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Title: -1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease
MED 1121 , VOL. 308 , issue. 2, Jan 2015
Authors: Nicola J. Sinden;Michael J. Baker;David J. Smith
subject: -1-antitrypsin; chronic obstructive pulmonary disease; reaction-diffusion model; enzyme kinetics; serine proteinase
Year: 2015
Abstract: Sinden NJ, Baker MJ, Smith DJ, Kreft JU, Dafforn TR, Stockley RA. -1-Antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 308: L179–L190, 2015. First published November 21, 2014; doi:10.1152/ajplung.00179.2014.—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.
Appears in Collections:American journal of physiology lung celular 2015

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