Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036421 (PSS)
 10,989 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal endothelin-1 (ET-1) expression has been observed in bronchial asthma and systemic sclerosis with lung involvement. The purpose of this study was to analyze the synthesis of ET-1 in human airway epithelial cells and macrophages under basal conditions and after challenge with tumor necrosis factor-alpha (TNF alpha) or with the glucocorticoid dexamethasone. The ET-1 mRNA level and peptide release were measured in the broncho-epithelial cells BEAS-2B and the monocytic cell line U937. At baseline, U937 cells released low amounts of ET-1 peptide, whereas ET-1 was not detectable in BEAS-2B cells. After TNF alpha treatment, BEAS-2B cells, but not U937 cells, showed a significant increase in ET-1 expression, both at the mRNA and peptide levels. In contrast, dexamethasone elicited an increased amount of ET-1 peptide in U937 medium, but not in BEAS-2B cells. In this latter cell line, dexamethasone pretreatment was unable to inhibit the TNF alpha-induced expression. We conclude that response to TNF alpha and glucocorticoids is cell-type specific with respect to ET-1 production. The response of lung tissue to these agents in vivo is likely to be the overall balance of induction and inhibition in local microenvironments.
 ...
PMID:Expression of endothelin-1 in human broncho-epithelial and monocytic cell lines: influence of tumor necrosis factor-alpha and dexamethasone. 910 6

CD30 is a member of the tumor necrosis factor (TNF) receptor family, originally described as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease, which has been found to be preferentially expressed by T cells producing Th2-type cytokines. The presence of CD30 expression was assessed by both immunohistochemistry and reverse transcriptase-polymerase chain reaction in the target organs of patients with Th1- or Th2-dominated disorders. CD30 expression was found in neither the gut of patients with Crohn's disease nor in the gastric antrum of Helicobacter pylori-infected patients, where there was high interferon-gamma (IFN-gamma) expression. In contrast, high CD30 expression in the apparent absence of IFN-gamma expression was observed in the skin of patients with systemic sclerosis or chronic graft versus host disease (GVHD), which can be considered Th2-dominated disorders. Moreover, high levels of soluble CD30 were found in the serum of both systemic sclerosis and GVHD patients but not in the serum of patients suffering from multiple sclerosis, a Th1-dominated disorder. Thus, CD30 expression appears to be preferentially associated with Th2-type responses not only in vitro but also in vivo.
 ...
PMID:In vivo CD30 expression in human diseases with predominant activation of Th2-like T cells. 912 1

Nerve growth factor (NGF) is the first discovered and best known neurotrophic factor and is required for the survival and differentiation of a variety of neuronal cell types in both the peripheral and central nervous system. Recent studies indicate that NGF is synthesized by cells of immune system lineage and that its level increases during inflammatory responses, while cytokines such as interleukin-1 beta and tumor necrosis factor-alpha are potent inducers of NGF secretion. The role played by NGF on cells of the immune system was strengthened by recent evidence demonstrating that cells normally present in inflammatory tissues, such as mast cells and lymphocytes, express NGF receptors and are receptive to the action of NGF. Studies carried out in our and other laboratories showed that NGF is expressed in the synovial fluid of patients with rheumatoid arthritis and other forms of chronic arthritis, as well as in the synovium of pharmacologically-induced arthritis in animal models. Moreover, arthritic transgenic mice which carry and express the human tumor necrosis factor-gene also showed elevated levels of NGF. Significant increases in NGF levels have been found in the sera of patients with systemic lupus erythematosus and in the dermis of patients affected by systemic sclerosis. In this paper the hypothesis that NGF is involved in the pathophysiology of autoimmune rheumatic arthritis is discussed.
 ...
PMID:Nerve growth factor and autoimmune rheumatic diseases. 927 7

We measured serum levels of circulating intercellular adhesion molecule-1 (cICAM-1) in patients with systemic sclerosis (SSc) and normal controls. The levels of cICAM-1 were determined by sandwich enzyme-linked immunosorbent assay in sera from 88 patients with SSc and in 20 healthy controls. In addition, these levels were examined in the supernatants of cultured peripheral blood mononuclear cells (PBMC) and dermal fibroblasts from 10 patients with SSc and 10 healthy control subjects. Serum levels of cICAM-1 were significantly higher in patients with SSc than in healthy controls. Serum cICAM-1 levels were significantly higher in patients with diffuse cutaneous SSc (dcSSc) than in patients with limited cutaneous SSc (lcSSc). These serum levels were correlated with the presence of contracture of phalanges, pulmonary fibrosis, joint involvement and increased erythrocyte sedimentation rate. The release of cICAM-1 was significantly increased in the supernatants of cultured PBMC from patients with SSc. Moreover, inflammatory cytokines (interferon-gamma, interleukin-1 and tumor necrosis factor-alpha) enhanced the release of cICAM-1 in vitro in SSc cells. These findings suggest that cICAM-1 may be involved in immune reactions in this disease.
 ...
PMID:Circulating intercellular adhesion molecule-1 in the sera of patients with systemic sclerosis: enhancement by inflammatory cytokines. 944 87

