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)

Elastin is critical to the structural integrity of a variety of connective tissues. Only a select group of enzymes has thus far been identified capable of cleaving insoluble elastin. Recently, we observed that human alveolar macrophages secrete elastase activity that is largely inhibited by the tissue inhibitor of metalloproteinases (TIMP). This finding suggested that one or more of the metalloproteinases released by alveolar macrophages has elastase activity. Accordingly, we tested pure human interstitial collagenase, stromelysin, 92-kDa type IV collagenase, and 72-kDa type IV collagenase for elastolytic activity using kappa-elastin zymography and insoluble 3H-labeled elastin. The 92- and 72-kDa type IV collagenases were found to be elastolytic in both assay systems. A recombinant preparation of 92-kDa type IV collagenase with gelatinolytic activity was also found to be elastolytic. Organomercurial activation was essential to detect elastolytic activity of the native 92- and 72-kDa type IV collagenases and enhanced the elastase activity of the recombinant 92-kDa enzyme. On a molar basis the recombinant 92-kDa type IV collagenase was approximately 30% as active as human leukocyte elastase in solubilizing 3H-labeled elastin. Exogenously added TIMP in significant molar excess abolished the elastase activity of the 92- and 72-kDa type IV collagenases. Stromelysin and interstitial collagenase showed no significant elastolytic activity, although both were catalytically active against susceptible substrates. Conditioned media from cultures of human mononuclear phagocytes containing the 92-kDa enzyme produced a distinct zone of lysis in the kappa-elastin zymograms at this molecular mass. These results definitively extend the spectrum of human proteinases with elastolytic activity to metalloproteinases and suggest the enzymatic basis for elastase activity observed with certain cell types such as human alveolar macrophages.
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PMID:Human 92- and 72-kilodalton type IV collagenases are elastases. 185 Apr 24

Mononuclear phagocytes have the capacity to directly participate in extracellular matrix turnover via secretion of neutral proteinases. We have studied the effects of in vivo and in vitro differentiation upon cellular content or secretion of a spectrum of neutral proteinases, along with a counter-regulatory metalloproteinase inhibitor (TIMP). We found 1) matrix-degradative serine proteinases (leukocyte elastase and cathepsin G) were lost during cellular maturation and/or differentiation; 2) the 92-kDa type IV/type V collagenase and TIMP were secreted earliest in mononuclear phagocyte differentiation, whereas stromelysin secretion was observed only by LPS-stimulated alveolar macrophages; 3) exposure of alveolar macrophages, but not monocytes, to phorbol esters and LPS resulted in markedly augmented secretion of all studied metalloproteinases and TIMP; 4) monocyte-derived macrophages partially (but not completely) mimicked the metalloproteinase secretory phenotype of alveolar macrophages; and 5) the secretory phenotype of alveolar macrophages for interstitial collagenase (but not TIMP) was largely lost during in vitro culture. These results underscore the complexity of the process of differentiation in human mononuclear phagocytes, and provide insights into the variable capacity of mononuclear phagocytes to degrade extracellular matrix components. Moreover, we anticipate that human mononuclear phagocytes at various stages of differentiation will provide a useful model system for study of the variable regulation of secretion of human matrix-degrading metalloproteinases.
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PMID:Neutral proteinases of human mononuclear phagocytes. Cellular differentiation markedly alters cell phenotype for serine proteinases, metalloproteinases, and tissue inhibitor of metalloproteinases. 199 67

alpha 1-antitrypsin, the primary physiologic inhibitor of human leukocyte elastase, is proteolytically inactivated by several matrix metalloproteinases including interstitial collagenase, stromelysin and 92 kDa gelatinase. In this report, we describe the catalytic effects of matrilysin, a recently identified metalloproteinase, upon alpha 1-antitrypsin. Matrilysin was found to be approximately 30-fold more effective than 92kDa gelatinase, 70-fold more effective than collagenase, and 180-fold more effective than stromelysin. Cleavage of alpha 1-antitrypsin by matrilysin produced two fragments of approximately 50 kDa and 4 kDa. The single cleavage occurred at the Phe352-Leu353 peptide bond, a locus within alpha 1-antitrypsin's active-site loop. These results suggest that apart from its activity against extracellular matrix, matrilysin provides a mechanism for the regulation of leukocyte elastase activity through its capacity to degrade alpha 1-AT.
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PMID:Matrilysin is much more efficient than other matrix metalloproteinases in the proteolytic inactivation of alpha 1-antitrypsin. 798 May 22

Synthetic inhibitors of interstitial collagenase, tri- and tetrapeptidyl hydroxamic acids, have been developed and tested for their inhibitory activities against human matrix metalloproteinases. A water soluble inhibitor, p-NH2-Bz-Gly-Pro-D-Leu-D-Ala-NHOH (FN-439) inhibited interstitial and granulocyte collagenases, granulocyte gelatinase and skin fibroblast stromelysin with IC50 of 1 x 10(-6) M, 3.0 x 10(-5) M and 1.5 x 10(-4), respectively, but not thermolysin and serine proteinases. FN-439 was found to retain its inhibitory activity against matrix metalloproteinases even after prolonged incubation with pronase or human granulocyte elastase, indicating a favorite candidate of the inhibitor to modulate metalloproteinase activities in vivo.
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PMID:Inhibition of matrix metalloproteinases by peptidyl hydroxamic acids. 814 88

