S-type α1-antitrypsin (α1AT) is a deficiency haplotype that differs from the common normal M1 (val213) α1AT haplotype by a single amino acid (glu264 to val264). To evaluate the adequacy of the antineutrophil elastase production associated wtih the S homozygous state, α1AT plasma and lung epithelial lining fluid (ELF) levels and antineutrophil elastase function were analyzed in 9 PiSS subjects. The plasma α1AT levels of SS subjects were intermediate between that of M1M1 and ZZ subjects (p < 0.001, all comparisons), and the plasma neutrophil elastase inhibitory capacity paralleled the differences in α1AT concentration (p < 0.001, all comparisons). The association rate constant for neutrophil elastase of the purified S protein was less than that of the normal molecule (S-type, 7.1 ± 0.1 x 106 M-1 s-1; M1-type, 9.6 ± 0.2 x 106 M-1 s-1; p < 0.001), but much greater than that for the Z molecule (p < 0.001). Exposure of the purified S protein to increasing oxidant burdens resulted in a dose-dependent reduction in the ability of the molecule to inhibit neutrophil elastase in a fashion parallel to that of the M1 and Z proteins. Quantification of ELF α1AT levels and antineutrophil elastase capacity demonstrated that the SS ELF parameters were, as in plasma, intermediate between M1 homozygotes and Z homozygotes. Using the association rate constant together with the quantification of ELF α1AT levels, the 'in vivo lung inhibition time' was estimated, yielding an assessment of the relative antineutrophil elastase screen of the PiSS lower respiratory tract. Interestingly, while the in vivo inhibition time of S molecules is longer than that of M1 homozygotes, it is not nearly as long as that of the Z homozygotes, consistent with the knowledge that the S homozygous state does not confer an increased risk of emphysema to the affected person.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine