Role of alpha-macroglobulin-elastase complexes in the pathogenesis of elastase-induced emphysema in hamsters.

Stone, Phillip J.; Calore, James D.; Snider, Gordon L.; Franzblau, Carl

doi:10.1172/jci110531

Cited by 45 publications

(31 citation statements)

References 29 publications

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“…3). Indeed, active A2M:NE complexes have been implicated in the pathogenesis of emphysema in animal models (48), the adult respiratory distress syndrome in humans (56), and the degradation of cartilage matrix in rheumatoid arthritis (30). Our data (Fig.…”

Section: Discussionmentioning

confidence: 52%

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: Discussionmentioning

confidence: 52%

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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“…a-2-Macroglobulin physically entraps enzymatically active elastase and sterically blocks the proteolytic activity of elastase towards all substrates over 8,500 D, including a-l-PI (64). Complexes ofa-2-macroglobulin and elastase are rapidly cleared from the circulation, but Stone and co-workers (64,65) have reported that complexes trapped in connective tissues can propogate additional damage after the slow release of active elastase from degraded a-2-macroglobulin. Thus, the oxidatively linked shunting of elastase from a-1-PI to a-2-macroglobulin may mediate either anti-or proinflammatory effects depending on the rate of clearance of the complex.…”

Section: Discussionmentioning

confidence: 99%

Oxidative regulation of neutrophil elastase-alpha-1-proteinase inhibitor interactions.

Ossanna¹,

Test²,

Matheson³

et al. 1986

J. Clin. Invest.

181

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Triggered human neutrophils were able to maintain released elastase in an active form in the presence of purified alpha-lproteinase inhibitor (a-l-PI), serum or bronchoalveolar lavage fluid (BAL). The accumulation of free elastase activity was associated with a decrease in the ability of the a-l-PI to inhibit porcine pancreatic elastase, an increase in proteinase activity associated with a-2-mac*roglobulin, and the oxidation of a-l-PI to a molecule containing four methionine sulfoxide residues. Neutrophils used both hypochlorous acid and long-lived N-chloroamines to oxidize the a-l-PI, but hypochlorous acid was preferentially used for suppressing the activity of the antiproteinase over short distances whereas the N-chloroamines were effective even when the phagocytes and a-l-PI were physically separated. Sodium dodecyl sulfate-polyacryhamide gel electrophoresis of purified a-l-PI, serum, or BAL that had been incubated with triggered neutrophils revealed that the released neutrophil elastase was not complexed with the antiproteinase and that a portion of the a-l-PI had undergone proteolysis. These data suggest that the presence of free neutrophil elastase as well as inactive, oxidized,and proteolyzed a-l-PI in fluids recovered from inflammatory sites in vivo could be directly mediated by triggered neutrophils alone.

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“…a-I-AP and alpha-2-macroglobulin are the two serum factors that inhibit the effects of elastase. It has been suggested that alpha-2-macroglobulin does not fully inhibit the destructive action of elastase (32). That a-I-AP is the prime elastase inhibitor is supported by the finding that congenital deficiency of this inhibitor is associated with emphysema.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Factors in Bronchopulmonary Dysplasia

et al. 1984

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SummarySerum factors related to oxygen exposure were studied in 56 full-term cord blood samples and in 69 newborn infants of varying gestational age (GA). Serum malondialdehyde (MDA), which reflects membrane lipid peroxidation, was elevated during the first 2 d of life and rose to a peak at 3-5 d of life. This peak value was unrelated to GA or to assisted ventilation.The serum antioxidant, vitamin E, showed a significant rise by 6-10 d, and came into the adult range after d 11. Vitamin E levels did not correlate with GA, assisted ventilation, or the development of bronchopulmonary dysplasia (BPD). Serum ceruloplasmin, another antioxidant, was measured both by activity assay and by protein concentration assay. Little activity was found in cord blood. Ceruloplasmin activity increased during the first 48 h of life, and both activity and protein concentration correlated with GA at that time. Infants who subsequently developed BPD had a less active protein than infants on ventilators who did not develop BPD. In addition, activity and protein levels on 3-5 d were lower in infants on ventilators than in those not requiring assisted ventilation.Serum levels of a-1-AP activity and protein concentration were also correlated with GA during the first 48 h of life. The less mature infants had levels of activity and protein which were significantly less than the more mature infants and significantly less than the full-term cord values. The proportion of active protein correlated with GA at 3-5 d, indicating that the less mature infants had a lower proportion of active protein. All infants had activity and protein levels within the normal range for healthy adults by 6-10 d.Abbreviations a-1-AP, alpha-1-antiprotease BPD, bronchopulmonary dysplasia GA, gestational age MDA, malondialdehyde OA, oxidase activity PAM, pulmonary alveolar macrophages RDS, respiratory distress syndrome TIC, trypsin inhibitory capacity Neonatal RDS is a life-threatening disorder of the premature infant. Respiratory therapy is essential for many infants. This therapy has been associated with pathologic findings in the lungs, starting as early as 48-72 h (22) after initiation of therapy. The respirator-induced lung disease is known as BPD (25).Highly reactive oxygen metabolites are thought to mediate pathologic changes in lungs exposed to oxygen (4, 33). Herein we show that all infants, regardless of GA, have evidence of oxidative damage during the first few days after birth, and that premature infants have much lower levels of antioxidants than adults.Neutrophil and macrophage invasion of the lung follows exposure to oxygen (10,21,22). In addition to releasing oxygen radicals, these cells elaborate elastase, a proteolytic enzyme which is primarily inhibited by a-1 -AP. We demonstrate that a-1 -AP protein concentration is decreased in the most immature babies, and that this protein has diminished activity in infants on assisted ventilation, a finding consistent with oxygen radical mediated inactivation (2, 3). Our data support the evolving concept of a mu...

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Role of alpha-macroglobulin-elastase complexes in the pathogenesis of elastase-induced emphysema in hamsters.

Cited by 45 publications

References 29 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

Oxidative regulation of neutrophil elastase-alpha-1-proteinase inhibitor interactions.

Pathogenic Factors in Bronchopulmonary Dysplasia

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