Excessive accumulation of fibrillar collagens is a hallmark of the cutaneous fibrosis in both systemic and localized scleroderma. Turnover of the collagenous extracellular matrix is dependent on the balance between collagenolytic matrix metalloproteinases and their specific inhibitors. We have examined the expression of the novel, matrix associated tissue inhibitor of metalloproteinases-3 (TIMP-3) in normal and scleroderma skin fibroblasts in culture and in vivo. The levels of TIMP-3 mRNA were elevated up to 2.5-fold in five of seven systemic sclerosis fibroblast strains, whereas TIMP-1 mRNA expression was elevated up to 1.8-fold in two and TIMP-2 mRNA expression up to 1.8-fold in two systemic sclerosis strains. Using in situ hybridization, TIMP-3 mRNA was detected in seven of 12 localized scleroderma skin samples, specifically in fibroblasts within fibrotic collagen fibers or in the vicinity of inflammatory cells. TIMP-1 mRNA was detected in three of eight scleroderma skin samples in fibroblasts adjacent to inflammatory cells. The expression of TIMP-3 mRNA by systemic sclerosis and normal skin fibroblasts was enhanced to a similar extent (by 8.6- and 8.1-fold, respectively) by transforming growth factor-beta, and suppressed down to 34 and 54%, respectively, by tumor necrosis factor-alpha. Specific activation of TIMP-3 gene expression in scleroderma skin fibroblasts in culture and in vivo suggests a role for TIMP-3 in the pathogenesis of dermal fibrosis via inhibition of turnover of fibrotic dermal extracellular matrix, possibly due to upregulation of TIMP-3 expression by transforming growth factor-beta.
 ...
PMID:Activation of tissue inhibitor of metalloproteinases-3 (TIMP-3) mRNA expression in scleroderma skin fibroblasts. 954 Sep 85

Therapeutic trials in rheumatoid arthritis (RA), osteoarthritis, seronegative spondyloarthopathies, back pain, systemic lupus erythematosus, and systemic sclerosis are reviewed. For RA, minocycline has been proven effective in some subsets of RA, whereas tumor necrosis factor receptor IgG fusion protein appears quite effective for treating the symptoms of RA in a more resistant group. The latter trial illustrates the importance of tumor necrosis factor in RA. Also, the triple combination of hydroxychloroquine, sulfasalazine, and methotrexate is very effective even in resistant RA. In osteoarthritis, the effects of nonsteroidal anti-inflammatory drugs, intra-articular steroids, and biologics are reviewed, with generally nondifferentiable nonsteroidal anti-inflammatory drug effects and some short-term intra-articular effects of new biologics. Sulfasalazine is moderately effective for ankylosing spondylitis and psoriatic arthritis, although the large placebo response in the latter makes it more difficult to show responses. Trials in the treatment of back pain are beginning to be published, with a large cohort study over 1 year favoring surgery for early relief of pain in both sciatica and lumbar stenosis, but not showing a clear advantage in functional outcome at 1 year. Finally, early reports show the ability of dihydroepiandrosterone to decrease steroid use in systemic lupus erythematosus, whereas Relaxin appears to be effective in decreasing skin involvement in systemic sclerosis. These trials demonstrate in numerous ways the need to consider the elements of good trial design when testing therapeutic modalities in the rheumatic diseases. These key elements include 1) careful patient definition and selection; 2) removal of bias (requiring blinding, randomization, prospective studies, and often, placebo); 3) use of well-defined outcomes; and 4) careful analytic techniques.
 ...
PMID:Update on clinical trials in the rheumatic diseases. 956 7

There are many different rheumatic symptoms of gastrointestinal (GI) disorders and a whole range of GI symptoms that occur in rheumatologic disorders. Spondyloarthropathies (SpA) are closely related to the GI tract. Bacterial DNA has been detected in peripheral but not the sacroiliac joints of patients, including enterobacteria; the significance of this finding is not clear yet because antibiotic therapy seems not to be effective. The synovial lymphocyte proliferation of reactive arthritis (ReA) patients to the 60-kD heat-shock protein of Yersinia plays a major role in the immune response. Anti-Klebsiella antibodies are associated with gut lesions in SpA; their significance for the pathogenesis of SpA remains uncertain. ReA patients seem to have an impaired TH1-cytokine response, which might contribute to disease persistence. HLA B27-positive subjects seem to have a low tumor necrosis factor-alpha secretor status, possibly leading to diminished immune responses against certain microbes. In patients with Whipple's disease, Tropheryma whippelii can be cultured from gut biopsy specimens when interleukin-4 is added. The gene for hemochromatosis has been identified. Hepatitis C virus DNA can be found in many patients with cryoglobulinemia. Treatment with interferon-alpha might help in some patients. Effective treatment for primary biliary cirrhosis with ursodeoxycholic acid is not helpful for rheumatic symptoms. The severity of esophageal dysfunction in systemic sclerosis does not correlate with symptoms. GI symptoms do, although not frequently, occur in vasculitides.
 ...
PMID:Rheumatologic manifestations of gastrointestinal disorders. 989 33

