Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the state of alpha 2-macroglobulin (alpha 2M), an important inhibitor of cartilage-degrading proteinases, in relation to activation of neutrophils in 82 patients with several types of arthritis, including 52 with rheumatoid arthritis and 11 with osteoarthritis. Levels of total inactive alpha 2M (i alpha 2M), which comprises alpha 2M complexed to proteinases and alpha 2M inactivated by oxidation or hydrolysis, were measured with a monoclonal antibody specific for i alpha 2M. In addition, levels of alpha 2M complexed to proteinases were quantitated with specific assays. Neutrophil activation was assessed by measuring elastase-alpha 1-antitrypsin complexes and lactoferrin. In 83% of the 82 patients tested, the synovial fluid (SF) to plasma ratio of i alpha 2M exceeded 1, indicating an intraarticular generation. Levels of i alpha 2M significantly correlated with neutrophil numbers (P less than 0.0005) and with levels of elastase-alpha 1-antitrypsin complexes and of lactoferrin (P less than 0.00001 for both). Moreover, part of i alpha 2M consisted of alpha 2M complexed to elastase-like and chymotrypsin-like proteinases, presumably, neutrophil elastase and cathepsin G, respectively. However, the amount of i alpha 2M was approximately 10-fold larger than the amount complexed to these proteinases. In vitro inactivation of alpha 2M by activated neutrophils was only partly inhibitable by eglin C, a specific inhibitor of both elastase and cathepsin G. Release of reactive oxygen species was presumably responsible for the additional inactivation of alpha 2M, because eglin C completely abolished the inactivation of alpha 2M by cell-free supernatant of activated neutrophils. Thus, our results suggest a predominant role of neutrophils in the inactivation of alpha 2M in the SF of patients with inflammatory joint diseases. However, this inactivation could be explained only in part by the release of neutrophilic proteinases. We propose that the inactivation of alpha 2M in SF was due to the concerted action of both reactive oxygen species and lysosomal proteinases.
Arthritis Rheum 1991 Sep
PMID:Predominant role of neutrophils in the inactivation of alpha 2-macroglobulin in arthritic joints. 171 87

The contribution of neutrophil-derived elastase and cathepsin G to joint pathology has been examined in immune arthritis in the mouse. Neutrophils from beige mice are genetically deficient in lysosomal elastase and cathepsin G, but have normal levels of the acid hydrolases, beta-glucuronidase, and N-acetyl-beta-glucosaminidase. The development of antigen-induced arthritis in normal mice has been compared with that in beige mice. The pattern of synovitis (both leukocyte accumulation and plasma leakage) were indistinguishable in normal and beige mice. Cartilage proteoglycan depletion was quantified by measuring the decrease in safranin O staining intensity, and this, too, was unaltered in mice lacking elastase and cathepsin G. These results suggest that neutrophil elastase and cathepsin G do not contribute to these aspects of joint pathology in antigen-induced arthritis in the mouse.
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PMID:Pathogenesis of antigen-induced arthritis in mice deficient in neutrophil elastase and cathepsin G. 224 Jan 59

The enzyme inhibitors alpha 2 macroglobulin (alpha 2M) and alpha antitrypsin (alpha 1AT) have been demonstrated previously in the pannus-cartilage junction area in 12 patients with rheumatoid arthritis (RA). These deposits were present in both inflammatory cells and in the cartilage matrix. As the tissue studied came from far advanced disease removed at the time of joint replacements, the initial phase of cartilage destruction was studied in a carrageenin-induced arthritis in rabbits. Sequential studies indicated that loss of proteoglycan from cartilage was necessary before alpha 2M penetrated the matrix. Explant cultures of synovial tissue from RA and osteoarthritis (OA) joints released an inhibitor of neutrophil elastase and plasminogen activator which was neither alpha 2M nor alpha 1AT. Synovial tissue (and cartilage) enzyme inhibitors may have important implications in relation to protective mechanisms within the joint in RA and OA over and above the effect of plasma inhibitors.
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PMID:The distribution of enzyme inhibitors in the joint in rheumatoid and experimental arthritis. 608 87

Human neutrophil elastase is thought to play an important role in connective tissue destruction in diseases such as emphysema and arthritis. In this article, it is demonstrated that the elastase activity of mature human peripheral blood neutrophils can be rapidly increased in vitro by treatment of the cells with lipopolysaccharide from E. coli and that this increase is inhibited by corticosteroid pretreatment of the cells and by inhibitors of protein synthesis. Alterations in intracellular enzyme content of the mature polymorph in response to bacterial products or other stimuli may be important for amplification of the inflammatory response.
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PMID:Polymorphonuclear leukocyte elastase activity is increased by bacterial lipopolysaccharide: a response inhibited by glucocorticoids. 636 52

