On the inhibition of elastase by serum. Some distinguishing properties of α1-antitrypsin and α2-macroglobulin

Meyer, Jean-François; Bieth, J G; Métais, P

doi:10.1016/0009-8981(75)90278-8

Cited by 58 publications

(14 citation statements)

References 26 publications

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“…Our data (Fig. 5) have shown that A2M:NE complexes are able to degrade elastin-fluorescein, and previous studies (29) have also shown that complexes of A2M with porcine pancreatic elastase (PPE) are capable of digesting chemically solubilized elastin. However, other studies have shown that NE complexes with A2M are unable to degrade mature elastin (21) although NE bound to A2M may be able to degrade the elastin precursor tropoelastin (13), which is secreted into the extracellular space before formation of the cross linkages found in elastin (42) and hence could affect the repair process.…”

Section: Discussionsupporting

confidence: 86%

“…The exact reasons for these findings remain uncertain, but there are several possibilities. First, the A1AT:NE complexes formed by F or I variant A1AT could dissociate in the presence of A2M, resulting in the transfer of the enzyme from A1AT to A2M, as described by Ohlsson (36) using trypsin in dog serum and Meyer et al (29) using PPE in the presence of the two inhibitors. Second, the F or I variant A1AT could be at least partly proteolytically inactivated by NE during the interaction, resulting in inactivated A1AT and free NE (which could then bind to A2M).…”

Section: L186 the Proteinase/antiproteinase Imbalance In Lung Diseasementioning

confidence: 99%

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α-1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease

Sinden

Baker

Smith

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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The excessive activities of the serine proteinases neutrophil elastase and proteinase 3 are associated with tissue damage in chronic obstructive pulmonary disease. Reduced concentrations and/or inhibitory efficiency of the main circulating serine proteinase inhibitor ␣-1-antitrypsin result from point mutations in its gene. In addition, ␣-2-macroglobulin competes with ␣-1-antitrypsin for proteinases, and the ␣-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of ␣-1-antitrypsin mutations on this partitioning. Subsequently, we have developed a three-dimensional reaction-diffusion model to describe events occurring in the lung interstitium when serine proteinases diffuse from the neutrophil azurophil granule following degranulation and subsequently bind to either ␣-1-antitrypsin or ␣-2-macroglobulin. We found that the proteinases remained uninhibited on the order of 0.1 s after release and diffused on the order of 10 m into the tissue before becoming sequestered. We have shown that proteinases sequestered to ␣-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with ␣-2-macroglobulin are able to degrade elastin. Although neutrophil elastase is implicated in the pathophysiology of emphysema, our results highlight a potentially important role for proteinase 3 because of its greater concentration in azurophil granules, its reduced association rate constant with all ␣-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to ␣-2-macroglobulin where it retains proteolytic activity.␣-1-antitrypsin; chronic obstructive pulmonary disease; reaction-diffusion model; enzyme kinetics; serine proteinase CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is a major cause of morbidity and mortality worldwide (40) and creates a significant economic burden (60). Several pulmonary phenotypes have been recognized, including chronic bronchitis, which affects the large airways and is associated with chronic mucus hypersecretion (28a), and emphysema, which is associated with destruction of alveolar walls and enlargement of airspaces distal to the terminal bronchioles (38). Although the main risk factor for the development of COPD is cigarette smoking (10), only around 20% of smokers develop clinically significant disease (49), indicating that other environmental and genetic risk factors are important in the etiology. To date, deficiency of the serine proteinase inhibitor (serpin) ␣-1-antitrypsin (A1AT) is the only widely recognized genetic predisposition.A1AT is secreted by hepatocytes (16), enters the lungs primarily by passive diffusion, and inhibits neutrophil serine proteinases (NSPs) irreversibly with 1:1 stoichiometry. Circulating levels of A1AT are in the range of 20 -53 M in individuals with the normal (protease inhibitor MM, PiMM) genotype (5). Over 100 naturally occurring genetic variants...

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Section: Discussionsupporting

confidence: 86%

Section: L186 the Proteinase/antiproteinase Imbalance In Lung Diseasementioning

confidence: 99%

α-1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease

Sinden

Baker

Smith

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…cathepsin D) might have more potent activity (Janoff, 1972). a,-Antitrypsin specifically binds and inhibits elastase, trypsin and a-chymotrypsin (Meyer, Bieth & Metais, 1975;Ohlsson & Olsson, 1973, while q-macroglobulin entraps and inhibits all classes of endopeptidases including cathepsins, elastase and a-chymotrypsin (Barrett & Starkey, 1973). A rise in mucosal collagenase was demonstrated by Sturzaker & Hawley (1975) in ulcerative colitis.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Enzymes in Human Inflammatory Bowel Disease with Reference to Neutrophil Granulocytes as Mediators of Tissue Injury

Kane

Vincenti

1979

Clinical Science

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1. Biopsies of rectal mucosa were obtained for histology and enzyme analysis from 32 patients with inflammatory and functional bowel disorders, and the biopsies were classified morphologically as active colitis, quiescent colitis or normal. 2. Supernatant fractions of biopsy homogenates were assayed for their content of the proteolytic enzymes alpha-chymotrypsin, elastase and cathepsin D, and of protein, unsaturated vitamin B12-binding capacity, lysozyme, myeloperoxidase and N-acetyl-beta-glucosaminidase. 3. Mean unsaturated vitamin B12-binding capacity was significantly raised above normal in the active colitic mucosa, and mean lysozyme activity was raised above normal in both active and quiescent mucosae. 4. In active colitic mucosa there was no rise above normal in mean activities of any of the proteolytic enzymes, though a significant fall below normal occurred in mean N-acetyl-beta-glucosaminidase activity in the active colitic group.

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“…Proteases in plasma bind preferentially to alpha-macroglobulins [19] but substantial amounts bind to alpha-1-proteinase inhibitor (alpha-1-antitrypsin). However, 125I-trypsinalpha-l-proteinase complexes are dissociated by alpha-2-macroglobulin which accepts the released enzyme [17] prior to removal by the recticuloendothelial system.…”

Section: Discussionmentioning

confidence: 99%

Collagenase and elastase in the serum of adjuvant arthritic rats

1984

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Collagenase and elastase activities in the serum of adjuvant arthritic rats declined with time as the disease progressed and did not parallel increases in alpha 1-macroglobulin or alpha 2-acute phase globulin levels. The fall in collagenase and elastase activities was accompanied by a decline in serum alpha 1-proteinase inhibitor levels. It was concluded that the fall in collagenase and elastase activities in serum was due to inactivation by serum anti-proteases.

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On the inhibition of elastase by serum. Some distinguishing properties of α1-antitrypsin and α2-macroglobulin

Cited by 58 publications

References 26 publications

α-1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease

α-1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease

Mucosal Enzymes in Human Inflammatory Bowel Disease with Reference to Neutrophil Granulocytes as Mediators of Tissue Injury

Collagenase and elastase in the serum of adjuvant arthritic rats

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