The effect of the Z mutation on the ability of α1-antirtrypsin to prevent neutrophil mediated tissue damage

Abstract

Recent studies have shown that ( α 1-AT) from Z antitrypsin subjects has a slightly lower association rate constant with neutrophil elastase (NE) than α 1-AT from normal subjects, although it is unknown wheter this is of clincial importance. We have purified α 1-AT from a normal (M α 1-AT) and from a deficient (Z α 1-AT) subject and have confirmed that the association 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 −1 s −1, respectively). We have assessed the abilitity of both these proteins to inhibit neutrophil mediated fibronectin (FN) degradation in vitro. Both proteins inhibited FN degradation in a dose depedendent manner although Z α 1-AT was less effective than M α 1-AT at equivalent concentrations of active inhibitor (< 0.05). Inhibition by M α 1-AT was 28.5% S.E. 3.9 at 0.01 μM; 35.5% S.E. 7..3 at 0.1 μM and 37% S.E. 8.4 at 0.5 μM, whereas inhibition by Z α 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 μM) became greater over the 3 h period of the assay. These results suggest that Z α 1-AT is less able than the M phenotype to inhibit connective tissue degradation by neutrophils at equivalent concentrations. This is probably due to the lower association rate constant although the reduced stability of the Z molecule may play a role. The differences, together with the reduced plasma concentration, may accentuate the susceptibility of deficient subjects to the development of emphysema.