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)

An extracellular connective tissue matrix, made up of components found in the pulmonary alveolar interstitium, was generated in vitro and used as a culture surface and substrate for proteolysis by human alveolar macrophages (AM) and neutrophil elastase (NE). The ability of human AM to modulate NE-mediated degradation of elastin and collagen in the surrounding matrix was studied to gain insights into the inflammatory process that accompanies the pathogenesis of emphysema in humans. Neutrophil elastase that had been internalized by AM showed a diminished but more prolonged time course of matrix proteolysis than did a similar amount of NE added to the matrix in the absence of AM. Collagen and elastin degradation were quantitated by release of hydroxylysine and desmosine, respectively, into the culture medium. Significantly more hydroxylysine and desmosine were released by AM that had internalized NE than by AM or by culture medium alone. When 14 X 10(6) AM were added to the extracellular matrix, followed 2 h later by addition of 2 micrograms of NE, collagen and elastin degradation measured at 24 h were not significantly different from that which occurred when matrix was incubated with NE in the absence of AM. Collagen degradation, determined in the same cultures during the period from 24 to 96 h, was significantly greater when matrix was incubated with both AM and NE. These findings suggest that AM can release previously internalized NE in an enzymatically active form and that AM may enhance collagen degradation in matrix that was also exposed to NE.
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PMID:Alveolar macrophage modulation of proteolysis by neutrophil elastase in extracellular matrix. 656 97

Connective tissue in biopsy specimens taken from the lower part of the uterine cervix in 40 pregnant women at various gestational ages was compared to that in similar biopsy specimens from 15 nonpregnant women. The concentrations of collagen, sulfated glycosaminoglycans, and hyaluronic acid decreased during pregnancy. At the gestational age of 10 weeks, the collagen concentration was 70%, and at term 30%, of that in the nonpregnant cervix. After delivery, no further decrease was observed. The extractability of collagen increased during pregnancy, as well as during labor. Also, the water concentration increased. An increase in the collagenolytic activity was observed with advancing gestational age. The 2,4-dinitrophenyl-Pro-Gln-Gly-Ile-Ala-Gly-Gin-D-Arg hydrolytic activity (collagenase) and the concentration of leukocyte elastase increased gradually by a factor of 10. The physiologic importance of the collagen was also demonstrated, since the cervical dilatation time during spontaneous labor was long in women with high concentrations of collagen and short in women with low concentrations of collagen.
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PMID:Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity. 663 10

We have identified the biological activity of three polypeptides released by limited proteolysis of human plasma fibronectin by leukocyte elastase. A Mr = 140,000 peptide contains cell-spreading activity; a Mr = 60,000 peptide mediates binding to denatured collagen (gelatin), and a Mr = 29,000 peptide contains glutaminyl residues responsible for the transglutaminase (blood coagulation factor XIIIa)-catalyzed incorporation of amines. More extensive proteolysis yielded numerous peptides, including a Mr = 40,000 peptide derived from the Mr = 60,000 peptide which retains gelatin-binding activity. Quantification of the gelatin-binding peptides is consistent with two binding sites per dimeric fibronectin molecule of Mr = 440,000. Both Mr = 60,000 and 40,000 gelatin-binding peptides were enriched with half-cystine residues, containing 28 and 25, respectively, but devoid of cysteine. This, coupled with the electrophoretic behavior of both peptides, was consistent with the presence of intramolecular disulfide bonds in the gelatin-binding domain. Intact fibronectin contains 1 free cysteine residue/monomer, as recently described. This cysteine reacts with 5,5'-dithiobis(2-nitrobenzoic acid) very slowly under nondenaturing conditions but rapidly when fibronectin is denatured. The free cysteine is located in the Mr = 140,000 peptide. While the Mr = 40,000 and 60,000 gelatin-binding peptides bind to gelatin with an affinity about 30-fold and 5-fold less than intact fibronectin (based on a monomeric fibronectin Mr = 220,000), neither gelatin-binding peptide supports spreading of fibronectin-deficient test cells on gelatin or tissue culture plastic substrates. The purified Mr = 140,000 peptide supported cell spreading on plastic, retaining about one-half of the spreading activity of intact fibronectin on a weight basis. These data confirm recent results, suggesting multiple, protease- resistant domains with discrete biological functions within fibronectin. Our results, together with established data, suggest a model for the location of the transglutaminase-reactive glutaminyl residues, gelatin binding, and cell-adhesive domains in fibronectin. The release of univalent, biologically active fibronectin fragments by elastase, a major physiologically released inflammatory protease of human leukocytes, suggests a new potential mechanism for alteration of cell connective tissue interactions at sites of inflammation in vivo.
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PMID:Degradation of fibronectin by human leukocyte elastase. Release of biologically active fragments. 690 25