A novel neutrophil elastase inhibitor, ONO-5046, was administered to BB/DR rats and DBA/1 mice immunized with type II collagen to study its effect on the development of collagen-induced arthritis (CA), an experimental model of human rheumatoid arthritis. ONO-5046 reduced the incidence as well as the severity of CA in both rats and mice. This suppressive effect on severity was correlated with improvement of the histological findings, particularly with reduced destruction of the articular cartilage. These results indicate that neutrophil elastase may play an important role in the pathogenesis of CA.
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PMID:Suppressive effect of a neutrophil elastase inhibitor on the development of collagen-induced arthritis. 767 22

Injection of lipopolysaccharide (LPS) into rabbit knee joints provoked leucocyte infiltration and loss of proteoglycan (PG) from the cartilage. We investigated the role of IL-1 and IL-1 receptor antagonist (IL-1Ra) and its significance in the pathogenesis of LPS-arthritis. Production of IL-1 beta peaked at 6 h (196.7 +/- 89.4 pg/joint) after injection of 10 ng of LPS, while IL-1Ra peaked at 9 h (34.5 +/- 13.4 ng/joint). The amount of IL-1Ra was 180-200-fold molar excess of IL-1, and a large amount of IL-1Ra was sustained for 1 week. Both IL-1 beta and IL-1Ra were mainly produced by synovial exudate cells. Arthritis was reproduced by rabbit IL-1 beta. LPS-induced leucocyte infiltration was inhibited 70-75% by rabbit IL-1Ra. Loss of PG in LPS-arthritis was prevented by IL-1Ra and also by neutrophil elastase inhibitor, and superoxide dismutase. In leucopenic rabbits, injection of LPS induced neither production of IL-1 beta nor loss of PG. Direct injection of inflammatory exudated cells in leucopenic rabbits reproduced loss of PG, and there was only a partial recovery by IL-1Ra. These results suggest that LPS-initiated IL-1 acts as a key mediator in LPS-arthritis and that endogenous IL-1Ra may suppress a part of IL-1 activity at the site, but its amount was too low for suppression of the produced IL-1. Loss of PG is a sequela of infiltrated leucocytes and leucocyte-derived elastase, and superoxide anion may play a pivotal role in the destruction of cartilage.
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PMID:Production of IL-1 and IL-1 receptor antagonist and the pathological significance in lipopolysaccharide-induced arthritis in rabbits. 834 45

The involvement of immune complexes during experimental arthritis in induction of metalloproteinases (MMP)-induced neoepitopes in aggrecan in cartilage, as well as the role of stromelysin-1 (SLN-1) in the induction of this neoepitope, was investigated. Passive immune complex arthritis was induced, and generation of the MMP-specific cleavage product (VDIPEN) was studied by immunolocalization. The role of SLN-1 was studied with use of SLN-1-deficient (SLN-1KO) mice. VDIPEN expression was studied in vitro by exposing the cartilage to IL-1 and subsequent activation of latent MMPs. Immune complex arthritis was characterized by an acute inflammation, with influx of mainly polymorphonuclear cells into the joint cavity. Expression of VDIPEN neoepitopes was consistently found in areas extensively depleted from proteoglycans. SLN-1KO mice did not show expression of the VDIPEN neoepitope, although inflammation and proteoglycan depletion was comparable to wild-type mice. In addition, erosions of cartilage were absent in SLN-1KO mice, but were present in wild-type mice, suggesting an important role for SLN-1 in cartilage destruction. In vitro studies showed that SLN-1 is also pivotally involved in IL-1-induced MMP activity. Stimulated polymorphonuclear neutrophils were able to activate latent MMPs present in the cartilage. Neutrophil elastase was also capable of activating IL-1-induced latent MMPs, which identifies elastase as a possible activator for latent VDIPEN-inducing MMPs. This study suggests that IC are important in the activation of latent MMPs in cartilage, possibly through polymorphonuclear neutrophil activation on the cartilage edge. SLN-1 is a pivotal enzyme in overall MMP-activity in cartilage during immune complex-mediated arthritis.
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PMID:Active matrix metalloproteinases are present in cartilage during immune complex-mediated arthritis: a pivotal role for stromelysin-1 in cartilage destruction. 1055 93

