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:3.4.21.37 (neutrophil elastase)
4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils play an important part in the development of acute inflammatory injury. Human neutrophils contain high levels of the serine protease elastase, which is stored in azurophilic granules and is secreted in response to inflammatory stimuli. Elastase is capable of degrading many components of extracellular matrix [1-4] and has cytotoxic effects on endothelial cells [5-7] and airway epithelial cells. Three types of endogenous protease inhibitors control the activity of neutrophil elastase, including alpha-1 protease inhibitor (alpha-1PI), alpha-2 macroglobulin and secreted leukoproteinase inhibitor (SLPI) [8-10]. A disturbed balance between neutrophil elastase and these inhibitors has been found in various acute clinical conditions (such as adult respiratory syndrome and ischemia-reperfusion injury) and in chronic diseases. We investigated the effect of NX21909, a selected oligonucleotide (aptamer) inhibitor of elastase, in an animal model of acute lung inflammatory disease [11-14]. This inhibitor was previously selected from a hybrid library of randomized DNA and a small-molecule irreversible inhibitor of elastase (a valine diphenyl ester phosphonate, Fig. 1), by the blended SELEX process [15]. We show that NX21909 inhibits lung injury and neutrophil influx in a dose-dependent manner, the first demonstration of efficacy by an aptamer in an animal disease model.
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PMID:Protective effects of an aptamer inhibitor of neutrophil elastase in lung inflammatory injury. 938 99

Serpins have a large external peptide loop known as the reactive loop. Part of the reactive loop functions as the primary recognition site for target proteases; however, the complete role of the reactive loop in determining serpin specificity is unclear. In the current study, we investigated the reactive loop region that could potentially interact with the extended binding site of target proteases; the P6-P3' region. We utilized a reactive loop switching strategy to determine the extent to which the inhibitory activity of alpha-1-protease inhibitor (PI) against human neutrophil elastase (HNE) could be transferred to alpha-1-antichymotrypsin (ACT), a serpin that does not inhibit HNE. A series of ACT-PI chimeras were constructed in which segments of increasing length taken from the P6-P3' region of PI replaced the corresponding residues of ACT. The effectiveness of each chimera as an inhibitor of HNE was assessed by measuring (1) the rate of inhibitory complex formation and (2) the rate of complex breakdown (complex stability). Although all the ACT-PI chimeras were fully functional against chymotrypsin-like proteases, the series of chimeras showed no consistent progress toward the production of an inhibitor with the inhibitory properties of PI. The most rapid complex formation and most stable complexes were observed for chimeras with the P3-P1 residues of PI, whereas extending the replacement region to the P6 residue resulted in a considerable decrease in both inhibitory parameters. In order to study two additional features of the PI reactive loop that may play a role in the presentation of the P6-P3' region to HNE, we constructed variants that contained a P4' proline and deleted the P6'-P9' residues. Changes on the prime side appeared to have little effect on rates of inhibition or complex stability. Overall, even the most effective chimeras demonstrated an inhibition rate constant at least 60-fold less than that observed for PI inhibition of HNE and the most long lived chimera-HNE complexes broke down more rapidly than PI-HNE complexes. These results indicate that residues in the reactive loop region predicted to contact a specific target protease cannot fully transfer inhibitory activity from one serpin to another, suggesting that specific reactive loop-serpin body and serpin body-protease body interactions play a significant role in determining serpin inhibitory activity against target proteases.
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PMID:Role of the P6-P3' region of the serpin reactive loop in the formation and breakdown of the inhibitory complex. 939 79

