Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both plasmin and elastase, a protease released from neutrophil granulocytes, are known to degrade fibrin(ogen). This raises the possibility that elevated plasma levels of split products such as D-dimer may in part result from elastase action. After incubation in vitro of fibrinogen and fibrin clots with elastase, a clearcut increase of D-dimer immunoreactivity was demonstrated by two commercial ELISA kits. In the plasma of 79 patients with inflammatory bowel disease, D-dimer values measured by one of the ELISA kits were correlated significantly not only with markers of thrombin and plasmin activation, but also with elastase-alpha 1-antitrypsin complexes (r = 0.3555; P = 0.014). Thus, the findings of this study suggest that indeed the D-dimer levels in patients with inflammatory disorders are influenced by neutrophil elastase. New tests discriminating effects of activated haemostasis from proteolysis by neutrophil enzymes might be helpful in differential diagnosis and monitoring of therapy.
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PMID:D-dimer tests detect both plasmin and neutrophil elastase derived split products. 778 49

Management strategies in Crohn's disease and ulcerative colitis should be based on up-to-date information on disease distribution, extent, activity and complications. A system of structured analysis is suggested, with separate consideration of destructive ulceration, inflammatory activity and other factors. Direct investigation of gut immunity by using whole gut lavage fluid (WGLF) is a valuable new technique of clinical investigation in IBD and related disorders. Recent studies have shown that the concentrations of plasma-derived proteins in WGLF provide objective measures of disease activity; and that this activity is a separate phenomenon from destructive ulceration and fibrosis. Neutrophils in the lumen can be in- investigated by cytology, or by assay of neutrophil elastase in WGLF. Cytokines and other immuno-regulatory mediators can also be detected. These new techniques can provide a description of intestinal immunity and inflammation, based on a non-invasive test of 2-4 h duration. Work in progress shows that patients who respond clinically to elemental diet treatment have unusually high concentrations of soluble IL2 receptor in WGLF; cytokine profiles may facilitate the selection of patients suitable for other new treatment modalities.
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PMID:Analysis of disease distribution, activity and complications in the patient with inflammatory bowel disease. 797 42

The activation of circulating polymorphonuclear leukocytes was determined in terms of superoxide radical generation and granulocyte elastase release in untreated patients with ulcerative colitis (N = 10) and Crohn's disease (N = 9) in remission and in control subjects (N = 10). Superoxide radical generation was determined by monitoring spectrophotometrically the reduction of ferricytochrome, after stimulation of cells with phorbol myristate acetate. Plasma elastase concentration was measured by a solid-phase enzyme immunoassay technique as the complex with alpha-1-proteinase inhibitor. Superoxide formation by polymorphonuclear leukocytes from patients with ulcerative colitis and Crohn's disease was significantly lower compared with controls [median (range) nmol/min/mg protein: Crohn's disease 7.8 (7.1-9.6); ulcerative colitis 8.25 (7.4-10.3); controls 14.7 (13.6-15.8)] (P < 0.001), while no difference was found between the two groups of patients. In contrast plasma elastase levels in patients with ulcerative colitis and Crohn's disease were similar to that of controls. This defective respiratory burst of polymorphonuclear leukocytes in patients with inflammatory bowel disease in remission, in absence of an altered degranulation, could represent an important factor for the pathogenesis of these diseases.
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PMID:Respiratory burst of circulating polymorphonuclear leukocytes and plasma elastase levels in patients with inflammatory bowel disease in remission. 813 91

Extravascular fibrin formation and dissolution is a pivotal event in numerous inflammatory and malignant diseases. In inflammatory cells such as monocytes/macrophages, neutrophil granulocytes appear to interact intimately with hemostasis and regulate the activity of the cascade systems of coagulation and fibrinolysis. Proteases such as neutrophil elastase are thought to influence components of hemostasis, and furthermore provide an alternative pathway of fibrinolysis. Histological, experimental, and clinical data suggest that extravascular fibrinolysis, mediated both by the plasmin system and by proteases like neutrophil elastase, is a prominent finding in various diseases such as lung cancer, chronic inflammatory bowel disease, vasculitis and connective tissue disease, bacterial sepsis, and septic shock.
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PMID:The role of inflammatory cells and their proteases in extravascular fibrinolysis. 912 14

