Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular injury in vasculitis may be due to activation of circulating neutrophils resulting in their increased adhesiveness to locally activated endothelium (Shwartzman phenomenon). Previously, we demonstrated up-regulation of endothelial intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in biopsies from patients with ANCA-associated vasculitis. In the present study, we investigated the expression of adhesion molecules (CD11b, ICAM-1, VLA-4, L-selectin) and activation markers (CD66b, CD64, CD63) on circulating neutrophils from patients with ANCA-associated vasculitis in comparison with their expression on cells from healthy volunteers and patients with sepsis. We related these findings to parameters of disease activity. Surface marker expression was determined by using a non-activating whole blood flow cytometric assay. The expression of activation markers, but not the expression of adhesion molecules, was increased on neutrophils from patients with active vasculitis. The expression of CD63 and CD66b on neutrophils correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). In contrast to patients with active vasculitis, patients with sepsis showed up-regulation of all markers, including adhesion molecules, suggesting that circulating neutrophils are fully activated in sepsis. We conclude that in ANCA-associated vasculitis, circulating neutrophils are not fully activated, since they do not express increased levels of adhesion molecules as sepsis or in the Shwartzman reaction. These findings are compatible with the concept that in vivo vascular damage in ANCA-associated vasculitides does not occur due to a Shwarzman-like reaction but only after ANCA-induced neutrophil activation at the endothelial cell surface.
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PMID:Are circulating neutrophils intravascularly activated in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides? 984 62

To date no specific serological parameter is available to assess disease activity in SLE. Soluble serum thrombomodulin is a new marker of endothelial cell injury and vasculitis. The objective of this study was to compare in vivo soluble thrombomodulin as marker of disease activity in SLE with established and recent serological parameters. One hundred and twenty-four sera of 30 patients with proven SLE with different disease activities were tested for serum levels of thrombomodulin, intercellular adhesion molecule-1 (ICAM-1), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), IL-2R, IL-6, IL-10, dsDNA by ELISA and dsDNA additionally by radioimmunoassay (RIA). C-reactive protein (CRP), complement component C3, IgG, creatinine, anti-nuclear antibodies (ANA) and intermediate filament antibodies were measured by standard laboratory tests. The clinical disease activity was evaluated by the Systemic Lupus Activity Measure (SLAM). Correlations of the different serological SLE disease activity parameters with the SLAM scores revealed the highest significance for serum thrombomodulin (correlation coefficient 0.82). This was further confirmed by the intra-individual analysis of follow-up sera. In addition, a moderate correlation could be found for IL-6, IL-10, ICAM-1, CRP and erythrocyte sedimentation rate (ESR). In summary, soluble thrombomodulin is the most important serological parameter of disease activity in SLE currently available, as shown by the in vivo studies. Soluble thrombomodulin might be a valuable serological parameter for therapeutical considerations.
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PMID:Serum thrombomodulin-a reliable marker of disease activity in systemic lupus erythematosus (SLE): advantage over established serological parameters to indicate disease activity. 1060 82

We have previously shown that the gold-containing disease-modifying anti-rheumatic drugs, auranofin (AF) and gold sodium aurothiomalate (GSTM) reduce human umbilical vein endothelial cell (HUVEC) adhesion molecule expression and neutrophil (PMN) adherence. AF diminishes E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cytokine-activated HUVEC, while GSTM decreases only E-selectin. Since tight adhesion is critical for PMN to damage EC, we tested whether these drugs modulated human PMN-mediated injury to TNF-alpha-activated HUVEC in vitro (as measured by 51Cr release). Here we show that TNF-alpha caused a prominent PMN-mediated cytotoxicity that was dose-dependently reduced when AF and GSTM were added to the assay system. We also found that a potent inhibitor of NF-kappaB, pyrrolidine dithiocarbamate (PDTC) in a dose-dependent manner impaired TNF-alpha-induced cytotoxicity, indicating a role of NF-kappaB activation in cytokine-induced endothelial injury. To examine the effects of AF and GSTM on TNF-alpha-induced NF-kappaB activation this was measured in HUVEC nuclear extracts by an electrophoretic mobility shift assay. AF, but not GSTM, decreased TNF-alpha-induced NF-kappaB activation in HUVEC. Thus, in this in vitro model of vasculitis, AF and GSTM dose dependently reduced TNF-alpha-mediated neutrophil-dependent cytotoxicity for HUVEC, and AF, but not GSTM, inhibited NF-kappaB mobilization, thereby providing possible mechanisms for effects of AF and GSTM.
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PMID:Effects of anti-rheumatic gold salts on NF-kappa B mobilization and tumour necrosis factor-alpha (TNF-alpha)-induced neutrophil-dependent cytotoxicity for human endothelial cells. 1075 67