We found that human matrix metalloproteases (MMPs) may be processed from their proenzyme forms (proMMP) to their active forms by two new and unique mechanisms: Firstly, by bacterial proteases such as Pseudomonas elastase and Vibrio cholerae protease, which cleave off the N-terminal autoinhibitory domain (so-called cysteine switch) from proMMPs. The second mechanism depends on free radical generation by activated polymorphonuclear leukocytes (PMNs). In this case, peroxynitrite (ONOO-) or nitrogen dioxide radical (.NO2), the reaction products of either superoxide (O2.-) or molecular oxygen (O2) and nitric oxide (.NO), are the key reactants. Both O2.- and .NO are generated by activated macrophages and PMNs as a result of immunologic responses involving various proinflammatory cytokines. .NO2 or ONOO- seems to interact with a single cysteine residue in the propeptide autoinhibitory domain, or so-called cysteine switch of proMMPs, thus transforming proMMPs into their active conformation. Furthermore, reactive oxygen species are known to inactivate the alpha1-protease inhibitor (alpha1-PI), a potent neutrophil elastase inhibitor in plasma. In addition, we found that such radicals activate MMPs which degrade and inactivate alpha1-PI by proteolysis. Thus, the activation of MMPs, accompanied by the inactivation of alpha1-PI, will bring about enhanced proteolytic damage to the matrix tissues of the infected sites by both MMPs and elastase.
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PMID:Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals. 952 71

Urinary trypsin inhibitor (UTI) is a physiological protease inhibitor and inter-alpha-trypsin inhibitor (ITI) is regarded as a precursor of UTI. The purpose of this study is to determine the mechanism of the UTI release from ITI. To examine this, ITI was digested by human neutrophil elastase at various concentrations, and UTI-related proteins which were of the same size as UTI were obtained. The amino acid sequence of the 15 amino acid residues at the N-terminal of UTI-related proteins, corresponded to that of UTI. The amino acid sequences of the small amount of peptides detected corresponded to those of peptides from the heavy chain1 (H1) and the heavy chain2 (H2) of ITI, suggesting that most UTI-related proteins do not combine with peptides from the H1 and H2 of ITI. It was also revealed that UTI-related proteins have several physiological activities similar to those of UTI, i.e., human trypsin inhibitory activity, human neutrophil elastase inhibitory activity, inhibition of tumor necrosis factor-alpha (TNF-alpha) production from rat macrophages and of superoxide production from rabbit leukocytes. These results demonstrated that ITI is a precursor of UTI which is digested by human neutrophil elastase to release UTI, and that its elastase inhibitory activity is derived from UTI.
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PMID:Human neutrophil elastase degrades inter-alpha-trypsin inhibitor to liberate urinary trypsin inhibitor related proteins. 970 43

Binding of human leukocyte elastase (HLE) to human plasma fibronectin (Fn) was determined by its competition with an oligopeptide chromogenic substrate. Kinetic curves of accumulation of the substrate hydrolysis product in the presence of Fn were specific for slow-binding one-step inhibitors of the enzyme. Values of rate constants for HLE association with Fn and for the dissociation of the complex were, respectively, 2.2.10(3) M(-1).sec(-1) and 1.4.10(-3) sec(-1) at pH 7.5 and 25 degreesC. The dissociation constant of the HLE--Fn complex determined independently by titration of the enzyme with the protein substrate and neglecting the hydrolysis was 3.9.10(-7) M. The resulting values were suggested to describe a high-affinity site in the Fn molecule which was subjected to the primary attack by HLE. The soybean Bowman--Birk protease inhibitor (BBI) efficiently inhibited the HLE-induced degradation of Fn under conditions of both inhibitor preincubation with the protease and its addition into the reaction mixture of the protease with Fn.
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PMID:Interaction of human leukocyte elastase with plasma fibronectin and its inhibition by soybean Bowman-Birk protease inhibitor. 979 79

