Alpha 1-antitrypsin (α1AT) deficiency resulting from homozygous inheritance of the Z-type α1AT gene is associated with serum α1AT levels of <50 mg/dl and the development of emphysema in the third to fourth decades. Despite the overwhelming evidence that the emphysema of PiZZ individuals develops because of a 'deficiency' of α1AT and hence an insufficient antineutrophil elastase defense of the lung, epidemiologic evidence has shown that levels of α1AT of only 80 mg/dl protect the lung from an increased risk of emphysema. With this background, we hypothesized that homozygous inheritance of the Z-type may confer and added risk beyond a simple deficiency of α1AT by virtue of an inability of the Z-type α1AT molecule to inhibit neutrophil elastase as effectively as the common M1-type molecule. To evaluate this hypothesis, the functional status of α1AT from PiZZ individuals (n = 10) was compared with that of α1AT from PiM1M1 individuals (n = 7) for its ability to inhibit neutrophil elastase (percent inhibition) as well as its association rate constant for neutrophil elastase (K association). Plasma α1AT concentration, measured by radial immunodiffusion, was 34 ± 1 mg/dl in PiZZ patients vs. 237 ± 14 mg/dl for PiM1M1 plasma, a sevenfold difference. When titrated against neutrophil elastase, the present inhibition of PiZZ plasma was significantly less than Pi M1M1 plasma (ZZ 78 ± 1% vs. M1M1 95 ± 1%, P < 0.001) as was purified Z type α1AT (ZZ, 63 ± 2% vs. M1M1 86 ± 2%, P < 0.001). Sodium dodecyl sulfate (SDS) gel comparisons of the complexes formed with M1-type α1AT and Z-type α1AT with elastase demonstrated the Z α1AT-elastase complexes were less stable than the M1 α1AT-elastase complexes, thus releasing some of the enzyme to continue to function as a protease. Consistent with these observations, the K association of purified Z-type α1AT for neutrophil elastase was lower than that of M1-type α1AT (ZZ 4.5 ± 0.3 x 106 M-1s-1 vs. M1M1 9.7 ± 0.4 x 106 M-1s-1, P < 0.001), suggesting that for the population of α1AT molecules, the active Z-type molecules take more than twice as long as the active M1-type α1AT to inhibit neutrophil elastase. Consequently, not only is there less α1AT in PiZZ individuals, but the population of Z-type α1AT molecules is less competent as an inhibitor of neutrophil elastase than M1-type α1AT molecules. This combination of defects suggests that PiZZ individuals have far less functional antielastase protection than suggested by the reduced concentrations of α1AT alone, further explaining their profound risk for development of emphysema.
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