The present studies deal with polymorphonuclear neutrophil (PMN) adhesion inhibitory properties of cartilage surface proteoglycans. Normal human PMN were used in adhesion experiments with bovine cartilage surfaces exposed to neutrophil elastase and reconstituted with fibronectin (Fn) or on plastic-bound Fn. An extract of cartilage surface small proteoglycans (SE) and purified fibromodulin (FM), decorin (DCN), biglycan (BGN), and aggrecan (AGN) on the surface of normal cartilage were used to test for inhibition of Fn-dependent cell adhesion. The PMN did not adhere to intact articular cartilage surfaces, whereas significant adhesion was measured using cartilage explants digested with elastase and reconstituted with Fn. Incubation of elastase-treated, Fn-reconstituted cartilage with 45 microg/ml SE inhibited PMN adhesion by 50.7 +/- 5.8% (P < 0.0001). Addition of 50 microg/ml purified FM to the reconstituted articular surfaces inhibited cell adhesion by 71.2 +/- 13.9% (P < 0.0001). Inhibition of PMN adhesion to plastic-bound Fn was seen with 1.7 microg/ml SE (20.4 +/- 8.0%). Maximal inhibition of 67.4 +/- 14.8% (P < 0.01) was obtained with 17.0 microg/ml SE. With FM, concentrations of 4.3 microg/ml resulted in 34.7 25.2 inhibition (P < 0.001), and maximal inhibition of 66.3 16.2% (P < 0.01) was obtained with 43.0 microg/ml. Similar results were obtained with purified bovine DCN and BGN. The main component of cartilage matrix, AGN, failed to inhibit cell adhesion significantly. The results indicate that macromolecules normally present on articular cartilage surfaces act as a barrier to PMN adhesion. Since cartilage surface proteins are susceptible to breakdown by proteases from synovial fluid inflammatory cells, we postulate that the degradation of this barrier may be responsible for increasing PMN adhesion and subsequent cartilage damage in inflammatory arthritis.
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PMID:Polymorphonuclear leukocyte adhesion to articular cartilage is inhibited by cartilage surface macromolecules. 1151 37

Leukocyte recruitment in inflammation is critical for host defense, but excessive accumulation of inflammatory cells can lead to tissue damage. Neutrophil-derived serine proteases (cathepsin G [CG], neutrophil elastase [NE], and proteinase 3 [PR3]) are expressed specifically in mature neutrophils and are thought to play an important role in inflammation. To investigate the role of these proteases in inflammation, we generated a mouse deficient in dipeptidyl peptidase I (DPPI) and established that DPPI is required for the full activation of CG, NE, and PR3. Although DPPI(-/-) mice have normal in vitro neutrophil chemotaxis and in vivo neutrophil accumulation during sterile peritonitis, they are protected against acute arthritis induced by passive transfer of monoclonal antibodies against type II collagen. Specifically, there is no accumulation of neutrophils in the joints of DPPI(-/-) mice. This protective effect correlates with the inactivation of neutrophil-derived serine proteases, since NE(-/-) x CG(-/-) mice are equally resistant to arthritis induction by anti-collagen antibodies. In addition, protease-deficient mice have decreased response to zymosan- and immune complex-mediated inflammation in the subcutaneous air pouch. This defect is accompanied by a decrease in local production of TNF-alpha and IL-1 beta. These results implicate DPPI and polymorphonuclear neutrophil-derived serine proteases in the regulation of cytokine production at sites of inflammation.
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PMID:Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. 1182 96

ONO-5046 (sivelestat) is a competitive inhibitor of human neutrophil elastase from Ono Pharmaceutical, which is awaiting FDA approval for the treatment of pulmonary fibrosis and idiopathic interstitial pneumonia [349488]. An NDA was filed in Japan in September 1998 [299667]. It is in phase II trials for the treatment of acute circulatory failure [171678]. It is also being investigated as a potential treatment of arthritis [230100]. In animal models of asthma, sivelestat decreased the level of hemorrhage and protein extravasation into the bronchoalveolar lavage fluid after the administration of a 40 mg/kg injection of phorbol myristate acetate [188186]. The compound also inhibited the growth of human lung cancer cell lines in SCID mice [269736]. Sivelestat inhibits gastric lesion formation in rats subjected to water immersion restraint stress. Low oral bioavailability in vivo is due to extensive hepatic first-pass metabolism. Endotoxin-induced lung injury in rabbits was attenuated by pretreatment with sivelestat [276401]. In 1996, analysts at Yamaichi estimated sivelestat would be launched in Japan between 1998/9 and peak annual sales would be less than 5 billion yen [216018].
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PMID:ONO-5046 (Ono Pharmaceutical). 1610 41


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