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)

1. The ability of analogues of L-arginine (N-iminoethyl-L-ornithine (L-NIO), NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME) and NG-nitro-L-arginine (L-NNA)) to protect against inflammatory injury induced by activated neutrophils was investigated in rats following intradermal or intrapulmonary deposition of immune complexes. 2. The descending order of potency for protective effects of these analogues was: L-NIO > L-NMMA > L-NNA = L-NAME. The approximate IC50 value for L-NIO in the dermal vasculitis model was 65 microM. For all other compounds, the IC50 values were > 5 mM. 3. The protective effect of L-NIO in the skin was reversed in a dose-dependent manner by the presence of L-arginine, but not by D-arginine. L-Arginine also reversed the protective effects of L-NIO in immune complex-induced lung injury. 4. The protective effects of L-NIO were not associated with reductions in neutrophil accumulation, as measured by extraction from tissues of myeloperoxidase. 5. These data demonstrate that L-NIO has the most potent protective effects against immune complex-induced vascular injury induced by activated macrophages. Furthermore, they indicate that this injury is dependent upon the generation of nitric oxide.
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PMID:Protective effects of inhibitors of nitric oxide synthase in immune complex-induced vasculitis. 128 19

The complement system represents an important nonspecific skin defense mechanism. Its activation leads to the generation of products that not only help to maintain normal host defenses but also mediate inflammation and tissue injury. Proinflammatory products of complement include large fragments of C3 with opsonic and cell-stimulatory activities (C3b and C3bi), low molecular weight anaphylatoxins (C3a, C4a, and C5a), and membrane attack complex. Among them C5a or its degradation product C5a des Arg seems to be the most important mediator because it exerts a potent chemotactic effect on inflammatory cells. Intradermal administration of C5a anaphylatoxin induces skin changes quite similar to those observed in cutaneous hypersensitivity vasculitis that occurs through immune complex-mediated complement activation. Complement activation is involved in the pathogenesis of the inflammatory changes in autoimmune bullous dermatoses. In pemphigus complement activation by pemphigus antibody in the epidermis seems to be responsible for the development of characteristic inflammatory changes termed eosinophilic spongiosis. In bullous pemphigoid (BP) interaction of basement membrane zone antigen and BP antibody leads to complement activation that seems to be related to leukocytes lining the dermoepidermal junction. Resultant anaphylatoxins not only activate the infiltrating leukocytes but also induce mast cell degranulation which facilitates dermoepidermal separation and eosinophil infiltration. Similar complement activation seems to play a more direct role in the dermoepidermal separation noted in epidermolysis bullosa acquisita and herpes gestationis. Anaphylatoxin generation via the alternative pathway activation under light irradiation is implicated in the development of the immediate erythematous phototoxic reactions induced by such well-known chemicals as porphyrin, chlorothiazide, demethylchlortetracycline, and chlorpromazine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of complement-derived mediators in inflammatory skin diseases. 128 51

Recent data has suggested a role for nitric oxide (NO) both in the induction of immunity and as an effector of tissue injury in experimental models of inflammation. In this study, we have tested the efficacy of two inhibitors of NO synthase, NG-monomethyl-L-arginine (L-NMMA) and aminoguanidine (AG), to modify the autoimmune leucocytoclastic necrotizing vasculitis which develops following the administration of mercuric chloride (HgCl2) to the Brown Norway rat. Neither agent affected the induction of autoimmunity as judged by plasma IgE titres or the degree of tissue neutrophil infiltration; however, L-NMMA did significantly attenuate tissue injury scores. We conclude that inhibition of NO synthase does not influence the induction of autoimmunity by HgCl2, but that NO does contribute to the development of tissue injury in this experimental model.
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PMID:Nitric oxide contributes to tissue injury in mercuric chloride-induced autoimmunity. 750 30

