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)

The aim of the study was to determine whether the amount of urinary trypsin inhibitor (UTI) in serum, a degenerate induced by neutrophil elastase (NE), reflects the degree of bronchial inflammation in children with acute asthma exacerbation. The involvement of neutrophil-mediated inflammation plays as important a role as eosinophil-mediated inflammation in the pathogenesis of acute asthma exacerbation. However, no measurable marker is sensitive enough to assess neutrophil-mediated inflammation in the airways. The pre-alpha-/inter-alpha-trypsin inhibitors are assumed to be precursors of UTI. NE degrades pre-alpha-/inter-alpha-trypsin inhibitors to liberate UTI. UTI concentrations in 25 childhood patients admitted with asthma exacerbation and 15 control subjects were measured by means of one-step sandwich-type enzyme immunoassay. Serum UTI concentrations in the patients at admission were significantly higher than control values (10.597+/-0.649 and 6.136+/-0.303 U x mL(-1), respectively (mean+/-SEM)). These levels returned to baseline values with improvement in the asthmatic symptoms. However, serum NE and alpha1 antitrypsin concentrations were not significantly different between patients and controls, even during acute exacerbation in the former. The findings suggest that neutrophil-mediated inflammatory events are involved in exacerbation of childhood asthma. The monitoring of urinary trypsin inhibitor concentrations might be useful for evaluating the neutrophil-mediated inflammation in childhood asthma attack.
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PMID:Increased serum concentration of urinary trypsin inhibitor with asthma exacerbation. 1462 Oct 78

Changes in granulocyte elastase (GLE) and Beta-gluculonidase (Beta-gl) were observed during open heart surgeries which were performed under deep hypothermia with surface cooling. In addition, the effect of urinary trypsin inhibitor, urinastatin, on the activities of these enzymes was studied. The patients were divided into three groups, namely group U-I with intravenous injection of 6000 u.kg(-1) of urinastatin before cooling, group U-II administered with an additional 6000 u.kg(-1) after warming to 30 degrees C, and an untreated group (Group C). The plasma level of GLE increased significantly in the three groups compared with the level before cooling respectively. In the group U-II, the GLE level after the warming was lower than that in the control group. The serum level of Beta-gl increased significantly in the three groups at the end of rewarming (36 degrees C). The release of GLE from lysosomes in granulocytes was inhibited in the group U-II. The insufficient inhibition of GLE release in the group U-I is probably due to relatively short half-life of urinastatin. Therefore double administration of 6000 u.kg(-1), before and after the cooling, may be required to achieve the therapeutic effect. Consequently, urinastatin appears to be useful in open heart surgery under deep hypothermia with surface cooling.
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PMID:The effects of urinastatin on the plasma levels of granulocyte elastase during open heart surgery under simple deep hypothermia. 1527 36

The bovine chymotrypsin-bovine pancreatic trypsin inhibitor (BPTI) interaction belongs to extensively studied models of protein-protein recognition. The accommodation of the inhibitor P1 residue in the S1 binding site of the enzyme forms the hot spot of this interaction. Mutations introduced at the P1 position of BPTI result in a more than five orders of magnitude difference of the association constant values with the protease. To elucidate the structural aspects of the discrimination between different P1 residues, crystal structures of five bovine chymotrypsin-P1 BPTI variant complexes have been determined at pH 7.8 to a resolution below 2 A. The set includes polar (Thr), ionizable (Glu, His), medium-sized aliphatic (Met) and large aromatic (Trp) P1 residues and complements our earlier studies of the interaction of different P1 side-chains with the S1 pocket of chymotrypsin. The structures have been compared to the complexes of proteases with similar and dissimilar P1 preferences, including Streptomyces griseus proteases B and E, human neutrophil elastase, crab collagenase, bovine trypsin and human thrombin. The S1 sites of these enzymes share a common general shape of significant rigidity. Large and branched P1 residues adapt in their complexes similar conformations regardless of the polarity and size differences between their S1 pockets. Conversely, long and flexible residues such as P1 Met are present in the disordered form and display a conformational diversity despite similar inhibitory properties with respect to most enzymes studied. Thus, the S1 specificity profiles of the serine proteases appear to result from the precise complementarity of the P1-S1 interface and minor conformational adjustments occurring upon the inhibitor binding.
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PMID:Crystal structures of five bovine chymotrypsin complexes with P1 BPTI variants. 1554 9

