KINETIC CHARACTERIZATION OF ALPHA-1-ANTITRYPSIN-F AS AN INHIBITOR OF HUMAN NEUTROPHIL ELASTASE

Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT ) have very low serum levels and are predisposed to emphysema. There h ave also been reports of emphysema being associated with the heterozyg ous phenotype FZ. To investigate whether F alpha 1AT was dysfunctional , the inhibitory activity of F alpha 1AT against human neutrophil elas tase (HNE) was compared with that of common alpha 1AT phenotypes. Time -dependent inhibition of HNE by alpha 1AT was used to calculate the as sociation rate constant (k assoc) for Rn, MZ, FM, FZ, F (partially pur ified from FZ or FS), Z and S alpha 1AT phenotypes in human sera. The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8 .0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M(-1)s(-1) respectively. F was found to have reduced activity much like that of Z, the alpha 1AT mast commonly associated with emph ysema. MZ (low risk for disease) and FZ heterozygotes had similar inte rmediate alpha 1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals. I n conclusion, F alpha 1AT is expressed in serum at low normal levels b ut is dysfunctional in its ability to inhibit HNE. Individuals who coi nherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema The disease risk for F homozygotes remains to be determined.