1. Mediators of inflammation can increase vascular permeability in at least two different ways: by acting directly on endothelial cells or, indirectly, through an incompletely understood mechanism, dependent on circulating neutrophils. Neutrophil-dependent oedema formation has been described in the skin of rabbits, rats, hamsters, mice and man. In contrast, we presented evidence in a previous study that local oedema formation induced by i.d. injection of chemoattractants in guinea-pig skin was neutrophil-independent. In the present study, we sought evidence of neutrophil-dependent oedema formation in immune-complex-mediated vasculitis, the reversed passive Arthus (RPA) reaction, in guinea-pig skin. We also investigated whether haemorrhage in the RPA reaction was neutrophil-dependent (as it is in other species) and the role of endogenous mediators of inflammation (prostaglandins, nitric oxide, histamine, PAF and leukotrienes) in contributing to the local inflammatory response. 2. In the RPA reaction, most oedema formation occurred over the first 60 min whereas 111In-neutrophil accumulation was still increasing from 60 to 240 min. The different kinetics of these two events suggested that they may be dissociated. 3. Oedema formation was partially inhibited by a long-acting PAF antagonist (UK-74,505) and an H1 histamine receptor antagonist (mepyramine) but not by a 5-lipoxygenase inhibitor (ZM 230487). A nitric oxide synthesis inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) suppressed oedema formation by 68% whereas a cyclo-oxygenase inhibitor suppressed oedema by 27%. 4. 111In-neutrophil accumulation in the RPA reaction was partially suppressed by UK-74,505. In contrast, ZM 230487 was without effect at doses which abrogated arachidonic acid-induced 111In-neutrophil accumulation. 5. The anti-CD18 monoclonal antibody, (mAb) 6.5E F(ab')2, effectively inhibited 111In-neutrophil accumulation induced by PAF, zymosan-activated plasma (ZAP) and in the RPA reaction. However, oedema formation measured in the same sites was not altered. In contrast, oedema formation in the RPA reaction was partially suppressed by 6.5E whole mAb which was 2.5 times more potent than 6.5EF(ab')2 at inhibiting guinea-pig neutrophil adhesion to protein-coated plastic. Haemorrhage induced by PAF and in the RPA reaction was significantly inhibited by 6.5E F(ab')2 pretreatment.6. We conclude that in the RPA reaction in guinea-pig skin, oedema formation is partially neutrophil dependent as assessed by using an anti-CD18 mAb, whereas ZAP-induced oedema formation is neutrophil-independent. Haemorrhage was also dependent on neutrophil accumulation. In addition, our studies support a role for PAF in mediating both oedema formation and "'In-neutrophil accumulation in the RPA reaction. Endogenous release of histamine also appears to be important in mediating oedema formation suggesting that mast cells play a critical role in increases of vascular permeability in inflammatory reactions in guinea-pig skin. Moreover, our results confirm previous findings which suggest a dominant role for nitric oxide in maintaining cutaneous blood flow in the guinea-pig.
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PMID:Studies on the mechanisms involved in the inflammatory response in a reversed passive Arthus reaction in guinea-pig skin: contribution of neutrophils and endogenous mediators. 788 93

Clinical and experimental studies indicate that nonimmunologic factors may modulate the alloreactivity of a renal transplant. Nitric oxide (NO) is an essential modulator of endothelial function. It was postulated that, in renal allografts, inhibition of constitutive NO synthase may lead to an aggravation of immunologic damage to endothelia and therefore may enhance dysfunction of the graft. Male Lewis (RT1l) rats received syngeneic or allogeneic Brown Norway (RT1n) renal grafts and were treated with cyclosporin A (CyA) or with CyA and an NO synthase blocker (NOS-B): N omega-nitro-L-arginine (L-NNA) or NG-monomethyl-L-arginine (L-NMMA). CyA was given at a dose of 3.5 mg/kg body weight for 14 days and the NOS-B at a dose of 66 mg/L drinking water for up to 28 days postoperatively. Animals (N = 6/group) were studied at 4 to 7, 14, and 28 days posttransplantation. Four to 5 days posttransplantation, renal blood flow and glomerular filtration rate of allogeneic grafts did not differ between animals treated only with CyA and those treated with CyA and NOS-B. Mean arterial pressure was significantly elevated by NOS-B (CyA+L-NNA: 115 +/- 13 versus CyA: 78 +/- 16 mm Hg). Combined NOS-B and CyA administration led to a pronounced increase in vascular and tubulointerstitial damage. The number of mononuclear cells in vessels, glomeruli, and tubulointerstitium increased significantly in allografts upon treatment with NOS-B. During NOS-B administration, adhesion molecules (intracellular adhesion molecule-1; leukocyte-function-associated molecules-1 alpha and-beta) were strongly expressed in endothelial and leukocytic cells of the allograft. A pronounced positivity for mRNA and protein of cytokines tumor necrosis factor-alpha and transforming growth factor-beta could be demonstrated in the inflammatory infiltrate. With L-NNA treatment, the total vascular injury index was 10-fold higher (14 days posttransplantation, CyA+L-NNA: 59.8 +/- 11.7 versus CyA: 6.0 +/- 1.8; p < 0.05). The tubulointerstitial damage score rose more than 2.5-fold after CyA and L-NNA therapy (28 days posttransplantation: CyA+L-NNA: 83 +/- 1 versus CyA:29 +/- 1). L-NNA was more potent than L-NMMA at the dosages used. Thus, pronounced vascular leukostasis, vasculitis, and T-cell and monocyte infiltration of the tubulointerstitium led to a severe damage of the allograft under therapy with CyA and NOS-B. Inhibition of NO synthesis may aggravate alloreactive immunemediated injury in kidney transplants acting primarily by a disturbance of endothelial function.
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PMID:Enhanced renal allograft rejection by inhibitors of nitric oxide synthase: a nonimmunologic influence on alloreactivity. 878 Jan 67

