Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Short-term exposure to ozone at peak ambient levels induces neutrophil influx and impairs lung function in healthy humans. In order to investigate the mechanisms contributing to neutrophil recruitment and to examine the role of T-cells in the acute inflammatory response, we exposed 12 healthy humans to 0.2 parts per million (ppm) of ozone and filtered air on two separate occasions for 2 h with intermittent periods of rest and exercise (minute ventilation = 30 L x min(-1)). Fibreoptic bronchoscopy was performed 6 h after the end of exposures. Total protein, tryptase, histamine, myeloperoxidase, interleukin (IL)-8 and growth-related oncogene-alpha (Gro-alpha) were measured and total and differential cell counts were performed in bronchoalveolar lavage (BAL) fluid. Flow cytometry was performed on BAL cells to study total T-cells, T-cell receptors (alphabeta and gammadelta), T-cell subsets (CD4+ and CD8+ cells) and activated T-cell subsets (CD25+). Using immunohistochemistry, neutrophils, mast cells, total T-cell numbers, T-cell subsets, CD25+ T-cells and leukocyte endothelial adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were quantified in the bronchial biopsies. Paired samples were available from nine subjects. Following ozone exposure there was a threefold increase in the proportion of polymorphonuclear neutrophils (PMNs) (p=0.07) and epithelial cells (p=0.05) in BAL fluid. This was accompanied by increased concentrations of IL-8 (p=0.01), Gro-alpha (p=0.05) and total protein (p=0.058). A significant positive correlation was demonstrated between the two chemokines and proportion of PMNs in BAL fluid. After ozone exposure there was a significant decrease in the CD4/CD8 ratio (p=0.05) and the proportion of activated CD4+ (p=0.01) and CD8+ T-cells (p=0.04). However, no significant changes were demonstrable in any of the inflammatory markers studied in the biopsies. Short-term exposure of healthy humans to 0.2 ppm ozone induced a neutrophil influx in peripheral airways at 6 h post exposure, but no apparent inflammatory response in proximal airways. This response seems to be mediated at least in part by interleukin-8 and growth-related oncogene-alpha.
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PMID:Effects of 0.2 ppm ozone on biomarkers of inflammation in bronchoalveolar lavage fluid and bronchial mucosa of healthy subjects. 965 69

Linear IgA bullous dermatosis (LAD) is an acquired, heterogeneous, subepidermal blistering disease characterized by linear IgA deposits at the dermoepidermal basement membrane zone (BMZ), often with circulating IgA antibodies to the BMZ. The pathogenetic mechanism, possibly related to the immunophenotype of infiltrating cells, as well as the potential role of cytokines in determining bullous lesions, have not yet been elucidated. An immunohistochemical study was performed with a large panel of monoclonal antibodies [to CD3, CD4, CD8, CD25, CD1a, CD30, CD54, CD50, endothelial leucocyte adhesion molecule-1, vascular cell adhesion molecule-1, myeloperoxidase (MPO), eosinophil cationic protein EG1 and EG2, tryptase, HLA-DR, human interleukin (IL)-3, human IL-5, human IL-8, human IL-4, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte/macrophage colony-stimulating factor] using the alkaline phosphatase-antialkaline phosphatase procedure on lesional and perilesional skin of nine patients (one male, eight female; age range 8 months-80 years) with clinical, histological and immunofluorescent proven LAD. The predominant infiltrating cells, distributed mostly inside and below the bullae, were neutrophils and eosinophils which showed intense activation (MPO +, EG1 +, EG2 +). The lymphocytic infiltrate, consisting principally of CD4 +, HLA-DR + and CD30 + T cells, had a predominantly perivascular distribution. Proinflammatory cytokines, such as TNF-alpha and IFN-gamma, showed a moderate focal expression on the dermal perivascular sites; IL-8 was found to have a particularly intense staining on all the epidermal cell layers and at perivascular and vascular sites. Other cytokines, such as IL-4 and IL-5, showed a prevalent intracytoplasmic staining on some cells of the dermal infiltrate (probably mastocytes and lymphocytes), and at the dermal-epidermal separation sites there was also an intense scattered distribution of IL-5. The specific tissue lesions of LAD may be the consequence of the IgA deposits at the BMZ and also of the release of these cytokines together with tissue damage enzymes derived from neutrophils or eosinophils.
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PMID:The role of lymphocytes, granulocytes, mast cells and their related cytokines in lesional skin of linear IgA bullous dermatosis. 1035 73

