DNA strongly impairs the inhibition of cathepsin G by alpha(1)-antichymotrypsin and alpha(1)-proteinase inhibitor

This paper explores the possibility that neutrophil-derived DNA interferes with the inhibition of neutrophil cathepsin G (cat G) and proteinase 3 by t he lung antiproteinases alpha(1)-proteinase inhibitor (alpha(1)PI), alpha(1 )-antichy-motrypsin (ACT), and mucus proteinase inhibitor (MPI), A 30-base pair DNA fragment ((30bp)DNA), used as a model of DNA, tightly binds cat G (K-d, 8.5 nm) but does not react with proteinase 3, alpha(1)PI, ACT, and MP I at physiological ionic strength, The polynucleotide is a partial noncompe titive inhibitor of cat G whose Ki is close to K-d. ACT and alpha(1)PI are slow binding inhibitors of the cat G-20(bp)- DNA complex whose second-order rate constants of inhibition are 2300 M-1 s(-1) and 21 M-1 s(-1), respecti vely, which represents a 195-fold and a 3190-fold rate deceleration. DNA th us renders cat G virtually resistant to inhibition by these irreversible se rpins, On the other hand, (30bp)DNA has little or no effect on the reversib le inhibition of cat Cf by MPI or chymostatin or on the irreversible inhibi tion of cat G by carbobenzoxy-Gly-Leu-Phe-chloromethylketone. The polynucle otide neither inhibits proteinase 3 nor affects its rate of inhibition by a lpha(1)PI. These findings suggest that cat G may cause lung tissue destruct ion despite the presence of antiproteinases.