This study examined the role of cysteine proteinases and their inhibitor in the development of emphysema in comparison with neutrophil elastase (NE) complexed with alpha1-protease inhibitor (NE-alpha1-PI), which was previously demonstrated to be increased in bronchoalveolar lavage (BAL) fluid from subjects with subclinical emphysema. Eight nonsmokers and 31 current smokers with (n=17) and without (n=14) emphysema, as evidenced by lung computed tomographic scans, were studied. The concentrations of immunologically detected cathepsin L and cystatin C, but not cathepsin B, were significantly increased in BAL fluid from the smokers with emphysema compared with those without emphysema, although the activity of cathepsin L, measured using a synthetic substrate and cathepsin L, released from cultured alveolar macrophages at 24 h, did not show any significant difference between the two groups. When comparison was made only for the subjects aged <60 yrs, the difference between the two groups disappeared for cathepsin L, but remained for NE-alpha1-PI. There was no significant correlation between the level of cathepsin L and that of NE-alpha1-PI in BAL fluid from the subjects with emphysema. In conclusion, increased levels of cathepsin L and cystatin C were demonstrated in bronchoalveolar lavage fluid from subjects with subclinical emphysema. However, the roles of cathepsin L and neutrophil elastase in the development of emphysema may vary between subjects and between the young and the old.
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PMID:Cysteine proteinases and cystatin C in bronchoalveolar lavage fluid from subjects with subclinical emphysema. 986 93

Various treatment regimens and difficulties with research design are encountered with cystic fibrosis (CF) because no standard diagnostic criteria exist for defining acute respiratory exacerbations. This study evaluated the role of serial monitoring of concentrations of selected cytokines and inflammatory mediators in serum and sputum as predictors of respiratory exacerbation, as useful outcome measures for CF, and to guide therapy. Interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha), neutrophil elastase-alpha-1-protease inhibitor complex (NE complex), protein, and alpha-1-protease inhibitor (alpha-1-PI) were measured in serum and sputum collected from CF patients during respiratory exacerbations and periods of well-being. Levels of NE complex, protein, and alpha-1-PI in sputum rose during respiratory exacerbations and fell after institution of antibiotic therapy (P = 0.078, 0.001, and 0.002, respectively). Mean (+/- standard error of the mean) levels of IL-8 and TNF-alpha were extremely high in sputum (13,780 +/- 916 and 249.4 +/- 23.5 ng/liter, respectively) but did not change significantly with clinical deterioration of the patient (P > 0.23). IL-8 and TNF-alpha were generally undetectable in serum, and therefore these measures were unhelpful. Drop in forced expiratory volume in 1 s was the only clinical or laboratory parameter that was close to being a determinant of respiratory exacerbation (P = 0.055). This study provides evidence of intense immunological activity occurring continually within the lungs of adult CF patients. Measurement of cytokines and inflammatory mediators in CF sputum is not helpful for identifying acute respiratory exacerbations.
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PMID:Cytokines and inflammatory mediators do not indicate acute infection in cystic fibrosis. 1006 64

Nafamostat mesilate (FUT-175) is a protease inhibitor, working as an inactivator of coagulation, fibrinolysis and platelet aggregation. Although FUT-175 directly blocks contact factors in coagulation, it also may decrease activation of humoral cascade systems when used in cardiopulmonary bypass circuits. We performed an in vitro study using fresh human blood in the following cardiopulmonary bypass circuits: standard circuit (C), biosurfaced circuit (B) and standard circuit containing FUT-175 (F). Each circuit was primed with 500 ml of electrolyte solution and 500 ml of fresh blood. Cardiopulmonary bypass was performed using a roller pump for four hours in two sets of each circuit configuration. Platelet factors (platelet count and beta-thromboglobulin), coagulation factors (thrombin-antithrombin III complex and fibrinopeptide A), fibrinolysis factors (alpha 2-plasmin inhibitor complex and alpha 2-plasmin inhibitor), complement factors (C3a, C4a), free hemoglobin, and granulocyte elastase were measured at the beginning and end of the study. Hemocytograms were measured concurrently. The FUT-175 group showed significantly lower levels of the measured indices than the biosurfaced group in thrombin-antithrombin III complex (7.4 +/- 2.1 vs. 54.9 +/- 38.1 ng/ml), fibrinopeptide A (7.2 +/- 2.0 vs. 20.2 +/- 14.6 ng/ml), beta-thromboglobulin (1940 +/- 250 vs. 2438 +/- 314 ng/ml) and free hemoglobin (25.2 +/- 14.3 vs. 73.8 +/- 18.4 mg/dl). There were no significant differences between Group F and Group B in platelet count, C3a, C4a and granulocyte elastase, although these indices were significantly lower in Groups F and B when compared to Group C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nafamostat mesilate reduces blood cell adhesion to cardiopulmonary bypass circuits: an in-vitro study. 1015 Jun 79

