THE EFFECT OF THE Z-MUTATION ON THE ABILITY OF ALPHA(1)-ANTITRYPSIN TO PREVENT NEUTROPHIL-MEDIATED TISSUE-DAMAGE

Recent studies have shown that alpha(1)-antitrypsin (alpha(1)-AT) from Z antitrypsin deficiency subjects has a slightly lower association ra te constant with neutrophil elastase (NE) than (alpha(1)-AT from norma l subjects, although it is unknown whether this is of clinical importa nce. We have purified alpha(1)-AT from a normal(M alpha(1)-AT) and fro m a deficient (Z alpha(1)-AT) subject and have confirmed that the asso ciation rate constants for NE are different (5.28; S.E. 0.06 10(7) M(- 1) s(-1) and 1.2; S.E. 0.2 10(7) M-l s(-1) respectively). We have asse ssed the ability of both of these proteins to inhibit neutrophil media ted fibronectin (FN) degradation in vitro. Both proteins inhibited FN degradation in a dose dependant manner although Z alpha(1)-AT was less effective than M alpha(1)-AT at equivalent concentrations of active i nhibitor (P < 0.05). Inhibition by M alpha(1)-AT was 28.5% S.E. 3.9 at 0.01 mu M; 35.5% S.E. 7.3 at 0.1 mu M and 37% S.E. 8.4 at 0.5 mu M, w hereas inhibition by Z alpha(1)-AT was 9.25% S.E. 3.9; 19.25% S.E. 7.7 and 21.2% S.E. 9.7, respectively. When the time course of inhibition of FN degradation was studied the difference (although less at 1.0 mu M) became greater over the 3 h period of the assay. These results sugg est that Z alpha(1)-AT is less able than the M phenotype to inhibit co nnective tissue degradation by neutrophils at equivalent concentration s. This is probably due to the lower association rate constant althoug h the reduced stability of the Z molecule may play a role. The differe nces, together with the reduced plasma concentration, may accentuate t he susceptibility of deficient subjects to the development of emphysem a.