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

The relationship between inter-alpha inhibitor (I alpha I) and urinary proteinase inhibitor (UPI) was examined by comparing purified UPI with a proteolytic fragment of I alpha I (I'), and by demonstrating that inflammatory cells produce similar fragments under physiologic conditions. Purified I', derived by chymotrypsin digestion of I alpha I, was similar to UPI in apparent molecular weight (68,000-69,000), amino acid composition, immunoreactivity, and inhibitory activity against trypsin, chymotrypsin, and neutrophil elastase. The production of similar inhibitory fragments by murine peritoneal macrophages, human neutrophils, and a murine mast cell line was quantified. Neutrophils were most efficient at proteolyzing I alpha I. Comparison of the pattern of I alpha I degradation by neutrophil preparations with that by pure enzymes, suggested that both elastase and cathepsin G mediate neutrophil proteolysis of I alpha I. These proteinases may thus be responsible for inflammation-related increases in UPI-like inhibitor levels in vivo.
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PMID:Inflammatory cells degrade inter-alpha inhibitor to liberate urinary proteinase inhibitors. 246 21

Polymorphonuclear leukocytes contain well-defined proteolytic enzymes in their azurophilic granules that can be released into tissues during inflammation, producing a localized excess of proteases that causes a protease-antiprotease imbalance with subsequent tissue destruction. The antiproteolytic compounds of the epidermis, such as the protease inhibitors elafin and antileukoprotease, are thought to counteract the proteolytic tissue damage. We investigated the urine of patients suffering from inflammatory skin conditions (e.g., erysipelas, psoriasis) for the presence of urinary antiprotease activities. Purification of elastase-inhibitory activities from pooled urine samples by cation exchange high-performance liquid chromatography and preparative and analytical reverse-phase high-performance liquid chromatography yielded two different types of inhibitors. One was a cationic, acid-stable, and elastase-specific inhibitor of M(r) 6,000 by size-exclusion high-performance liquid chromatography. N-terminal amino acid sequence analysis of the first 28 residues showed identity with elafin, an elastase-specific inhibitor recently isolated from psoriatic scales. The second anti-protease activity was due to two forms of urinary bikunin, the inhibitory subunit of inter-alpha-inhibitor. Both bikunin fragments, with M(r) 4,000 and 16,000, were identified by N-terminal amino acid sequence analysis of the first 10 residues and were characterized by an antiproteolytic profile against human leukocyte elastase, cathepsin G, and trypsin. Urinary protease inhibitors may serve as diagnostic markers of inflammatory diseases.
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PMID:Antiprotease activity in urine of patients with inflammatory skin disorders. 756 Nov 59

A glycoprotein with a high inhibitory activity against trypsin was isolated in 1961 from human plasma and named inter-alpha trypsin inhibitor (ITI). Since then, several other proteins that share antigenic and structural similarities with ITI have been identified and classified as members of the ITI protein family. These glycoproteins built up from different combinations of four polypeptides HC1, HC2, HC3 and bikunin are encoded by four genes H1, H2, H3, L on three chromosomes. Bikunin has two proteinase inhibitor domains and belongs to the Kunitz-type protease inhibitor family; it displays an inhibitory activity against trypsin, leukocyte elastase and plasmin. The heavy chains do not have any protease inhibitory properties but have the capacity to interact in vitro and in vivo with hyaluronic acid. This binding promotes the stability of the extra-cellular matrix. Consequently, the ITI protein family is suspected of playing a key role in the extra-cellular matrix biology. Isolation of free heavy chains in bronchial secretions and the recent emphasis about the bikunin role in tumoral invasion should enhance the interest about ITI protein family in the pathophysiology of chronic bronchopulmonary diseases or lung cancer progression.
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PMID:[Proteins of the inter-alpha trypsin inhibitor (ITI) family. A major role in the biology of the extracellular matrix]. 1085 62

Bikunin (BK) is a Kunitz-type proteinase inhibitor responsible for most of the antitryptic activity of urine and so is known as the urinary trypsin inhibitor. As its excretion increases in inflammatory conditions, it is often considered to be a positive acute phase protein (APP). However, the gene for BK is downregulated in inflammation. In human plasma the major part of BK is covalently linked through a glycosaminoglycan chain to one or two homologous peptide heavy chains, thus forming high molecular weight proteinase inhibitors called pre-alpha-inhibitor (PalphaI) and inter-alpha-inhibitor (IalphaI), respectively. The C-terminal parts of these heavy chains are very sensitive to proteolysis. Neutrophil proteinases in particular are able to release from IalphaI and PalphaI BK (M, about 25,000) which retains its antitryptic activity and is quickly excreted in urine. It was therefore an early supposition that the higher urinary excretion of BK occurring during inflammatory diseases should be, at least in some respect, related to a partial proteolysis of IalphaI and PalphaI. In this study we observed that BK, determined as antitryptic activity, was clearly increased in urine from 35 patients with inflammatory diseases varying in origin and severity (76.5 +/- 75.5 IU/g vs. reference value <10 IU/g creatinine). This increase seems mainly to be associated with polymorphonuclear leukocyte activation, monitored by human leukocyte elastase (HLE) determination rather than with the acute phase response assessed by C-reactive protein (CRP) measurement. For all the patients we found that the urinary levels of BK and serum concentration of intact IalphaI correlated inversely (r=-0.36; p=0.03), in agreement with the presumed precursor-product relationship linking IalphaI and BK. We also proved that urinary BK was significantly higher, and serum IalphaI was significantly lower, in samples with plasma HLE values above the reference: 90 microg/l. Taken together, our results demonstrate that BK, the urinary excretion of which is increased in inflammatory conditions, originates, at least partly, from IalphaI and PalphaI by proteolytic cleavage. Consequently, urinary BK determination provides information on the severity of systemic proteolysis occurring in inflammation. We also demonstrated that during inflammatory diseases IalphaI and PalphaI concentrations in serum are dependent on their increased utilization as well as on the regulation of their biosynthesis.
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PMID:Urinary bikunin determination provides insight into proteinase/proteinase inhibitor imbalance in patients with inflammatory diseases. 1221 52

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