Antiendothelial cell antibodies (AECA), a heterogeneous group of antibodies quite distinct from the ANCA family, have been detected in variety of diseases which share a varying degree of vessel wall damage. This review is mainly focused on Wegener's granulomatosis, Takayasu's arteritis and Kawasaki syndrome, which provide the best examples to evaluate the pathogenic and prognostic value of AECA. There is increasing evidence to show that AECA might be pathogenic in inducing autoimmune vascular disease. It is relevant to note that the presence and titre of AECA has been correlated with disease activity in systemic vasculitis. Experimental in vitro and in vivo models support a potential pathogenic role for AECA in sustaining immune-mediated vessel inflammation. Rather than being cytotoxic to endothelial cells, AECA are able to up-regulate the expression of adhesion molecules (E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and to induce the secretion of cytokine and chemokine which, in turn, cause leukocyte recruitment and adhesion. A recent idiotypic animal model has provided further evidence that AECA can be pathogenic.
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PMID:Pathogenic role of anti-endothelial cell antibodies in systemic vasculitis. 1102 Sep 52

High-dose corticosteroids in combination with cytotoxic drugs are universally accepted as the initial approach in vasculitides that are associated with anti-neutrophil cytoplasmic antibodies. Cyclophosphamide is the most effective cytotoxic drug and is used in more severe cases. Because cyclophosphamide has more severe short- and long-term side-effects than methotrexate, methotrexate is used in less severe cases. New prospects for the treatment of vasculitis include novel immunosuppressive agents (e.g. mycophenolate, 15-deoxyspergualin, and leflunomide), sequential chemotherapy (e.g. cyclophosphamide followed by azathioprine or cyclophosphamide followed by methotrexate), intravenous immunoglobulin, tumour necrosis factor-alpha directed therapy, anti-lymphocyte directed therapy (e.g. antithymocyte globulin or anti CD52/anti CD4 antibodies), anti-adhesion molecule directed therapy (e.g. anti-CD18 or intercellular adhesion molecule-1 antisense) or immunoablation using high-dose cytotoxic medication with or without stem cell rescue.
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PMID:Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis. 1122 96

Wegener's granulomatosis is an autoimmune disease that is characterized by systemic vasculitis and granuloma formation. Early influx of polymorphonuclear neutrophils (PMN), followed at a later stage by mononuclear cells, contributes to the granulomatous inflammation. Previous studies have shown that proteinase 3 (PR3), the major autoantigen in Wegener's granulomatosis, specifically binds to endothelial cells and plays a possible role in activation of these cells by enhancing interleukin-8 production, thus providing a chemotactic and activating stimulus for PMN. The present study demonstrated that PR3 enhances the production of monocyte chemoattractant protein-1 (MCP-1) by human umbilical vein endothelial cells (HUVEC) in a dose- and time-dependent manner. The PR3-induced increase in MCP-1 production was demonstrated at both the protein and the mRNA levels and was chemotactic for monocytes. In addition, it was demonstrated that PR3 induces a dose- and time-dependent increase in the expression of intercellular adhesion molecule-1 (ICAM-1) as determined by fluorescence-activated cell sorter analysis. The PR3-induced increase in expression of ICAM-1 was also demonstrated at the mRNA level. PR3 induced a slight increase in vascular cell adhesion molecule-1 expression and had no effect on the expression of both P- and E-selectin. Incubation of HUVEC for 24 h in the presence of PR3 resulted in a significant increase in adhesion of PMN, which was reduced to baseline levels in the presence of blocking monoclonal antibody anti-ICAM-1 or anti-CD18 or a combination of both. Monocytes showed a slight but statistically not significant increase in adhesion. Incubation of HUVEC with PR3 for 4 h did not result in enhanced adhesion of either PMN or monocytes. It was hypothesized that PR3, which may be released locally at inflammatory sites after activation of cytokine primed PMN, plays a role in endothelial cell activation by enhancing both interleukin-8 and MCP-1 production, thus providing a chemotactic and activating stimulus for both PMN and monocytes. In addition, PR3 may contribute to the ongoing inflammation by enhancing the adhesion of PMN to endothelial cells by upregulating ICAM-1 expression.
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PMID:Proteinase 3 enhances endothelial monocyte chemoattractant protein-1 production and induces increased adhesion of neutrophils to endothelial cells by upregulating intercellular cell adhesion molecule-1. 1131 51

Idiopathic interstitial pneumonia (IIP) can occur after stem cell transplantation, but the aetiology is unknown. Based on the association between angiitis syndrome and Helicobacter pylori infection, we identified possible risk factors common to these two conditions. Among 83 patients who underwent stem cell transplantation, four developed IIP. We elucidated various parameters and clinical features in four patients with IIP and 79 patients without, after allogeneic stem cell transplantation. In all four patients, (1) the conditioning regimen induced total body irradiation, (2) serological reactivation of cytomegalovirus and/or human herpesvirus-6 preceded the onset of IIP, (3) their human leucocyte antigen types were among those suspected to increase susceptibility to angiitis syndrome, (4) serum anti-H. pylori antibody was positive before conditioning and remained positive throughout the post-transplantation course, (5) inflammatory cytokines (interleukin-6, 8 and 12) were increased during the period of leucocyte recovery after transplantation and (6) the levels of intercellular adhesion molecule-1, thrombomodulin and plasminogen activator inhibitor-1 were increased at the onset of IIP. These findings suggest the possibility that angiitis syndrome and H. pylori infection are involved in the pathogenesis of post-transplantation IIP.
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PMID:Idiopathic interstitial pneumonia following stem cell transplantation. 1286 90