Fibroblasts are known to have chemotactic responses to two components of the extracellular matrix, collagen and fibronectin. To extend these observations to other extracellular connective tissue macromolecules and their proteolytic fragments, fibroblasts from adult human skin and from late-gestation (270 d), fetal bovine ligaments were studied for chemotactic responsiveness to tropoelastin and elastin-derived peptides. Bovine ligament tropoelastin and elastin-derived peptides, generated from either human aortic elastin with human neutrophil elastase or from bovine ligament elastin with pancreatic elastase, elicited chemotactic responses that were maximal at 0.2 micrograms/ml (3 X 10(-9) M) and 0.5-2.0 micrograms protein/ml, respectively. Fractionation of the elastin-derived peptides by gel filtration (Bio-Gel P-10) indicated that comparable levels of chemotactic activity were present in all fractions, and amino acid analysis of the fractions showed no relationship between chemotactic activity and desmosine concentration. Taken in conjunction with the observations on tropoelastin, it appears that fibroblast chemotaxis to elastin components does not involve the cross-links of elastin. These results demonstrate that the influences of the connective tissue matrix upon fibroblast migration might include elastin precursors and fragments of elastin.
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PMID:Chemotactic responses of fibroblasts to tropoelastin and elastin-derived peptides. 710 97

The interaction of fibronectin with native collagen during collagen fibril formation was investigated. Fibronectin prepared from serum, or from the cell surface, bound to the forming collagen fibrils while less fibronectin bound to preformed fibers. Denatured collagen competed with native collagen in binding fibronectin. Fibronectin delayed the precipitation of collagen fibrils but did not alter the total amount of fibrils formed. Fibronectin which was heated to 30 degrees C for 30 min did not promote cell adhesion but still bound to native collagen and delayed fiber formation. The collagen-binding fragment of fibronectin produced by digestion either with chymotrypsin or with neutrophil elastase had a similar effect in delaying fibril formation, but the cell-binding fragment was not active. These studies indicate that fibronectin can bind to aggregating collagen fibers probably at the same site shown previously to bind to denatured collagen. Since fibronectin inhibits the rate of collagen fibrillogenesis, it may regulate the size of collagen fibers.
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PMID:Interaction of fibronectin with collagen fibrils. 723 4

Antisera against a Mr = 60,000 peptide containing the gelatin-binding domain of human plasma fibronectin (McDonald, J. A., and Kelley, D. G. (1980) J. Biol. Chem. 255, 8848-8858) bound the Mr = 60,000 peptide and intact fibronectin but not three other fragments released by leukocyte elastase proteinolysis (the Mr = 25,000 amino-terminal sequence, Mr = 140,000 sequence containing cell adhesive activity, and a Mr = 31,000 fragment). Affinity-purified Fab' blocked Mr = 60,000 peptide binding to gelatin and inhibited plasma and cellular fibronectin gelatin binding without affecting fibronectin-mediated cell spreading. In contrast, antifibronectin Fab' absorbed with the gelatin-binding fragment completely blocked fibronectin-mediated cell spreading. These data indicate that the gelatin-binding domain of fibronectin is immunogenic, and antisera against this domain recognize cellular fibronectin gelatin-binding sites. Inhibition of gelatin binding but not cell spreading by anti-gelatin binding domain Fab' confirms the hypothesis that fibronectin has separate sites mediating these activities. Selective inhibition of fibronectin-collagen binding by domain-specific antisera may help elucidate the role of fibronectin in organization of the extracellular matrix.
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PMID:Gelatin-binding domain-specific anti-human plasma fibronectin Fab' inhibits fibronectin-mediated gelatin binding but not cell spreading. 724 Jan 56

1. In order to characterize the physiological functions of the domain structure of secretory leukoprotease inhibitor (SLPI), the biological capacities of half-length SLPIs, (Ser1-Pro54)SLPI and (Asn55-Ala107)SLPI, were investigated and compared with those of full-length SLPI. 2. The activities of these inhibitors against several serine proteases were determined using synthetic chromogenic substrates. The inhibitory capacity of the C-terminal domain, (Asn55-Ala107)SLPI, was as strong as that of full-length SLPI against human neutrophil elastase (NE), cathepsin G and chymotrypsin. It possessed less trypsin inhibitory activity than intact SLPI. For the N-terminal domain of SLPI, (Ser1-Pro54)SLPI, no inhibitory activity could be detected against the serine proteases tested in this study. 3. The inhibitory activity of (Asn55-Ala107)SLPI against the proteolysis of the natural substrates elastin and collagen by NE was comparable with that of full-SLPI (elastin, IC50 = 907 +/- 31 nM for SLPI, 767 +/- 33 nM for (Asn55-Ala107)SLPI; collagen, IC50 = 862 +/- 36 nM for SLPI, 727 +/- 47 nM for (Asn55-Ala107)SLPI). 4. The binding affinities of full- and half-length SLPIs for heparin were measured by affinity column chromatography. Full-length SLPI showed high affinity for heparin while the binding capacities of both half-length SLPIs were lower. (Concentration of NaCl for elution, 0.45 M for SLPI, 0.24 M for (Ser1-Pro54)SLPI, 0.27 M for (Asn55-Ala107)SLPI). 5. The effects of full-SLPI and (Asn55-Ala107)SLPI on blood coagulation were measured using the activated partial thromboplastin time (APTT). Full-length SLPI prolonged clotting time dose dependently(1.25, 2.5 and 5.0 microM), whereas (Asn55-AlalO7)SLPI had no effect even at the highest concentration.6. In conclusion, the C-terminal domain of SLPI is a promising candidate for the treatment of inflammatory diseases in which participation of neutrophil proteases has been suggested.
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PMID:Pharmacological activity of the C-terminal and N-terminal domains of secretory leukoprotease inhibitor in vitro. 758 15