The selectin family of adhesion molecules (E-, P- and L-selectins) is involved in leukocyte recruitment to sites of inflammation and tissue damage. Recently it has been shown that L-selectin is involved not only in leukocyte tethering and rolling, but also plays an important role in leukocyte activation. For example, glycosylation-dependent cell-adhesion molecule 1 (GlyCAM-1), a known ligand for L-selectin, has been shown to enhance beta2-integrin function. GlyCAM-1 is a secreted protein and is present in mouse serum at a concentration of approx. 1.5 microg/ml. There is no obvious GlyCAM-1 homologue in man and, to date, L-selectin ligand(s) from human serum have not been characterized. Therefore we have used L-selectin affinity chromatography, followed by ion-exchange chromatography, to isolate specific ligand(s) for L-selectin. Using this procedure, we have isolated three major glycoproteins of apparent molecular masses 170 kDa, 70kDa and 50 kDa. The 170 kDa protein band was digested with trypsin and peptides were analysed by delayed extraction matrix-assisted laser desorption ionization MS and protein database searching. The 170 kDa protein was identified as the human complement protein Factor H. Human Factor H, isolated by a different method, was shown to bind specifically to L-selectin in the presence of CaCl2, and binding was inhibited by anti-L-selectin antibodies, fucoidan and lipopolysaccharide. Only a part of the purified Factor H preparation bound to immobilized L-selectin. The interaction of Factor H with leukocyte L-selectin was shown to induce the secretion of tumour necrosis factor-alpha (TNF-alpha). Pretreatment of Factor H with sialidase reduced both the binding of L-selectin to Factor H and the Factor H-induced L-selectin-mediated TNF-alpha secretion by leukocytes. Taken together, these results demonstrate that a post-translationally modified form of human plasma Factor H is a potential physiological ligand for L-selectin.
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PMID:Identification of human complement Factor H as a ligand for L-selectin. 1037 45

There is a microcirculation system within the islets of Langerhans. However, little is known about the phenotypic and functional characterization of islet microvascular endothelial cells (MVEC). In this study, we purified MVEC from human pancreatic islets by using Ulex europaeus (Sigma, St. Louis, MO) agglutinin-1 (UEA-1)-coated dynabeads (Dynal A.S., Oslo, Norway). These purified human islet MVEC (HI-MVEC) express von Willebrand factor, take up high levels of acetylated LDL, and upregulate endothelial cell leukocyte adhesion molecule 1 in response to tumor necrosis factor-alpha. Ultrastructure examination shows the presence of microvilli and fenestrations on the cell surface, Weibel-Palade bodies in the cytoplasm, and tight junctions between cells. Furthermore, we show that vascular endothelial cell growth factor contributes to the formation of surface fenestrations on cultured HI-MVEC. After purification, HI-MVEC exhibit a very low proliferation capacity and are strongly resistant to trypsin, compared with other original MVEC. We also demonstrate that alpha-1 proteinase inhibitor (Api) is expressed on HI-MVEC and specifically located at the area of cell-cell junctions. By reverse transcription-polymerase chain reaction, a significant messenger RNA band of Api was found only in HI-MVEC, but not in other organ-derived MVEC, indicating that expression of Api is islet MVEC specific. Antibodies to Api significantly reversed the resistance to trypsin and promoted proliferation of HI-MVEC, suggesting that these specific functional characteristics of HI-MVEC are related to the expression of Api. These results indicate that HI-MVEC exhibit some specific morphological and functional characteristics that differ from MVEC derived from other organs.
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PMID:Expression of alpha-1 proteinase inhibitor in human islet microvascular endothelial cells. 1048 Jun 7

