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Published ahead of print on January 15, 2003, doi:10.1165/rcmb.2002-0258OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 1, July 2003, 57-61

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Submitted on November 19, 2002
Revised on January 14, 2003

Inhibition of proteinase 3 by {alpha}1-antitrypsin in vitro predicts very fast inhibition in vivo

Jerome Duranton1 and Joseph G Bieth1*

1 Enzymology, INSERM U392, ILLKIRCH, France

* To whom correspondence should be addressed. E-mail: jgbieth{at}aspirine.u-strasbg.fr.

Neutrophil proteinase 3 cleaves elastin and other matrix proteins and is thought to cause lung tissue destruction in emphysema and cystic fibrosis. Its deleterious action is theoretically prevented by {alpha}1-antitrypsin, a serpin present in lung secretions. We have evaluated the anti-proteinase 3 activity of this inhibitor to decide whether it may play a physiological proteolysis-preventing function in vivo. We show that (i) the oxidized inhibitor does not inhibit proteinase 3, (ii) the inhibitor competes favorably with elastin for the binding of proteinase 3 but is less efficient for inhibiting elastin-bound proteinase than for complexing free enzyme, (iii) the inhibition takes place in at least two steps : the enzyme and the inhibitor first form a high affinity reversible inhibitory complex EI* with an equilibrium dissociation constant Ki* of 38 nM ; EI* subsequently transforms into an irreversible complex EI with a first-order rate constant k2 of 0.04 s-1. Since the {alpha}1-antitrypsin concentration in the epithelial lining fluid is much higher than Ki*, any proteinase 3 molecule released from neutrophils will be taken up as an EI* complex within much less than one second, indicating very efficient inhibition in vivo.




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