The functions of Thy-1, a 35-kDa cell-surface glycoprotein, and its natural ligand are still unknown. Anchoring to the membrane via linkage to phosphatidyl-inositol (PI) raises the possibility of cleavage off the membrane by PI-specific phospholipases. Soluble Thy-1 (sThy-1) could interfere with the binding of the unknown natural ligand followed by regulation of different cell functions. In this study we established an enzyme-linked immunosorbent assay (ELISA) to measure and quantify sThy-1 in serum and wound fluid. Recombinant human Thy-1 (rhThy-1) was expressed in Drosophila S2 cells, purified from culture supernatant and used as standard for quantitation of sThy- by the ELISA technique. There were no differences in sThy-1 levels in serum of healthy donors and patients with systemic sclerosis, leg ulcers, or rheumatoid arthritis, respectively, detected by ELISA. In contrast, at the local site of inflammation, in wound fluid of venous leg ulcers and in synovial fluid from joint puncture, we found strongly elevated levels of sThy-1 compared with sThy-1 in the serum of the same patient. Thy-1 is expressed in humans on brain cells, fibroblasts, a subpopulation of CD34+ blood stem cells, and possibly activated human dermal microvascular endothelial cells. In this study, we never found Thy-1 mRNA or protein expression in resting endothelial cells as shown by reverse transcriptase polymerase chain reaction (RT-PCR) and flow-cytometry. Thy- expression could be induced on endothelial cells by phorbol myristate acetate and to a lesser extent by tumor necrosis factor-alpha (TNF-alpha). In situ, monoclonal antibodies to Thy-1 did not stain endothelial cells in normal skin, whereas endothelial cells in the synovial membrane of rheumatoid arthritis patients and endothelial cells surrounding melanoma express Thy-1. In summary, our data indicate that Thy-1 is present in soluble form in serum. Furthermore, Thy-1 seems to be a marker for endothelial cell activation. Therefore, activated endothelial cells as well as fibroblasts might be a possible source of sThy-1.
 ...
PMID:Detection of human soluble Thy-1 in serum by ELISA. Fibroblasts and activated endothelial cells are a possible source of soluble Thy-1 in serum. 1057 Nov 19

The regulation of matrix biosynthesis in systemic sclerosis has been the focus of many studies, because excessive matrix synthesis causes pathologic changes, and because this would seem to be a good target for therapies aimed at ameliorating the disease. Possible targets for antifibrotic therapies include both matrix gene stimulatory and inhibitory pathways. Much recent progress has been made in understanding the mechanism of action of transforming growth factor-beta (TGF-beta), an important profibrotic cytokine with pleiotropic effects on fibroblasts. It appears that TGF-beta may use multiple signal transduction pathways in fibroblasts and it is possible that defects in any of these pathways may result in an abnormal response to TGF-beta, resulting in fibrosis. Studies on negative regulation of matrix gene expression have singled out the antifibrotic cytokines tumor necrosis factor-alpha and interferon-gamma. Finally, a new approach that compares mRNA expression in normal versus diseased fibroblasts has already lead to the discovery of genes that may play a role in the development of fibrosis. This represents an important advance because genes can be identified that have not previously been implicated in the control of matrix synthesis, and thus might not otherwise have been studied in this context.
 ...
PMID:Regulation of matrix biosynthesis and degradation in systemic sclerosis. 1109 4

A minority of children suffering from severe rheumatic diseases are unresponsive to conventional treatments. These patients can now be managed with a variety of immunosuppressive therapies. Methotrexate is considered the first choice disease-modifying agent for adult and juvenile rheumatoid arthritis. In patients unresponsive to low doses of methotrexate, medium or high-doses can be useful. Instead of methotrexate, a recently developed immunosuppressive drug, mycophenolate-mofetil, which inhibits T- and B-lymphocyte proliferation, can be used. Another possibility for refractory rheumatic diseases, with no increase in toxicity, is combination therapy, for example methotrexate plus cyclosporine, or methotrexate plus salazopyrine or intravenous pulses of cyclophosphamide and methylprednisone. More recently two distinct inhibitors of tumor necrosis factor (etanercept and infliximab have been used successfully for intractable rheumatic diseases (juvenile idiopathic arthritis, psoriatic arthritis, spondyloarthropathies) but the follow-up is still too short to establish their long-term effectiveness. If all these treatments are unsuccessful, an autologous bone marrow transplantation can be proposed to selected patients. Interesting results have been obtained in pediatric rheumatic diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus and systemic sclerosis. Further studies are required to assess the best procedures able to induce remission with a minimal risk of fatal events.
 ...
PMID:Autologous bone marrow transplantation versus alternative drugs in pediatric rheumatic diseases. 1126 32


<< Previous 1 2 3 4 5 6 Next >>