endothelin-1 and Arthritis--Rheumatoid

A chronic inflammatory disorder, rheumatoid arthritis (RA) is an autoimmune and systemic disease characterized by progressive and prolonged destruction of joints. This results in increased mortality, physical disability and destruction. Cardiovascular disorders are one of the primary causes of mortality in patients with RA. It is multifactorial in nature and includes genetic, environmental and demographic factors which contribute to the severity of disease. Endothelin-1 (ET-1) is a peptide which acts as a potent vasoconstrictor and is generated through vascular smooth muscle and endothelial cells. Endothelins may be responsible for RA, as under certain circumstances they produce reactive oxygen species which further promote the production of pro-inflammatory cytokines. This enhances the production of superoxide anion, which activates pro-inflammatory cytokines, resulting in RA. The aim of this review is to elucidate the role of endothelin in the progression of RA. This review also summarizes the natural and synthetic anti-inflammatory drugs which have provided remarkable insights in targeting endothelin.

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Cytokines; Endothelial Cells; Endothelin-1; Endothelins; Humans; Reactive Oxygen Species; Superoxides; Vasoconstrictor Agents

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Biomarkers; Endothelin-1; Humans; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial

Endothelins (ETs) are involved in several inflammatory events. The present study investigated the efficacy of bosentan, a dual ETA/ETB receptor antagonist, in collagen-induced arthritis (CIA) in mice.. CIA was induced in DBA/1J mice. Arthritic mice were treated with bosentan (100 mg/kg) once a day, starting from the day when arthritis was clinically detectable.. CIA progression was assessed by measurements of visual clinical score, paw swelling and hypernociception. Histological changes, neutrophil infiltration and pro-inflammatory cytokines were evaluated in the joints. Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology. PreproET-1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells (PBMCs) was evaluated by real-time PCR. The differences were evaluated by one-way ANOVA or Student's t test.. Oral treatment with bosentan markedly ameliorated the clinical aspects of CIA (visual clinical score, paw swelling and hyperalgesia). Bosentan treatment also reduced joint damage, leukocyte infiltration and pro-inflammatory cytokine levels (IL-1β, TNFα and IL-17) in the joint tissues. Changes in gene expression in the lymph nodes of arthritic mice returned to the levels of the control mice after bosentan treatment. PreproET mRNA expression increased in PBMCs from rheumatoid arthritis (RA) patients but returned to basal level in PBMCs from patients under anti-TNF therapy. In-vitro treatment of PBMCs with TNFα upregulated ET system genes.. These findings indicate that ET receptor antagonists, such as bosentan, might be useful in controlling RA. Moreover, it seems that ET mediation of arthritis is triggered by TNFα.

Topics: Adult; Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Bosentan; Cells, Cultured; Cytokines; Endothelin Receptor Antagonists; Endothelin-1; Female; Gene Expression Profiling; Humans; Leukocytes, Mononuclear; Lymph Nodes; Male; Methotrexate; Mice; Mice, Inbred DBA; Middle Aged; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Sulfonamides

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Coronary Circulation; Diabetes Mellitus; Endothelin-1; Humans; Hyperalgesia; Hypertension, Pulmonary; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Myocardial Infarction; Pneumonia; Receptors, Tumor Necrosis Factor; Syndrome

G-protein beta 3 subunit (GNB3) C825T (rs5443) single nucleotide polymorphism (SNP) has been implicated as a risk factor for essential hypertension in the general population. The effects of this SNP may be more prominent in subjects with endothelial dysfunction (ED). Rheumatoid arthritis (RA) is associated with ED and has a high prevalence of hypertension. Thus far, this SNP has not been studied in RA patients. We genotyped 383 RA patients and 432 controls. GNB3 C825T was identified using real-time polymerase chain reaction (PCR) and melting curve analysis. There were no differences in the frequencies of the GNB3 C825T genotype and alleles between RA and controls. Within RA patients, prevalence of hypertension did not differ across genotypes. The TT versus CC+CT contrast yielded an adjusted odds ratio (OR) of 0.92 (95% CI: 0.49 to 1.76, p = 0.813), the contrast of TT+CT versus CC an adjusted OR of 2.17 (95% CI: 0.885 to 5.30, p = 0.091), whereas that of the T allele versus C allele an adjusted OR of 1.11 (95% CI: 0.76 to 1.61, p = 0.604). Systolic and diastolic blood pressure levels were not significantly different across the three genotypic groups. No significant interaction was observed between GNB3 825C/T polymorphism and serum endothelin levels. Data from the present study suggest that the T825 variant of the G protein beta 3 subunit gene is unlikely to constitute major susceptibility loci for essential hypertension in Caucasian RA patients. Further larger studies are required to confirm our findings and assess the interaction of rs5443 with environmental factors.