Proteinases are important at several phases of physiological and pathological inflammation, mediating cellular infiltration, cytokine activation, tissue damage, remodeling, and repair. However, little is known of their role in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess the role of tissue proteases in a mouse model of colitis. Proteolytic activity was analyzed, using gel and in situ zymography, in colonic tissues from severe combined immunodeficient mice with colitis induced by transfer of CD4(+) T lymphocytes. Serine proteinase levels increased in colitic tissue, with major species of 23 kd, 30 kd, and 45 kd. Co-migration and inhibition studies indicated that the 23-kd proteinase was pancreatic trypsin and that the 30-kd species was neutrophil elastase. Matrix metalloproteinase (MMP)-9 expression, and MMP-2 and MMP-9 activation, was elevated in colitic tissues. Proteinase levels followed a decreasing concentration gradient from proximal to distal colon. Proteolysis was localized to infiltrating leukocytes in diseased severe combined immunodeficient mice. Transmural inflammation was associated with serine proteinase and MMP activity in overlying epithelium and with marked subepithelial proteolytic activity. The results demonstrate a clear elevation in the levels and activation of proteases in colitis, potentially contributing to disease progression through loss of epithelial barrier function.
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PMID:The role of up-regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis. 1110 65

ONO-6818 (CP-955) is the lead compound in a series of orally bioavailable neutrophil elastase inhibitors licensed from Cortech and under investigation by Ono for the potential treatment of inflammatory conditions, such as rheumatoid arthritis, inflammatory bowel disease and chronic obstructive pulmonary disease (COPD) [174095]. ONO-6818 was in phase I studies for COPD in Japan as of December 1999 [366431]. Phase I trials for this indication in Japan and the US were ongoing in September 2001 [368565], [422782], [446138]. As of June 2002, however, a number of unconfirmed reports stated that the compound had moved into phase II trials in Japan and was in preparation for phase II trials in the US [456596], [456597].
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PMID:ONO-6818 Cortech/Ono. 1221 8

Elafin (or skin-derived antileukoprotease) and secretory leukocyte protease inhibitor (SLPI) are serine antiproteases antagonizing human neutrophil elastase (HNE), thereby preventing tissue injury from excessive release of proteolytic enzymes by inflammatory cells. Furthermore, elafin and SLPI are "defensin-like" molecules with broad antimicrobial activity. The balance between proteases and antagonists may critically determine inflammatory processes in Crohn's disease (CD) and ulcerative colitis (UC). Real-time PCR was performed to quantitate colonic, proinflammatory cytokine IL-8, protease (HNE), and antiprotease mRNA (elafin and SLPI) in a total of 340 biopsies from 117 patients (47 CD, 45 UC, 25 controls). Histological inflammation was scored, and HNE, elafin, and SLPI were localized and semiquantified by immunostaining in 51 colonic paraffin sections (23 CD, 11 UC, 17 controls). Proinflammatory IL-8, degree of histological inflammation, and granulocyte content were similar in UC and CD. Elafin stained predominantly in the epithelium and SLPI in mucosal inflammatory cells. HNE mRNA levels and immunostaining were increased equally in both forms of inflammatory bowel disease. Levels of mRNA and immunostaining of the antiproteases elafin and SLPI were enhanced strongly in inflamed versus noninflamed UC. It is surprising that comparing inflamed versus noninflamed CD, this increase was significantly less pronounced for elafin and even lacking for SLPI. Despite comparable degrees of inflammation and protease levels, the induction of both antiproteases was attenuated in CD. This could contribute to the transmural depth of tissue destruction in CD. Elafin and SLPI may be added to the list of defensin-like peptides with diminished induction in CD versus UC.
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PMID:Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn's disease. 1720 Jan 45