Mycophenolate mofetil (MMF) is a potent immunosuppressant that inhibits the activity of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. MMF has been used widely in solid-organ transplantation. Increased evidence indicated that MMF exhibited beneficial effects on various types of vasculitis, for reasons that were not fully understood. Endothelial cells play a pivotal role in the pathogenesis of vasculitis. Endothelium may not only be the main target for injury, but also be able to amplify the inflammatory response by adhesion molecule expression, leukocyte adhesion, cytokine production and angiogenesis. In the present study, the effect of mycophenolic acid (MPA), the active metabolite of MMF, on human umbilical vein endothelial cells (HUVECs) was investigated. MPA markedly inhibited tumor necrosis factor-alpha (TNFalpha)-induced intercellular adhesion molecule-1 (ICAM-1) mRNA and surface expression, suppressed TNFalpha-induced neutrophils adhesion to endothelial cells, and reduced TNFalpha-induced interleukin-6 (IL-6) secretion. The inhibitory effects of MPA on ICAM-1 surface expression and IL-6 secretion were not attenuated by addition of guanosine, implying that inhibition of these processes were not due to intracellular guanosine nucleotides depletion. MPA also decreased angiogenesis of endothelial cells in three-dimensional collagen gel culture system, reduced the migration in a wounded monolayer of endothelial cells, and inhibited the proliferation of endothelial cells. In conclusion, MPA exhibited multifarious effects on endothelial cells including inhibition of ICAM-1 expression, neutrophil attachment, IL-6 secretion, and the process of angiogenesis, which might contribute to the efficacy of MMF in the treatment of vasculitis.
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PMID:Effects of mycophenolic acid on endothelial cells. 1582 18

In search of a noninvasive diagnostic test for rheumatoid vasculitis (RV), this study addressed the questions whether changes in capillary blood cell velocity (CBV) detected by laser Doppler anemometry in patients with rheumatoid arthritis (RA) were correlated with the levels of soluble adhesion molecules and whether cutaneous flow abnormalities may reflect extraarticular manifestations in RA. In 31 RA patients and 20 patients with osteoarthritis (OA), CBV was measured in the skin above the left ring finger at rest and after 3-min arterial occlusion. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and soluble P-selectin (sP-selectin) were assessed by enzyme linked immunosorbent assay. Peak CBV was reduced in RA patients compared to OA patients (0.42 +/- 0.07 mm/s vs. 0.70 +/- 0.13 mm/s; P = 0.013). Both CBV during rest and reactive hyperemia were not correlated with the levels of soluble adhesion molecules. There were no significant differences in resting or peak CBV between RA patients with or without extraarticular manifestations. The lack of an inverse correlation between the levels of soluble adhesion molecules and CBV during rest and reactive hyperemia contradicts the assumption that inflammatory vascular damage indicated by increased levels of soluble adhesion molecules was the main reason for the impairment of microcirculation. The present results do not suggest that cutaneous flow abnormalities may reflect extraarticular manifestations in RA.
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PMID:Microvascular dysfunction in rheumatoid arthritis assessed by laser Doppler anemometry: relationship to soluble adhesion molecules and extraarticular manifestations. 1760 11

Erythema nodosum leprosum (ENL) is an immune-mediated complication of leprosy presenting with inflammatory skin nodules and involvement of multiple organ systems, often running a protracted course. Immune complex production and deposition as well as complement activation have long been regarded as the principal aetiology of ENL. However, new data show that cell-mediated immunity is also important. We have performed a critical analysis of studies on the pathology of ENL. Our main findings are as follows. ENL is characterised by an inflammatory infiltrate of neutrophils with vasculitis and/or panniculitis. There is deposition of immune complexes and complement together with Mycobacterium leprae antigens in the skin. Changes in serum levels of Igs indicate a transient, localised immune response. The major T-cell subtype in ENL is the CD4 cell, in contrast to lepromatous leprosy where CD8 cells predominate. The cytokines TNFalpha and IL-6 are consistently found whilst IL-4 is low or absent in ENL lesions, indicating a T(H)1 type response. Keratinocyte 1a and intercellular adhesion molecule-1 (ICAM-1) have been shown to be present in the epidermis in ENL, which is evidence of a cell-mediated immune response. Co-stimulatory molecules such as B7-1 have also been studied but further work is needed to draw strong conclusions. We also highlight potential areas for future research.
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PMID:Towards understanding the pathology of erythema nodosum leprosum. 1831 6


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