Topics: Aged; Arthritis, Rheumatoid; Blood Pressure; Case-Control Studies; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Male; Middle Aged; Polymorphism, Single Nucleotide; White People

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with a wide range of extra-articular manifestations. Recent studies emphasise a key inflammatory role of the endothelial cells, either by overexpression of inflammatory mediators or by the proliferation of new blood vessels, in the disease process leading to the systemic organ involvement. To evaluate the relationship between internal organ manifestations and immunological markers of endothelial activation, serum levels of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 64 RA patients and in 32 healthy controls. In comparison with a control group, higher serum concentrations of VEGF and ET-1 (p<0.001) in RA patients were demonstrated. A comparison between both RA groups with (20 patients) and without systemic involvement (44 patients) showed significantly higher concentrations of VEGF (p<0.05) and ET-1 (p<0.01) in the sera of patients with systemic manifestation. Moreover, a significant positive correlation between VEGF and ET-1 (r=0.475, p<0.001) in RA patients was found. A positive correlation between VEGF and Disease Activity Score (DAS) 28 index (r=0.39, p<0.005) as well as erythrocyte sedimentation rate (ESR) (r=0.564, p<0.0001) and C-reactive protein was found. ET-1 serum level correlated significantly with ESR (r=0.326, p<0.05) and DAS 28 index (r=0.307, p<0.05). These results suggest that the elevated serum levels of VEGF and ET-1 are associated with systemic organ involvement in RA patients and may play a key role in the pathogenesis of extra-articular manifestation of the disease.

Topics: Amyloidosis; Arthritis, Rheumatoid; Blood Sedimentation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Glomerulonephritis; Health Status; Humans; Male; Middle Aged; Neovascularization, Pathologic; Pulmonary Fibrosis; Severity of Illness Index; Vascular Endothelial Growth Factor A

Topics: Adrenomedullin; Arthritis, Rheumatoid; Cells, Cultured; Depression, Chemical; Dose-Response Relationship, Drug; Endothelin-1; Humans; Immunohistochemistry; Interleukin-6; Osteoarthritis; Peptides; Synovial Fluid; Synovial Membrane

Contradictory results on plasma endothelin-1 (ET-1) levels in patients with rheumatoid arthritis have been reported in previous studies. We therefore evaluated whether plasma ET-1 levels in patients with rheumatoid arthritis differ from those of normal controls. Since systemically increased levels of ET-1 are known to occur in tandem with primary or secondary vascular dysregulation, we also measured peripheral blood flow by means of nailfold capillaroscopy combined with a cold provocation test.. We measured plasma levels of ET-1 in twelve patients with different stages of rheumatoid arthritis by means of a specific radioimmunoassay, and compared ET-1 values to those of healthy controls. Capillary blood flow and the frequency of cold-induced vasospasm were studied in parallel, using nailfold capillaroscopy combined with a cold provocation test.. Plasma ET-1 levels were significantly increased in patients with rheumatoid arthritis (p = 0.01) when compared to controls (2.38+/-0.95 pg/ml vs. 1.53+/-0.38 pg/ml). Capillary blood flow was reduced when compared to our own normal values, and a cold-induced blood standstill was seen in 58% of the patients.. Patients with rheumatoid arthritis exhibit significantly elevated levels of ET-1, which may be associated with the symptoms of vascular dysregulation observed in nailfold capillaroscopy. Even though the clinical conclusions should be drawn from this study with caution, additional therapy with calcium channel blockers or, possibly in the future, with ET-1 receptor blockers, may be beneficial in patients with rheumatoid arthritis.

Topics: Adult; Aged; Arthritis, Rheumatoid; Case-Control Studies; Endothelin-1; Female; Humans; Male; Microscopic Angioscopy; Middle Aged; Radioimmunoassay; Regional Blood Flow; Time Factors

