Kinetic characterisation of ALPHA-1-Antitrypsin F as an inhibitor of human neutrophil elastase

doi:10.1080/00313029600169074

Pathology

Volume 28, Issue 3, 1996, Pages 242-247

https://doi.org/10.1080/00313029600169074 Get rights and content

Summary

Patients homozygous for the Z allete of alpha-l-antitrypsin (α1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether Fα1AT was dysfunctional, the inhibitory activity of Fα1AT against human neutrophil elastase (HNE) was compared with that of common MAT phenotypes. Time-dependent inhibition of HNE by α1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S α1AT phenotypes in human sera. The results for k assoc at 25°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)×106 M^–1s^–1 respectively. F was found to have reduced activity much like that of Z, the α1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate α1AT 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.

In conclusion, Fα1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit 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.

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Kinetic characterisation of ALPHA-1-Antitrypsin F as an inhibitor of human neutrophil elastase

Summary

Historic perspectives

J Clin Epidemiol

Lancet

Br J Dis Chest

Chest

Am J Med

J Biol Chem

Chest

J Biochem Biophys Methods

Biochem Biophys Res Commun

Biochem Med

J Biol Chem

Biochem Biophys Res Commun

Chest

Gastroenterology

Chest

J Biol Chem

J Mot Biol

J Biol Chem

Survival of patients with severe cd-antitrypsin deficiency with special reference to non-index cases

Thorax

Putative role of neutrophil elastase in the pathogenesis of emphysema

Ann NY Acad Sci

Anfielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema

J Clin Invest

Replacement therapy for alpha-l-antitrypsin deficiency associated with emphysema

N Engl J Med

Evaluation of the S-type of alpha-l-antitrypsin as an in vivo mad in vitro inhibitor of neutrophil elastase

Am Rev Respir Dis

Z-type α1-antitrypsin is less competent than Ml-type αl-antitrypsin as an inhibitor of neutrophil elastase

J Clin Invest