uses of ulinastatin have been reported in hematological, hepatic, renal, OB/Gy diseases and cardiovascular diseases including vasculitis syndromes. The efficacy of ulinastatin in aKD remained to be investigated.
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PMID:[Clinical utility of ulinastatin, urinary protease inhibitor in acute Kawasaki disease]. 1826 58

Improved knowledge regarding the pathogenetic mechanisms involved in autoimmune diseases has contributed to the development of biological therapies, with advances in cytokine research in particular revolutionizing the treatment of several autoimmune diseases. Anti-TNF agents are the most promising drugs for reducing symptoms, slowing or arresting joint damage, and preventing functional disability in patients with rheumatoid arthritis who fail to respond to standard disease-modifying antirheumatic drugs. Anti-TNF agents may also be useful in the treatment of other rare disorders, such as various forms of vasculitis, polymyositis and dermatomyositis. However, clinical trials of TNF inhibitors and inhibitors of the proinflammatory cytokines IL-1, IL-6, IL-12, IL-15, IL-17 and IL-23 demonstrated that the activity of such compounds is accompanied by a series of adverse events that needs to be addressed. This review describes the efficacy and adverse events associated with anti-cytokine treatments for autoimmune rheumatic diseases.
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PMID:Anti-cytokine antibodies for rheumatic diseases. 1987 88

Lipopolysaccharide (LPS) induced-vascular inflammation plays a central role in vasculitis and atherosclerosis. The stimulation of toll-like receptor 4 (TLR4) by LPS elicits the release of major proinflammatory cytokines that aggravates cardiovascular disorders. Peroxisome proliferator- activated receptor alpha (PPARalpha) agonists have been shown to reduce cardiovascular events by controlling lipid metabolism as well as inflammation. However, the role of PPARalpha agonist fenofibrate in modulating LPS-mediated inflammatory responses in vascular smooth muscle cells (VSMCs) remains elusive. The present study demonstrated that fenofibrate exerted a potent anti-inflammatory action through reducing interleckin-1(IL-18), tissue inhibitor of metalloproteinase-1(TIMP-1), TLR4 and enhancing PPARalpha in LPS-stimulated VSMCs. Additionally, treatment of VSMCs with the TLR4 inhibition or TLR4 small-interfering RNA illustrated that the modulatory effects of fenofibrate on LPS-mediated inflammatory responses in VSMCs were reliant on TLR4. Especially, the results suggested that beneficial effects of fenofibrate on LPS-stimulated inflammatory responses in VSMCs were mediated through interference of TLR4 and its downstream signaling components such as Toll-interleckin-1(IL-1) receptor domain- containing adaptor inducing interferon-beta (TRIF), interferon regulatory factor 3 (IRF3) and interferon-gamma inducible protein 10 (IP-10). In conclusion, PPARalpha agonist fenofibrate exerts anti-inflammatory property by antagonizing LPS-mediated inflammatory responses in VSMCs. More importantly, the modulation of the TRIF-dependent signaling pathway (TLR4/TRIF/IRF3/IP-10) might be a useful and novel anti-inflammatory strategy of fenofibrate.
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PMID:Modulation of LPS-mediated inflammation by fenofibrate via the TRIF-dependent TLR4 signaling pathway in vascular smooth muscle cells. 2051 8

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