RT Journal Article
SR Electronic
T1 Inhibitory profiles of alpha-1-antitrypsin from PiZ & PiSZ individuals and implications for tissue destruction in emphysema
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP p3909
VO 38
IS Suppl 55
A1 Nicola Sinden
A1 Timothy Dafforn
A1 Robert Stockley
YR 2011
UL http://erj.ersjournals.com/content/38/Suppl_55/p3909.abstract
AB Introduction: Neutrophil elastase (NE) causes emphysema in animal models. Homozygote (ZZ) deficiency of its inhibitor alpha-1-antitrypsin (AAT) is associated with human emphysema. The role of heterozygote deficiency (SZ) is unclear.Aims: To compare the inhibitory profiles of equimolar amounts of AAT from Z & SZ serum with pure AAT & M serum. The hypothesis is that Z AAT inhibits NE less efficiently than SZ & M AAT.Methods: AAT concentration was measured in serum from Z, SZ & M patients. Increasing amounts of AAT were added to a fixed amount of NE. Residual NE activity was measured spectrophotometrically using both a chromogenic substrate and elastin. This was repeated with pure AAT & alpha-2-macroglobulin (A2M).Results: With a low molecular weight chromogenic substrate, M serum AAT increasingly inhibited NE as the inhibitor:enzyme molar ratio increased to 1:1. Beyond 1:1 inhibition 15% residual NE activity remained, but not for pure AAT. For SZ serum residual activity was 60%. For Z serum and pure A2M enhanced NE activity was seen as inhibitor:enzyme ratio increased.With elastin, inhibitory profiles of M, SZ & Z serum were similar to each other.Conclusion: Enhanced NE activity with Z serum likely represents binding to A2M. Deficiency of AAT means that NE is more likely to bind to A2M. A2M:NE complexes retain proteolytic potential. These data may have implications for tissue destruction in emphysema.