In this paper, we report the purification and partial characterization of human platelet aggregation factor form the extracellular products (ECP) of Streptococcus mitis (S. mitis) isolated from a patient with Kawasaki disease (KD). Platelet aggregation reaction was carried out using platelet-rich plasma (PRP) and washed platelets suspended in ACD-PBS. The aggregation factor was designated as S. mitis-derived human platelet aggregation factor (Sm-hPAF). The results obtained were as follows. 1) Sm-hPAF was isolated by chromatography on DEAE-Sepharose CL-6 B, hydroxyapatite and Superdex 75 columns. The purified Sm-hPAF showed a single band upon SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and molecular weight of approximately 66 kDa on SDS-PAGE. The isoelectric point (pI) of Sm-hPAF was 8.5, and Sm-hPAF showed an absorption peak at 278 nm on absorption spectra. When the platelet aggregation activity of the Sm-hPAF was compared with that of ECP, the specific aggregation activity of the of Sm-hPAF was significantly increased (up to 28-fold). Sugars were not found in Sm-hPAF. The sequence of the first 15 amino-terminal amino acid residues were H.Asp-Glu-Gln-Gly-Asn-Arg-Pro-Val-Glu-Thr-Glu-Asn-Ile-Ala-Arg. The platelet aggregation activity of Sm-hPAF was inactivated by heating at 45 degrees C for 10 min. 2) PGE2 was released from platelets after incubation for 10 min with Sm-hPAF in a dose-dependent fashion. Platelet aggregation by the Sm-hPAF was totally inhibited by either PGE1, or GRGDS, but these reagents did not inhibit the platelet aggregation by collagen. 3) Histological examination of the rabbit skin sites showing an early reaction revealed increased dilatation of the veins and capillaries with cellular infiltration in the perivascular space of the dermis. Hyperplasia of the endothelial cells was noted. Degeneration of the vascular walls was observed in the later stages of the reaction. Aggregation of red cells in the vascular endothelium was also observed. Sm-hPAF was capable of producing vasculitis. 4) Twenty (76.9%) platelet-rich plasma samples (PRP) derived from 26 healthy human volunteers reacted with Sm-hPAF, but the remaining 6 PRPs were not reactive. Preliminary study suggests the existence of an inhibitory factor in plasma from nonreactive donors.
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PMID:[Purification and partial characterization of a novel human platelet aggregation factor in the extracellular products of Streptococcus mitis, strain Nm-65]. 898 63

Nitric oxide (NO) is an important mediator of the inflammatory response. MRL-lpr/lpr mice overexpress inducible nitric oxide synthase (NOS2) and overproduce NO in parallel with the development of an autoimmune syndrome with a variety of inflammatory manifestations. In previous studies, we showed that inhibiting NO production with the nonselective nitric oxide synthase (NOS) inhibitor NG-monomethyl-arginine reduced glomerulonephritis, arthritis, and vasculitis in MRL-lpr/lpr mice. To define further the role of NO and NOS2 in disease in MRL-lpr/lpr mice, mice with targeted disruption of NOS2 were produced by homologous recombination and bred to MRL-lpr/lpr mice to the N4 generation. MRL-lpr/lpr littermates homozygous for disrupted NOS2 (-/-), heterozygous for disrupted NOS2 (+/-), or wildtype (+/+) were derived for this study. Measures of NO production were markedly decreased in the MRL-lpr/lpr (-/-) mice compared with MRL-lpr/lpr (+/+) mice, with intermediate production by the MRL-lpr/lpr (+/-) mice. There was no detectable NOS2 protein by immunoblot analysis of the spleen, liver, kidney, and peritoneal macrophages of the (-/-) animals, whereas that of (+/+) was high and (+/-) intermediate. The (-/-) mice developed glomerular and synovial pathology similar to that of the (+/-) and (+/+) mice. However, (-/-) mice and (+/-) mice had significantly less vasculitis of medium-sized renal vessels than (+/+) mice. IgG rheumatoid factor levels were significantly lower in the (-/-) mice as compared with (+/+) mice, but levels of anti-DNA antibodies were comparable in all groups. Our findings show that NO derived from NOS2 has a variable impact on disease manifestations in MRL-lpr/lpr mice, suggesting heterogeneity in disease mechanisms.
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PMID:Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2. 923 88