The cell-mediated immune reaction was studied in the cutaneous lesion of chromomycosis, using monoclonal antibodies against polymorphonuclear neutrophils, macrophage and lymphocyte subsets, endothelial and fibroblast cells. In addition, immunostaining of the main degradative enzymes (neutrophil elastase and interstitial collagenase) and certain important cytokines (transforming growth factor-beta, tumour necrosis factor-alpha and interferon-gamma) suggested an explanation for the granulomatous reaction and the associated tissue remodelling. The distribution pattern of neutrophils and macrophage subsets, observed by computer-aided image analysis, suggests that the in situ persistence of fungi is the main pathological factor.
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PMID:Granulomatous reaction and tissue remodelling in the cutaneous lesion of chromomycosis. 850 21

Matrix metalloproteinases (MMPs) secreted by connective tissue cells are capable of acting on extracellular matrix components of glomerular basement membrane at a slow rate and thus may play a role in the control of protein permeability and in the progression of certain kinds of glomerulonephritis. We have used an in vitro assay to measure the direct effect of three MMPs and human neutrophil elastase on glomerular albumin permeability (Palbumin). Glomeruli were isolated from normal male Sprague-Dawley rats and suspended in isolation medium with or without interstitial collagenase, gelatinase-A, stromelysin-1, or elastase and were incubated at 37 degrees C for up to 4 hours. A tissue-specific inhibitor of matrix metalloproteinases (TIMP-1) and a plasma proteinase inhibitor, alpha2-macroglobulin (alpha2M), were used to block the activity of MMPs. Palbumin was calculated from the change in glomerular volume in response to an applied oncotic gradient. In this study stromelysin-1 (10 microg/ml) and elastase (5 microg/ml) increased Palbumin significantly. Stromelysin-1 increased Palbumin after 4 hours, whereas elastase had an effect after 2 hours. Lower concentrations of stromelysin-1 or shorter incubation time had no effect on Palbumin. Incubation for up to 4 hours with interstitial collagenase (10 microg/ml) or gelatinase-A (10 microg/ml) had no effect on Palbumin. Coincubation with TIMP-1 and alpha2M blocked the stromelysin-1-mediated increase in Palbumin. We conclude that stromelysin-1 is capable of affecting the glomerular filtration barrier directly and that it may play an important role in causing proteinuria in glomerular diseases.
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PMID:Matrix metalloproteinase (stromelysin-1) increases the albumin permeability of isolated rat glomeruli. 878 37

The ability of purified human neutrophil elastase (EC 3.4.21.37) to cleave native type I collagen has been investigated. Soluble human, bovine or rat type I collagen was incubated with neutrophil elastase for 16 h at 25 degrees C before catalysis was stopped with 3, 4-dichloroisocoumarin. Analysis by SDS/PAGE of the collagen digests revealed 3/4-length fragments similar in size to those produced by interstitial collagenase. The collagenolytic activity was dose dependent and was not due to a contaminating metalloproteinase or cysteine proteinase, as it was not inhibited by 1,10-phenanthroline, EDTA or L-trans-epoxysuccinyl-leucylamido-(4-guanidino)butane. The identity of the cleavage products was confirmed using a new antibody that recognizes the unwound alpha2(I)-chain. This detected the 3/4-length fragment of type I collagen following neutrophil elastase cleavage. In addition to cleaving soluble collagen, neutrophil elastase also cleaved reconstituted, radiolabelled type I collagen fibrils, at a rate of 16 microg/min per nmol. These results indicate that neutrophil elastase can cleave native type I collagen in the helix, an activity that might contribute to its roles in connective-tissue pathology.
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PMID:Cleavage of native type I collagen by human neutrophil elastase. 948 Sep 7

We investigated the role of polymorphonuclear neutrophil (PMN) proteinases, elastase, and gelatinase B in rat models of acute lung injury. Three groups of rats were studied 6 hours after unilateral instillation of hydrochloric acid (HCl; 0.1 N), lipopolysaccharide (LPS) (4 microg), or saline. The results demonstrated that HCl-induced lung injury, as compared with LPS-induced lung injury, was associated with an increase in permeability (wet/dry weight ratio and proteins in bronchoalveolar lavage fluid). In contrast, there was similar PMN recruitment (in bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenates) and similar proteinase exocytosis (residual alveolar PMN content of elastase and gelatinase B) in both types of lung injury. In situ zymography, evaluating interstitial protease/inhibitor balance, demonstrated a decrease in gelatinolytic activity in both HCl- and LPS-injured lungs compared with normal lung. The increase in interleukin 6 concentration in lung homogenates, which is observed after both injuries compared with saline-instilled animals, could be involved in up-regulation of tissue inhibitor of matrix metalloproteinase-1, shown by immunocytochemistry to participate in antiproteinase excess. Neither inhibition of alveolar neutrophil influx using a leukocyte elastase inhibitor (EPI-hNE-4) nor inhibition of gelatinase activities by recombinant adenovirus for the human tissue inhibitor of matrix metalloproteinase 1 gene transfer decreased lung edema in HCl-induced injury. These data suggest that PMN proteinases do not contribute to HCl-induced acute lung injury in rats.
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PMID:Neutrophil proteinases in hydrochloric acid- and endotoxin-induced acute lung injury: evaluation of interstitial protease activity by in situ zymography. 1185 May 27