Elastin degradation has been reported to be increased in patients with cystic fibrosis (CF). In order to further explore evidence for elastin degradation in a group of 18 patients with CF with a wide range of disease severity, we used an isotope dilution method to measure urinary desmosine (DES) and isodesmosine (IDES), amino acids derived exclusively from cross-linked elastin, and hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), amino acids derived exclusively from cross-linked collagen. Urinary DES and IDES (mean +/- SD) were 23.9 +/- 30.7 and 18.5 +/- 22.4 micrograms/g creatinine, respectively, in the patients with CF versus 7.5 +/- 1.7 and 6.8 +/- 1.4 micrograms/g creatinine, respectively, in 10 healthy control subjects (p < 0.001); only two patients with CF had DES values within the control range. The values of urinary HP and LP in the CF group were 54.9 +/- 39.1 and 12.3 +/- 8.6 nmol/mmol creatinine, respectively, versus 24.5 +/- 5.8 and 5.1 +/- 2.7 nmol/mmol creatinine, respectively, in the controls (p < 0.005). Both HP and LP were highly correlated (r = 0.71, p < 0.0001). Patients with CF had active pulmonary inflammation; neutrophils were abundant in the bronchoalveolar lavage fluid of the CF group and correlated with elastase activity measured with methoxysuccinyl Ala-Ala-Pro-Val paranitroanilide (r = 0.61, p < 0.05). Airway neutrophils had decreased expression of the complement receptor CR1 (CR1/CR3 of 0.17 +/- 0.15 versus 1.0 for blood neutrophils), a change known to be caused by uninhibited neutrophil elastase. We conclude that lung elastin is the most likely source of the increased DES and IDES in CF.
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PMID:Elastin and collagen degradation products in urine of patients with cystic fibrosis. 759 16

A growing body of evidence suggests that neutrophil-derived proteinases play a major role in lung tissue damage in cystic fibrosis (CF). Most previous studies have focused on serine proteinases such as neutrophil elastase, providing no information on the extent to which metalloproteinases participate in proteolytic processes in CF. To address this issue, we evaluated the contribution of one of the major neutrophil metalloproteinases, i.e., 95 kDa gelatinase (type IV collagenase), to the total gelatinolytic activity measured in sputum specimens from 27 patients with CF. Compared with asthmatic children (n = 9), CF patients had a 6.7 times greater level of total gelatinase activity in sputum revealed by zymography. The 95 kDa gelatinase was increased 3.7-fold in the CF subjects (2,441 +/- 411 [SEM] arbitrary units [AU] x 10(6) per ml of sputum versus 665 +/- 201 in asthmatics) and the 88-kDa active form 23.2-fold (2,272 +/- 372 AU x 10(6) per ml of sputum versus 98 +/- 43, respectively). Using radiolabeled 3H-gelatin as the substrate, we demonstrated uninhibited gelatinolytic activity in all CF patients; this activity was significantly correlated to disease severity as assessed by pulmonary function tests. Western blotting using anti-tissue inhibitor of metalloproteinase (anti-TIMP) and anti-95/88-kDa gelatinase antibodies demonstrated a more than 10-fold excess of 95/88 kDa gelatinase over TIMP. Bacterial proteinases from Pseudomonas aeruginosa were shown to contribute little to the gelatinolytic activity measured in sputum supernatants from patients with CF, although culture supernatants from various P. aeruginosa strains expressed gelatinolytic activity in vitro. Finally, lung damage, as assessed by increased type IV collagen degradation products in sputum, was significantly correlated to concentrations of active 88 kDa gelatinase. These data argue for a significant role of 95/88 kDa gelatinase in airway damage in CF.
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PMID:Imbalance between 95 kDa type IV collagenase and tissue inhibitor of metalloproteinases in sputum of patients with cystic fibrosis. 763 40

A novel neutrophil elastase inhibitor, ONO-5046, was administered to BB/DR rats and DBA/1 mice immunized with type II collagen to study its effect on the development of collagen-induced arthritis (CA), an experimental model of human rheumatoid arthritis. ONO-5046 reduced the incidence as well as the severity of CA in both rats and mice. This suppressive effect on severity was correlated with improvement of the histological findings, particularly with reduced destruction of the articular cartilage. These results indicate that neutrophil elastase may play an important role in the pathogenesis of CA.
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PMID:Suppressive effect of a neutrophil elastase inhibitor on the development of collagen-induced arthritis. 767 22


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