Tryptase Clara, a trypsin-like protease localized exclusively in and secreted by Clara cells of the bronchial epithelium, is a prime host factor that processes viral envelope glycoproteins and determines the infectivity of influenza A and Sendai viruses (H. Kido, Y. Yokogoshi, K. Sakai, M. Tashiro, Y. Kishino, A. Fukutomi, and N. Katunuma, The Journal of Biological Chemistry, 1992, Vol. 267, pp. 13573-13579). We report here that human mucus protease inhibitor (MPI), a major inhibitor of granulocyte elastase in the lining fluid of the human respiratory tract, significantly inhibited induction of the infectivity of influenza A and Sendai viruses by tryptase Clara in vitro and multicycles of mouse-adapted influenza A virus replication in rat lungs in vivo. Recombinant MPI and the C- but not the N-terminal domain of MPI inhibited both the activity of tryptase Clara and the induction of virus infection by tryptase Clara. The 50% inhibitory concentrations of MPI and the C-terminal domain peptide (Pro50-Ala107) of MPI for tryptase Clara were 7.4 and 61.6 nM, respectively, with Sendai virus envelope glycoproteins as the substrate. Studies on deletion mutants of the C-terminal domain of MPI revealed that the minimal size of MPI required for the inhibition of tryptase Clara is the peptide Lys60-Ala107. Studies involving site-directed mutagenesis of the C-terminal domain of MPI indicated that the Leu72-Met73 site of MPI is the inhibitory site for tryptase Clara. Substitution of residue Leu72 with a basic amino acid significantly increased in the inhibitory activity of the C-terminal domain of MPI, but further substitution of residue Met73 with various amino acids in these mutants reduced the inhibitory activity. Since there is evidence suggesting that the concentration of MPI in respiratory fluid is insufficient for prevention of virus infection, the administration of MPI, the recombinant C-terminal domain of MPI, and their mutants, with residue Leu72 substituted with residues Arg72 and Lys72, may be useful for treatment of such pneumotropic virus infections.
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PMID:The human mucus protease inhibitor and its mutants are novel defensive compounds against infection with influenza A and Sendai viruses. 1038 Mar 55

High levels of active neutrophil elastase (HNE) are present in the respiratory secretions of patients with cystic fibrosis (CF). We hypothesized that aerosolized Prolastin (alpha(1)-protease inhibitor or alpha(1)PI, purified from human blood) could suppress airway neutrophil inflammation and accelerate bacterial clearance from the lung in a model of chronic Pseudomonas aeruginosa lung infection. Because human alpha(1)PI effectively inhibits rat as well as human neutrophil elastase (NE) activity in vitro, we choose to test this hypothesis using a rat agar bead model of chronic P. aeruginosa lung infection. In this model, aerosolized Prolastin significantly decreased elastase activity (p < 0.01), lung neutrophil counts (p < 0.01), and bacterial colony counts (p < 0.01). Prolastin had no direct bactericidal effect on P. aeruginosa in vitro. Lung tissue histopathology revealed a marked decrease in lung inflammation in animals treated with Prolastin. These studies indicate that Prolastin can significantly decrease the elastase burden in the chronically infected lung. In addition, not only does Prolastin suppress lung inflammation, but it also markedly decreases P. aeruginosa density in a rat model of chronic P. aeruginosa lung infection. These data suggest that aerosolized alpha(1)PI may represent a useful nonantibiotic adjunct in the treatment and control of infection and inflammation associated with CF lung disease.
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PMID:Aerosolized prolastin suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection. 1050 98


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