Nucleophilic cleavage of the complex between human alpha-1-antitrypsin and porcine pancreatic elastase

Cohen, Allen B.; James, Harold L.; Geczy, Dagmar

doi:10.1016/0006-291x(81)91840-4

Cited by 7 publications

(4 citation statements)

References 10 publications

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“…The mean of the three values was 1.56±0.03 (mean±sE). This compares with molar ratios of 1.5-1.8 previously reported by us for HNE [1 I, 14] and by other investigators for porcine pancreatic elastase [20][21][22]. The excess of API required has been attributed to nonproductive proteolysis of API by elastase rather than the presence of inactive API in the purified preparation [20].…”

Section: Discussionsupporting

confidence: 81%

Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters

Stone

Lucey²,

Virca³

et al. 1990

Eur Respir J

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A study was undertaken to determine whether emphysema and airway secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be moderated by pretreatment with human alpha 1-protease inhibitor (API). API (4.9 mg) was given intratracheally to hamsters 1 h before 0.3 mg HNE. Eight weeks later, lung volumes and pressure-volume relationships were measured in the anaesthetized animals. Mean linear intercepts and secretory cell indices were measured in lung sections. API given 1 h before HNE moderated the development of bronchial secretory cell metaplasia. The severity of emphysema was reduced by 75%. Clearance studies indicated that 80% of the functional activity of instilled API could be lavaged from the lungs after 1 h, indicating a 4 h half-life in the lavageable compartment of the lungs. We calculate that for 50% protection from emphysema the molar ratio of lavageable API to HNE at the time of HNE instillation was 4.8 as compared with 0.78 for 50% inhibition of elastolytic activity in vitro, indicating that API is only 16% as efficient in vivo as compared with its in vitro HNE inhibitory effectiveness. Nevertheless, we conclude that human API given intratracheally is efficacious against HNE-induced emphysema and secretory cell metaplasia.

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Section: Discussionsupporting

confidence: 81%

Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters

Stone

Lucey²,

Virca³

et al. 1990

Eur Respir J

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“…With tryp sin this ratio has been reported as 2.0 [29], Some investigators have found a value of 1.0 for the ratio of functional to immunoreactive human a-l-Pl with HNE or PPE [9,30], while others, like us, have reported ratios of 0.50-0.66 [16. 31-34], The lower ratios we found using fresh plasma, hu man BAL samples and purified human a-1 -PI, including that used to check the cali bration of the a-l-Pl radial immunodiffu sion plates, can be explained on the basis of a combination of nonproductive and productive proteolysis of a-l-Pl by the elastase [31][32][33][34][35]. Productive proteolysis re sults in inhibition of elastolytic activity by formation of a stable complex.…”

Section: Discussionmentioning

confidence: 99%

Defenses of the Hamster Lung against Human Neutrophil and Porcine Pancreatic Elastase

Stone

Lucey²,

Calore³

et al. 1988

Respiration

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Instillation of human neutrophil elastase (HNE) into hamster lungs produces milder emphysema but more pulmonary hemorrhage than an equivalent amount of porcine pancreatic elastase (PPE), whether equivalence is determined by elastolytic units or moles. We undertook a study of the mechanisms of these differences. ¹²⁵I-HNE or ³H-PPE were instilled intratracheally into hamsters. The partitioning of radioactivity between bronchoalveolar lavage fluid (BAL) and lung tissue was similar for HNE and PPE as were the half-lives, 45 and 51 min, respectively, for uncomplexed, enzymatically active HNE and PPE. In BAL there was preferential binding and inactivation of HNE by the hamsters’ alpha-1-protease inhibitor (a-1-PI) whereas PPE was preferentially bound by alpha-2-macroglobulin (a-2-M). This was also observed in vitro when HNE and PPE were incubated with plasma from untreated hamsters. Nevertheless, when the sum of the elastase binding capacity of a-1-PI and a-2-M was considered, hamster plasma had similar binding capacities for HNE and PPE. It is known that the enzymatic activity of elastases is inhibited by formation of a stable complex with a-1-PI. On the other hand, elastases bound to a-2-M are protected against a-1-PI inhibition but can free themselves by proteolysis and exhibit elastolytic activity. Preferential inactivation of HNE by a-1-PI may be one mechanism that accounts for the lesser emphysema-inducing potency of HNE than of PPE

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“…Antiprotease Levels Alpha-1-PI forms a stable covalent bond with elastase, yielding a complex which exhibits no proteolytic activity [30]. However, proteolytic interaction of elas tase with alpha-2-M produces a complex in which the enzyme is still functional to ward small polypeptides and is protected from inactivation by alpha-l-PI [16,31].…”

Section: Discussionmentioning

confidence: 99%

“…These values are similar to the ratio of 1.7 for trypsin to elastase inhibition by purified human alpha-l-PI [36], The values we obtained for elastase and trypsin binding by alpha-2-M and alpha-l-PI in the serum samples were approximately one-half the values expected from the levels of immunoreac tive alpha-2-M and alpha-l-PI. That is, 2 mol of elastase can be bound by 1 mol of purified alpha-2-M [37], and approxi mately 0.7 mol elastase can be bound by 1 mol of alpha-l-PI [30,36]. However, from table II we calculate that 1.1 mol of elastase was bound by 1 mol of alpha-2-M and 0.27 mol of elastase was bound by 1 mol of alpha-l-PI.…”

Section: Discussionmentioning

confidence: 99%

Serum Antielastase and Neutrophil Elastase Levels in PiM Phenotype Cigarette Smokers with Airflow Obstruction

Binder¹,

Stone²,

Calore³

et al. 1985

Respiration

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In order to assess blood factors which might explain why some cigarette smokers develop airflow obstruction while others do not, we compared two groups of PiM phenotype volunteers matched for age, sex and total pack-years of cigarette smoking; one group had airflow obstruction and the other did not. Functional levels of alpha-2-macroglobulin (alpha-2-M) and alpha-1-protease inhibitor (alpha-1-PI) were separately assessed by a protease binding procedure. Neutrophils were isolated from blood by counterflow centrifugation, and their elastase content was assayed with ³H-elastin-SDS (sodium dodecyl sulfate). The obstructed and nonobstructed groups were not different with respect to functional or immunoreactive levels of alpha-1-PI and alpha-2-M or elastase levels in their neutrophils. We do not find imbalances of circulating elastase or antielastase levels in PiM phenotype smokers with airflow obstruction.

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Nucleophilic cleavage of the complex between human alpha-1-antitrypsin and porcine pancreatic elastase

Cited by 7 publications

References 10 publications

Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters

Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters

Defenses of the Hamster Lung against Human Neutrophil and Porcine Pancreatic Elastase

Serum Antielastase and Neutrophil Elastase Levels in PiM Phenotype Cigarette Smokers with Airflow Obstruction

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