Serpin B1 is a monocyte neutrophil elastase (NE) inhibitor and is one of the most efficient inhibitors of NE. In the present study, we investigated the role of serpin B1 in the pathogenesis of ulcerative colitis by using clinical samples and an experimental model. The colonic expression of serpin B1 was determined by real-time polymerase chain reaction (PCR), Western blot analysis, and immunohistological studies in both normal and inflamed mucosa from patients with ulcerative colitis. Serpin B1 mRNA expression was determined by real-time PCR in the mouse dextran sodium sulfate (DSS)-induced colitis model. Young adult mouse colonic epithelial (YAMC) cells were used to determine the role of serpin B1. Serpin B1 gene transfected YAMC cells were treated with H(2)O(2) to measure cell viability. The expression of NE was determined in YAMC cells treated with H(2)O(2). NE-silenced YAMC cells were also treated with H(2)O(2) and then measured for viability. Upregulated expression of serpin B1 in colonic mucosa was confirmed from patients with active ulcerative colitis. Immunohistochemical studies showed that serpin B1 expression was localized not only in inflammatory infiltration cells but also in epithelial cells. Serpin B1 mRNA expression was also increased in colonic mucosa of mouse DSS-induced colitis. Serpin B1-transfected YAMC cells were resistant against the treatment of H(2)O(2). H(2)O(2) treatment significantly induced NE in YAMC cells, and NE-silenced YAMC cells were also resistant against the treatment of H(2)O(2). These results suggest that serpin B1 may be a novel marker of active ulcerative colitis and may play an important role in the pathogenesis of inflammatory bowel disease.
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PMID:Serpin B1 protects colonic epithelial cell via blockage of neutrophil elastase activity and its expression is enhanced in patients with ulcerative colitis. 2242 20

CD-68 is widely regarded as a selective marker for human monocytes and macrophages and is commonly used in human pathology studies. The purpose of this study was to investigate the expression of CD-68 in human peripheral blood mononuclear cells (PBMCs), neutrophil granulocytes (NGs) and in inflamed intestinal tissue samples for comparison. PBMCs and NGs were isolated from heparinized human blood samples. Intestinal biopsies were obtained during routine endoscopic procedures from patients with inflammatory bowel disease (IBD), e.g. ulcerative colitis and Crohn's disease. Gene and protein expression was analyzed by real-time RT-PCR, Western blot and immunohistochemistry. Both PBMCs and NGs preparations contained cells that were positive for CD-68 and either neutrophil elastase (NE), or myeloperoxidase (MPO). CD-68(+)/NE(-)/MPO(-) cells were regarded as monocytes. CD-68 mRNA expression was detected in PBMCs and NGs preparations. With Western blot and by performing immunoprecipitation of cell lysate, we could clearly detect CD-68 in NGs, U-937, THP-1, Hep-G2, Jurkat cells and PBMCs. Identification of inflammatory cells in acutely inflamed colonic mucosa obtained from patients with IBD revealed a strong accumulation of CD-68(+)/MPO(+) cells compared to normal colonic mucosa. The uptake of the marker by phagocytosis was excluded by performing a double staining with CD-163/NE and CD-163/MPO in PBMCs, NGs cultures and in inflamed colonic mucosa. These results identify CD-68(+) NGs in peripheral blood and inflamed colonic mucosa. CD-68 is not only a marker for the macrophages-monocytes but also for NGs.
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PMID:Identification of CD68(+) neutrophil granulocytes in in vitro model of acute inflammation and inflammatory bowel disease. 2357 3

Polymorphonuclear leukocytes (PMNs) are innate immune cells whose principal function is to migrate from the blood to sites of inflammation, where they exert crucial anti-infectious and immunomodulatory effects. However, dysregulated migration of PMNs into mucosal epithelial tissues is characteristic of chronic inflammatory disorders, including inflammatory bowel disease. Carbohydrate-mediated binding interactions between PMN Lewis glycans and endothelial glycan-binding proteins are critical for initial migration of PMN out of the vasculature. However, the role of Lewis glycans during transepithelial migration (TEM) has not been well characterized. Herein, we show that antibody blockade of Lewis X (Le(x)) displayed as terminal glycan residues on the PMN surface blocks chemotaxis and TEM while enhancing PMN-adhesive interactions with intestinal epithelia. Unexpectedly, targeting of subterminal Le(x) residues within glycan chains had no effect on PMN migration or adhesive interactions. There was increased surface expression of Le(x) on PMN after TEM, and blockade of terminal Le(x) regulated post-migratory PMN functions, increasing PMN phagocytosis and the surface mobilization of azurophilic (CD63, myeloperoxidase, and neutrophil elastase) and specific (CD66b and lactoferrin) granule markers. These findings suggest that terminal Le(x) represents a potential target for regulating PMN trafficking and function in inflamed mucosa. Furthermore, given its abundant expression on migrating PMN, Le(x) may be a rational target for modulating inflammation in diseases where dysregulated PMN influx is associated with host tissue damage.
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PMID:Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation. 2668 91


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