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis in Japan. Recent studies have demonstrated that serine protease inhibitors may play an anti-inflammatory role beyond merely an inhibitory action on neutrophil elastase at the site of inflammation at least in vitro. To clarify the direct contributions of UTI to inflammatory condition in vivo, we analyzed its roles in experimental systemic inflammatory response induced by intraperitoneal administration of lipopolysaccharide (LPS) using UTI deficient (-/-) mice and corresponding wild-type (WT) mice. After LPS (1 mg/kg) challenge, UTI (-/-) mice revealed a significant elevation of plasma fibrinogen and fibrinogen/fibrin degradation products and a decrease in white blood cell counts compared with WT mice. LPS treatment induced more severe neutrophilic inflammation in the lung and the kidney obtained from UTI (-/-) mice than in those from WT mice, which was confirmed by histological examination. The protein levels of proinflammatory mediators, such as macrophage chemoattractant protein (MCP)-1 in the lungs, MCP-1 and keratinocyte chemoattractant (KC) in the kidneys, and interleukin-1beta, macrophage inflammatory protein-2, MCP-1, and KC in the liver, were significantly greater in UTI (-/-) mice than in WT mice after LPS challenge. Our results suggest that UTI protects against systemic inflammatory response and subsequent organ injury induced by bacterial endotoxin, at least partly through the inhibition of the enhanced expression of proinflammatory cytokines and chemokines.
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PMID:Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide. 1557 31

We investigated the mechanisms by which serine proteases alter lung fluid clearance in rat lungs and vectorial ion transport in airway and alveolar epithelial cells. Inhibition of endogenous protease activity by intratracheal instillation of soybean trypsin inhibitor (SBTI) or alpha(1)-antitrypsin decreased amiloride-sensitive lung fluid clearance across rat fluid-filled lungs; instillation of trypsin partially restored this effect. Gelatin zymography demonstrated SBTI-inhibitable trypsin-like activity in rat lung lavage fluid. Apical trypsin and human neutrophil elastase, but not agonists of protease activated receptors, increased Na(+) and Cl(-) short-circuit currents (I(sc)) and transepithelial resistance (R(TE)) across human bronchial and nasal epithelial cells and rat alveolar type II cells, mounted in Ussing chambers, for at least 2 h. The increase in I(sc) was fully reversed by amiloride and glibenclamide. The increase in R(TE) was not prevented by ouabain, suggesting that trypsin decreased paracellular conductance. Apical trypsin also induced a transient increase in intracellular Ca(2+) in human airway cells; treatment of these cells with BAPTA-AM mitigated the trypsin-induced increases of intracellular Ca(2+) and of I(sc) and R(TE). Increasing intracellular Ca(2+) in airway cells with either ionomycin or thapsigargin reproduced the increase in I(sc), whereas inhibitors of phospholipase C (PLC) prevented the increases in both Ca(2+) and I(sc). These data indicate trypsin-like proteases and elastase, either present in lung cells or released by inflammatory cells into the alveolar space, play an important role in the clearance of alveolar fluid by increasing ion transport and paracellular resistance via a PLC-initiated rise of intracellular Ca(2+).
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PMID:Apical trypsin increases ion transport and resistance by a phospholipase C-dependent rise of Ca2+. 1562 48

In many complexes formed by serine proteinases and their inhibitors, the hydroxyl group provided by water molecule or by the inhibitor Ser residue is located close to the inhibitor P1-P1' reactive site. In order to investigate the role of this group, we synthesized analogues of trypsin inhibitor SFTI-1 isolated from the seeds of sunflower modified in P1 by alpha-hydroxymethylserine (HmSer) and both enantiomers of alpha-hydroxymethylvaline (HmVal). All the synthesized analogues inhibited bovine beta-trypsin and human leukocyte elastase. SFTI-1 analogues with HmVal and HmSer appear to be potent inhibitors of bovine beta-trypsin, whereas [Val5]SFTI-1 is practically inactive. Also trypsin inhibitory activity of [Ser5]SFTI-1 is significantly lower. Since the electrostatic interaction between protonated epsilon-NH2 group of the inhibitor P1 position and beta-carboxylate of trypsin Asp189 is the main driving force for interaction of both molecules, the results obtained are very interesting. We believe that these SFTI-1 analogues belong to a novel class of serine proteinase inhibitors.
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PMID:Introduction of alpha-hydroxymethyamino acid residues in substrate specificity P1 position of trypsin inhibitor SFTI-1 from sunflower seeds retains its activity. 1638 77

