Detection of antileukoprotease in connective tissue of the lung

Willems, L. N. A.; Otto-Verberne, C. J. M.; Kramps, J. A.; Have-Opbroek, A. A. W. Ten; Dijkman, J. H.

doi:10.1007/bf00493382

Cited by 31 publications

(11 citation statements)

References 7 publications

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“…It is conceivable that alveolar endothelial and epithelial septal cell death contributes to the elastase/antielastase imbalance by reducing the amount of available antiprotease proteins, such as the secretory leukoprotease inhibitor (SLPI). SLPI is expressed in association with the amorphous elastin present in the extracellular matrix of the alveolar walls, in bronchi and bronchioles, and in blood vessels (32). In addition, activated caspases may trigger matrix protease activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

Kasahara

Tuder²,

Taraseviciene‐Stewart³

et al. 2000

J. Clin. Invest.

1,006

790

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Section: Discussionmentioning

confidence: 99%

Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

Kasahara

Tuder²,

Taraseviciene‐Stewart³

et al. 2000

J. Clin. Invest.

1,006

790

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“…In addition, neutrophils, air dried on glass slides, bound MPI, whereas monocytes did not. Potential binding sites for MPI include target enzymes such as human leukocyte elastase or cathepsin G. A variety of other structures, such as elastic fibers (31) or mucins (32), may also bind MPI. The cytosolic inhibitor of human neutrophil elastase and cathepsin G previously demonstrated in neutrophils (33) has a molecular mass of 43 kDa, and is different from the inhibitors investigated in this study.…”

Section: Discussionmentioning

confidence: 99%

Cellular association of antiproteases in lavages from ventilated preterm human neonates.

Griese¹,

M²,

Hochstrasser³

et al. 1997

Am J Respir Crit Care Med

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Lung antiprotease activity is routinely assayed in the supernatant of bronchoalveolar lavage fluid (BALF). In this study the cellular fraction of lavages was also analyzed. Functionally active acid-resistant inhibitors with molecular masses characteristic of the mucus proteinase inhibitor (MPI, 14 kDa) and elastase-specific inhibitor (ESI, 7 kDa) were demonstrated by gel chromatography. Immunocytochemical studies of cells obtained at various postnatal time points from lavages of 10 premature infants with chronic lung disease showed that the inhibitors were confined to neutrophils and macrophages. At each time point, about 70% and 21% of these cells, respectively, stained positively. The polyclonal antibodies usually used to detect MPI did not distinguish between MPI and ESI. Because of this cross reactivity, it was not possible to differentiate between MPI and ESI. Analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) of cells from lavages and of nucleated cells isolated from the peripheral blood showed the production of ESI only, but not of MPI. Nevertheless, MPI can associate with neutrophils and macrophages, as was shown in binding studies with the recombinant protein. These data suggest that when assaying bronchoalveolar lavages (BALs) for these antiproteases in the supernatant only, the total pool of inhibitors may be underestimated.

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“…Because SLPI does not inhibit PR3 (4), incorporation of this inhibitor into the model may result in an even greater role for PR3 in the pathogenesis of COPD, especially in A1ATD. However, SLPI is predominantly present in the upper airways (55) and may play a less important role in the antiproteinase protection of the distal airways where emphysema occurs although SLPI has been identified in the lung interstitium associated with elastin (58). Second, the model does not incorporate any elimination kinetics of A2M:NSP complexes from the system.…”

Section: L187mentioning

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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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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Detection of antileukoprotease in connective tissue of the lung

Cited by 31 publications

References 7 publications

Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

Inhibition of VEGF receptors causes lung cell apoptosis and emphysema

Cellular association of antiproteases in lavages from ventilated preterm human neonates.

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

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