To study the effect of endothelin-1 (ET-1) on the expression of intercellular adhesion molecule-1 (ICAM-1) by synovial fibroblasts derived from individuals with rheumatoid arthritis (RA) or osteoarthritis (OA).. The expression of ICAM-1 protein and the abundance of ICAM-1 mRNA in synovial fibroblasts derived from individuals with RA or OA, or healthy controls, was assessed by flow cytometry and Northern blot analysis, respectively. mRNA expression of ET type A (ETA) and ET type B (ETB) receptors was assessed by reverse transcription polymerase chain reaction.. Tumor necrosis factor-alpha (TNF-alpha) increased the expression of ICAM-1 by RA and OA fibroblasts. While ET-1 alone had no significant effect on ICAM-1 expression by either cell type, it inhibited the TNF-alpha induced increase in ICAM-1 expression, and this effect was more marked in RA fibroblasts. TNF-alpha also increased the amount of ICAM-1 mRNA in both cell types, and ET-1 inhibited this increase to a greater extent in RA fibroblasts than in OA fibroblasts. This inhibitory effect of ET-1 was reversed by addition of specific antagonist of ETA receptor. mRNA expression of ETA and ETB receptors was significantly greater in RA fibroblasts stimulated with TNF-alpha or even medium alone than in OA fibroblasts.. These results suggest that ICAM-1 expression by fibroblasts is regulated not only by proinflammatory cytokines such as TNF-alpha and interleukin-1beta, but also by the vasoactive peptide ET-1, and that ET-1 may play an important role in inflammatory responses, especially in rheumatoid synovitis.

Topics: Aged; Arthritis, Rheumatoid; Cells, Cultured; Cycloheximide; Dactinomycin; DNA Primers; Dose-Response Relationship, Drug; Down-Regulation; Endothelin-1; Female; Fibroblasts; Flow Cytometry; Humans; Immunoenzyme Techniques; Intercellular Adhesion Molecule-1; Interleukin-1; Male; Middle Aged; Osteoarthritis; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synovial Membrane; Tumor Necrosis Factor-alpha

To determine the endothelin-1 (ET-1) concentrations in synovial fluid and serum of rheumatoid arthritis (RA) patients, this study was designed to examine if serum ET-1 concentration of control subjects has any correlation either with the ET-1 concentration of synovial fluid or ET-1 concentration of serum from RA patients. Twenty-eight patients were studied of whom eight males and twenty females with confirmed rheumatoid arthritis. Twenty-eight healthy volunteers were also included as controls. The immunoreactive concentration of ET-1 was measured using commercially available radioimmunoassay (RIA) kits (Peninsula Laboratories, Belmont CA) specific for ET-1. All the samples were performed in duplicate and after plotting % B/Bo for each standard directly on Y axis and endothelin concentrations on the X axis, the "best fit" curve was drawn and the amount of ET-1 was calculated. Mean ET-1 level in synovial fluid was 15.53 +/- 2.82 pg/me. In serum samples from RA patients, the mean ET-1 level was detected as 16.42 +/- 3.07 pg/ml (n = 28). Sera from twenty-eight healthy volunteers were analyzed as controls and mean ET-1 concentration was 8.68 +/- 1.96 pg/ml. A significant difference (P < 0.001) was found between ET-1 level of sera from RA patients and ET-1 levels from control sera. Highly significant difference (P < 0.001) was also detected between synovial fluid ET-1 and control ET-1 levels. However, no significant difference was found between ET-1 levels of synovial fluid and serum ET-1 levels of RA patients. Results of this study confirmed the presence of elevated levels of ET-1 concentration in synovial fluid and serum samples of patients with RA. The clinical significance and physiological role of endothelin in synovial fluids and sera of patients suffering from a variety of pathophysiological conditions of arthritis deserves further studies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Endothelin-1; Female; Humans; Male; Middle Aged; Synovial Fluid

Immunoreactive (ir)-endothelin (ET)-1 concentrations in serum samples and synovial fluids from patients with rheumatoid arthritis were higher than concentrations in sera obtained from healthy volunteers. No significant difference in ir-ET-1 concentrations in synovial fluid was observed between rheumatoid arthritis patients and osteoarthritis patients. Cultured fluids of synovial cells collected from synovial tissues and leucocytes from synovial fluids of rheumatoid arthritis patients were studied to determine the origin of ir-ET-1 in synovial fluids. Ir-ET-1 was detected in the cultured fluids of synovial macrophage-like type A cells, but not in those of fibroblast-like type B cells from the synovial tissues or leucocytes from the synovial fluids. Longitudinal studies showed that the ir-ET-1 concentration in the cultured fluid reached a peak around 24 h after starting the culture. ET-1 secreted from macrophage-like synoviocytes may be involved in the pathogenesis of inflammatory arthritis.

Topics: Arthritis, Rheumatoid; Cells, Cultured; Endothelin-1; Female; Humans; Macrophages; Middle Aged; Osteoarthritis; Synovial Fluid