Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 308, Issue 2, Pages L179-L190Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00179.2014
Keywords
alpha-1-antitrypsin; chronic obstructive pulmonary disease; reaction-diffusion model; enzyme kinetics; serine proteinase
Categories
Funding
- GlaxoSmithKline
- Boehringer Ingelheim
- Napp Pharmaceuticals
- CSL
- Grifols
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/K000683/1] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available