Nitric oxide (NO) is an important factor in tissue trauma, but its detailed role in the pathogenesis remains unknown. In autoimmune vasculitis, it is possible that NO in one of the factors underlying tissue trauma and induction of autoimmune antibodies. To study its role on an animal model using mercury chloride (HgCl2), Brown Norway rats (BN rats) were given five injections of] HgCl2, each 1 mg/kg, over 10 days. Vasculitis and production of some autoimmune antibodies developed after HgCl2 injections. Urine nitrate/nitrite, metabolic production of NO, was produced in advance of the production of other autoimmune antibodies. To elucidate the role of NO, NG-nitro-L-arginine methyl ester (L-NAME), which is a nitric oxide synthase (NOS) inhibitor, was given in addition to HgCl2, at the daily dose of 30 mg/kg. There was no difference in production of autoimmune antibodies between this group and the control group, but urine protein excretion was suppressed in the HgCl2 + L-NAME group (p < 0.001). By immunohistochemical study, inducible NOS was positive in small vessels and mesangial cells in rat kidney. We conclude that in this animal model, over-production of NO leads to the production of autoimmune antibodies and inhibition of NOS production ameliorates proteinuria. These results suggest that NO plays an important role in the induction of renal injury in the rat model of autoimmune vasculitis.
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PMID:[The role of nitric oxide in mercury chloride-induced vasculitis in the brown Norway rat]. 928 9

The aim of the study was to investigate endothelium-dependent vasodilator responses in the forearm vasculature of patients with systemic vasculitis. We studied 10 patients with systemic vasculitis and 16 healthy control subjects using forearm venous occlusion plethysmography to assess changes in forearm blood flow in response to acetylcholine (ACh). NG-monomethyl-L-arginine (L-NMMA), was also used to assess the contribution of endothelium derived relaxing factor/nitric oxide (EDRF/NO) to the vasodilator responses to acetylcholine. A significantly greater vasodilator response to ACh was seen in the patient group at all doses infused (p < 0.01). After pre-infusion of L-NMMA, the differences in ACh dilator responses were no longer significant. There was a greater magnitude of inhibition of ACh responses by L-NMMA in the patient group. The enhanced vasodilator response to ACh observed was in part abolished by L-NMMA, suggesting that EDRF/NO is produced in excess in systemic vasculitis. The precise role played by EDRF/NO in the pathogenesis of systemic vasculitis requires further study.
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PMID:Enhanced endothelium-dependent vasodilator responses in patients with systemic vasculitis. 931 Jan 14

Nitric oxide (.NO) may exhibit proinflammatory features. .NO synthase type 2 (NOS2) is overexpressed and .NO overproduced in rodent models of induced inflammation. Blockage of .NO production by administration of NOS inhibitors prevents or reduces various types of induced inflammation in mice and rats. We have shown that autoimmune MRL-lpr/lpr mice overexpress NOS2 and overproduce .NO in an age-dependent fashion that parallels expression of arthritis, glomerulonephritis, and vasculitis. Blocking .NO production by oral administration of the NOS inhibitor NG-monomethyl-L-arginine reduced the arthritis, glomerulonephritis, and vasculitis, but it did not modify serum anti-DNA antibody levels or glomerular deposition of immune complexes. When mice with genetically disrupted NOS2 were backcrossed to MRL-lpr/lpr mice, the resultant (-/-) mice expressed no NOS2 and produced no .NO, the wild-type (+/+) mice overexpressed NOS2 and overproduced .NO (in comparison to normal, control mice), and the heterozygous (+/-) mice expressed and produced intermediate levels. Nephritis and arthritis in the (-/-) mice were comparable to that in MRL-lpr/lpr mice, but vasculitis was markedly decreased. Levels of anti-DNA antibodies were comparable in all mice, but IgG rheumatoid factor production was markedly reduced in the (-/-) mice. These results of studies in MRL-lpr/lpr mice with genetically disrupted NOS2 highlight the heterogeneity and complexity of the role of NOS2 and .NO in inflammation.
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PMID:Nitric oxide as an inflammatory mediator in autoimmune MRL-lpr/lpr mice. 978 87


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