Tryptase and myeloperoxidase respectively represent 2 specific markers of activated mast cells or neutrophils. Therefore, establishing the levels of these enzymes may be useful to quantify the cell involvement in the tissues or fluids of different origins and in different pathologies. The aim of this study was to analyse the levels of these 2 markers in both the sera and blister fluids of patients affected with bullous pemphigoid. These levels were then correlated to the concentrations of 19 cytokines and 2 soluble adhesion molecules determined in the same samples and also with the log (anti-basement membrane zone antibody) titres, evaluated in the patients' sera. For these purposes, 15 patients with bullous pemphigoid (10 males and 5 females; median age: 84 years, range 66-87; median disease duration: 0 years, range 0-3: median number of skin lesions: 17, range 14-30; median anti-basement membrane zone antibody titre: 1:320, range 0.0-1:2560) and 15 normal subjects (11 males and 4 females, median age: 81 years, range 59-86) were analysed by means of commercially available kits. Results showed that blister fluid myeloperoxidase and tryptase levels were increased as compared with the respective sera (P<0.01) and several correlations were observed with cytokines and adhesion molecules. In fact, significant correlations of blister fluid tryptase levels were observed with IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, VEGF, RANTES and sICAM-1, while myeloperoxidase was correlated with IL-1beta, IL-13 and IL-15. The blister fluid tryptase levels were also significantly correlated with the anti-basement membrane zone antibody titres (R=0.53, P=0.05). In conclusion, these findings are in accord with an involvement of both mast cells and neutrophils in bullous pemphigoid and their recruitment may be mediated by different biological modulators. Our findings seem to indicate that the cytokine (IL-3, IFN-gamma and OSM) or adhesion molecule (sICAM-1) concentrations in blister fluid are logarithmically related to the anti-basement membrane zone antibody titers.
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PMID:Increased tryptase and myeloperoxidase levels in blister fluids of patients with bullous pemphigoid: correlations with cytokines, adhesion molecules and anti-basement membrane zone antibodies. 1077 87

Malaria merozoite surface and apical organellar molecules facilitate invasion into the host erythrocyte. The underlying molecular mechanisms of invasion are poorly understood, and there are few data to delineate roles for individual merozoite proteins. Apical membrane antigen-1 (AMA-1) is a conserved apicomplexan protein present in the apical organelle complex and at times on the surface of Plasmodium and Toxoplasma zoites. AMA-1 domains 1/2 are conserved between Plasmodium and Toxoplasma and have similarity to the defined ligand domains of MAEBL, an erythrocyte-binding protein identified from Plasmodium yoelii. We expressed selected portions of the AMA-1 extracellular domain on the surface of COS-7 cells to assay for erythrocyte-binding activity. The P. yoelii AMA-1 domains 1/2 mediated adhesion to mouse and rat erythrocytes, but not to human erythrocytes. Adhesion to rodent erythrocytes was sensitive to trypsin and chymotrypsin, but not to neuraminidase. Other parts of the AMA-1 ectodomain, including the full-length extracellular domain, mediated significantly less erythrocyte adhesion activity than the contiguous domains 1/2. The results support the role of AMA-1 as an adhesion molecule during merozoite invasion of erythrocytes and identify highly conserved domains 1/2 as the principal ligand of the Plasmodium AMA-1 and possibly the Toxoplasma AMA-1. Identification of the AMA-1 ligand domains involved in interaction between the parasite and host cell should help target the development of new therapies to block growth of the blood-stage malaria parasites.
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PMID:Erythrocyte-binding activity of Plasmodium yoelii apical membrane antigen-1 expressed on the surface of transfected COS-7 cells. 1155 31

Allergen specific immunotherapy (IT) represents a cornerstone of allergic rhinitis treatment and his efficacy has been confirmed, through open and double blind trials and meta-analysis. In the last few years non invasive routs for IT (oromucosal, nasal) were developed gained general acceptation mainly in children and were validated by WHO. The efficacy of IT could be markers, the pattern of specific antibody response or by the effect on sequential nasal challenges. We have evaluated the effect of IT in allergic rhinitis by different methods. Nasal IT decreased mean symptoms and pharmacological scores as well as in seasonal as in perennial rhinitis. The same decrease has been observed after oromucosal IT. The effect of IT in allergic inflammation has been confirmed by a decrease in the level of soluble adhesion molecule sVCAM-1 which is related to eosinophilic inflammation but not statistically for sICAM-1. We have also evaluated the immunoblotting pattern or specific IgE after oromucosal IT for house dust mites. For D. pteronyssinus in 4 patients the bands intensity decreased and in 3 patients the bands decreased and in 10 disappeared. IT decreases tryptase and ECP in nasal lavage after sequential nasal challenges. Therefore IT decreases clinical scores, inflammation markers, specific IgE immunoblotting bands and response to allergen challenge. These different results confirm his efficacy and usefulness in allergic rhinitis.
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PMID:Immunotherapy in allergic rhinitis. 1176 23

