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

作者：Sinden Nicola J; Baker Michael J; Smith David J; Kreft Jan Ulrich; Dafforn Timothy R; Stockley Robert A^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2015, 308(2): L179-L190.

DOI：10.1152/ajplung.00179.2014

• alpha-1-antitrypsin
• chronic obstructive pulmonary disease
• reaction-diffusion model
• enzyme kinetics
• serine proteinase

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 alpha-1-antitrypsin result from point mutations in its gene. In addition, alpha-2-macroglobulin competes with alpha-1-antitrypsin for proteinases, and the alpha-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of alpha-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 alpha-1-antitrypsin or alpha-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 mu m into the tissue before becoming sequestered. We have shown that proteinases sequestered to alpha-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with alpha-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 alpha-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to alpha-2-macroglobulin where it retains proteolytic activity.

• 出版日期2015-1-15