Several BPTI-Kunitz-type serine proteinase inhibitors were described in tick Boophilus microplus and Rhipicephalus sanguineus species. In this work, we present a synthetic gene based on two tick BPTI-Kunitz-type serine proteinase inhibitors, the first domain of B. microplus trypsin inhibitor-A (BmTI-A) and the carrapatin, the inhibitors were named BmTIsint and BmTIsint Mut. Our present results showed that BmTIsint and BmTIsint Mut inhibited trypsin (K(i) 3.3 and 1.0 nM) and human plasma kallikrein (K(i) 16.5 and 35 nM), but in contrast to BmTI-A, the inhibitors did not inhibit human neutrophil elastase. BmTIsint was able to produce immunological response in mice but not in bovines. In addition, it is the first description of a BPTI-Kunitz-type inhibitor as a cysteine proteinase inhibitor, BmTIsint apparent dissociation constant (K(i)) for cathepsin L was 108 nM. Our findings open the possibility up to obtain new molecules as potent serine or cysteine proteinase inhibitors using BmTIsint as a model.
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PMID:An unexpected inhibitory activity of Kunitz-type serine proteinase inhibitor derived from Boophilus microplus trypsin inhibitor on cathepsin L. 1641 23

BmSI-7 and BmSI-6, two Boophilus microplus subtilisin inhibitors (BmSI) were purified and characterized from eggs. The inhibitors isolated by classical purification methods presented molecular masses of 7408 and 7271Da, respectively, by MALDI-TOF-MS. Both BmSI-7 and BmSI-6 inhibited neutrophil elastase (K(i) 0.4 and 0.3nM) and subtilisin A (K(i) 1.4nM for both inhibitors). They also strongly inhibited Pr1 proteases from the fungus Metarhizium anisopliae; BmSI-7 (K(i) 50nM) and BmSI-6 (K(i) 2.2nM). The BmSI-7 full length cDNA was obtained using amino acid sequence information of BmSI-7 peptides generated by proteolytic digestion. BmSI-7 belongs to trypsin inhibitor like cysteine rich domain family (TIL), and it is transcribed in ovary, fat body, gut, salivary gland and haemocytes. BmSI-7 is the first TIL inhibitor described with inhibitory activity toward subtilisin A and Pr1 proteases of entomopathogenic fungi.
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PMID:BmSI-7, a novel subtilisin inhibitor from Boophilus microplus, with activity toward Pr1 proteases from the fungus Metarhizium anisopliae. 1788 50

To investigate the relationship between the inflammatory responses and postresuscitation syndrome, we prospectively examined the serial changes of neutrophil elastase (NE), urinary trypsin inhibitor (UTI), and TNF-alpha) in successfully resuscitated patients after out-of-hospital cardiac arrest. This study included 36 patients with out-of-hospital cardiac arrests who were admitted to our intensive care unit after return of spontaneous circulation (ROSC). The 11 patients who restored to spontaneous circulation within 30 min after cardiac arrest were defined as the short cardiac arrest group. The 25 patients who restored to spontaneous circulation more than 30 min after cardiac arrest were defined as the long cardiac arrest group. Eight healthy volunteers served as control group. Daily plasma levels of NE, UTI, and TNF-alpha were measured from days 1 to 5 after ROSC. The releases of NE from activated neutrophil just after ROSC in the patients with long cardiac arrest were statistically higher than those of the short cardiac arrest group. There was a significant correlation between the NE levels and the duration of cardiac arrest. A high but insufficient production of UTI for NE release was observed on day 1, especially in the patients with a long duration of cardiac arrest. The cerebral performance category of the short cardiac arrest group was better than that of the long cardiac arrest group. Although high levels of TNF-alpha were sustained in the postresuscitation period, the levels of TNF-alpha were unrelated to the duration of cardiac arrest. In conclusion, a massive release of NE in proportion to the duration of cardiac arrest and an insufficient production of UTI for the NE release may contribute to the pathogenesis of postresuscitation syndrome after out-of-hospital cardiac arrest.
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PMID:Insufficient production of urinary trypsin inhibitor for neutrophil elastase release after cardiac arrest. 1799 87

Boophilus microplus is a rich source of trypsin inhibitors, numerous Kunitz-BPTI (bovine pancreatic trypsin inhibitor) inhibitors have been described from larvae and eggs, named BmTIs. Among them, were characterized inhibitors for trypsin, human neutrophil elastase, human plasma kallikrein and plasmin. BmTIs elicited a protective immunological response against B. microplus infestation in cattle. However, only a small amount of purified natural BmTIs can be obtained from larvae and eggs by chromatographic methods, thus if BmTIs are to be used as vaccine antigens (immunogens) the production of recombinant BmTIs (rBmTIs) is essential. In this work we describe the cloning, expression, purification and characterization of rBmTI-6. rBmTI-6 is a three-headed Kunitz-BPTI inhibitor, expressed in the Pichia pastoris system. Although rBmTI-6 was processed by proteases and glycosylated during the expression process, these post-translational modifications did not alter the ability of rBmTI-6 to inhibit protease activity. Purified rBmTI-6 inhibited trypsin and plasmin.
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PMID:rBmTI-6, a Kunitz-BPTI domain protease inhibitor from the tick Boophilus microplus, its cloning, expression and biochemical characterization. 1850 87


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