Junctional adhesion molecule-A (JAM-A) regulates key inflammatory responses, such as edema formation and leukocyte transmigration. Although it has been reported that the inflammatory cytokine tumor necrosis factor (TNF) causes the disassembly of JAM-A from the intercellular junctions, the mechanism has not been elucidated fully. Here, we report that TNF enhances the solubility of JAM-A in Triton X-100 and increases the amount of Triton-soluble JAM-A dimers at the cell surface but does not change the total levels of cellular JAM-A. Thus we hypothesized that TNF causes the redistribution of JAM-A from the junctions to the cell surface and that junction disassembly is sufficient to account for JAM-A redistribution. Intriguingly, however, even after complete disassembly of the junctions (with EDTA and trypsin), higher levels of JAM-A are detectable at the cell surface (by FACS analysis) in cells that had been previously incubated in the presence of TNF than in its absence. Thus we propose that TNF causes not only the disassembly of JAM-A from the junctions and its subsequent redistribution to the cell surface but also its dispersal in such a way that JAM-A becomes more easily accessible to the antibodies used for FACS analysis. Finally, we evaluated whether soluble fibronectin might attenuate the effects of TNF on JAM-A, as some inflammatory conditions are associated with the depletion of plasma fibronectin. We found that fibronectin reduces the effect of TNF on the disassembly of JAM-A, but not on its dispersal, thus further stressing that disassembly and dispersal can be functionally dissociated.
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PMID:Opposite effects of tumor necrosis factor and soluble fibronectin on junctional adhesion molecule-A in endothelial cells. 1588 98

The spectrum of ocular allergy ranges from mild, non-sight threatening disease, such as hay fever, to disorders such as atopic keratoconjunctivitis (AKC) which cause permanent ocular surface changes and reduced vision. The ideal treatment is with topical preparations. Launched topical preparations include anti-histamines and mast cell (MC) stabilisers, which are safe, but only moderately potent, steroids, which are very potent, but carry very serious side-effects, and cyclosporin A, which is not widely available and difficult to tolerate. There are a number of anti-histamines, MC stabilisers (and combinations thereof) and steroids in development which are of potential interest. Other possibilities for therapeutic intervention include inhibition of tryptase, cyclooxygenase (COX), leukotrienes (LTs), bradykinins (BKs), platelet activating factor (PAF) and immunoglobulin E (IgE). Therapies based on cytokine antagonism and agonism, T-cell inhibition and adhesion molecule antagonism might be expected to provide safe, but potent new modes of treatment. The increasing interest in research into the pathogenesis of ocular allergic inflammation may lead to more relevant approaches, such as eosinophil inhibition. Success will be highly dependent on the ability to produce suitable topical ophthalmic preparations.
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PMID:Drug therapy for ocular allergy. 1599 17

Proteinase-activated receptors (PARs) are a novel family of G-protein-coupled receptors. PAR2 has been implicated in inflammatory airways disease. Although fibroblasts are pathologically important in the airways, the proinflammatory role of PAR2 in these cells remains unknown. We assessed PAR expression and functionality in human primary bronchial fibroblasts (HPBFs) before assessing PAR2-mediated HPBF proliferation, cytokine production, and adhesion molecule expression. RT-PCR and flow cytometry demonstrated that HPBFs express hPAR1, hPAR2, and hPAR3, but not hPAR4. Intracellular calcium signaling in HPBFs in response to PAR agonists showed that only hPAR1 and hPAR2 were functional receptors. We used the MTT assay to assess HPBF proliferation. Of the PAR2 agonist proteinases or selective PAR2-activating peptides (PAR2-APs) tested, none stimulated HPBF proliferation, whereas thrombin was a HPBF growth factor. mRNA for IL-8 and granulocyte colony-stimulating factor (G-CSF) was upregulated after addition of SLIGKV-NH2 when assessed by RT-PCR. No significant increase in G-CSF or IL-8 protein was detected. Trypsin stimulated IL-8 and G-CSF release from HPBF in a time- and dose-dependent manner. Leupeptin and soya trypsin inhibitor abrogated trypsin-stimulated cytokine release, indicating a requirement for trypsin's proteolytic activity. Trypsin and SLIGKV-NH2 stimulated an increase in VCAM-1 expression at 12 h after treatment, which declined thereafter. PAR2-driven upregulation of VCAM-1 cell surface expression and the release of IL-8 and G-CSF from bronchial fibroblasts may be important in promoting neutrophilic airways inflammation.
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PMID:Proteinase-activated receptor2 agonists upregulate granulocyte colony-stimulating factor, IL-8, and VCAM-1 expression in human bronchial fibroblasts. 1649 82


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