title: α-1-antitrypsin variants and the proteinase/antiproteinase imbalance in chronic obstructive pulmonary disease.
abstract: 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 α-1-antitrypsin result from point mutations in its gene. In addition, α-2-macroglobulin competes with α-1-antitrypsin for proteinases, and the α-2-macroglobulin-sequestered enzyme can retain its catalytic activity. We have studied how serine proteinases partition between these inhibitors and the effects of α-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 α-1-antitrypsin or α-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 μm into the tissue before becoming sequestered. We have shown that proteinases sequestered to α-2-macroglobulin retain their proteolytic activity and that neutrophil elastase complexes with α-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 α-1-antitrypsin variants studied here, its greater diffusion distance, time spent uninhibited following degranulation, and its greater propensity to partition to α-2-macroglobulin where it retains proteolytic activity.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Sinden
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Baker
authors.forename: David J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Jan-Ulrich
authors.initials: JU
authors.lastname: Kreft
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Dafforn
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stockley
mesh_terms: D004549:Elastin / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D053146:Myeloblastin / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics*; D000511:alpha-Macroglobulins / Q000378:metabolism*
chemical_list: D000515:alpha 1-Antitrypsin; D000511:alpha-Macroglobulins; D004549:Elastin; D019272:Leukocyte Elastase; D053146:Myeloblastin