NEUTROPHIL LYSOSOMAL DYSFUNCTIONS IN MUTANT C57 B1 6J MICE - INTERSTRAIN VARIATIONS IN CONTENT OF LYSOSOMAL ELASTASE, CATHEPSIN-G AND THEIRINHIBITORS/

In this paper we report the serum antiprotease screening and the bioch emical and functional characteristics of neutrophils in a variety of m ouse strains with different susceptibilities for developing a protease -mediated injury. C57 B1/6J mice and their mutants tight-skin and pall id have a lower serum elastase inhibitory capacity (-30, -65 and -70% respectively) than other inbred strains (i.e. NMRI and Balb/c, which b oth have similar values). We demonstrate that these values are a conse quence of a decreased concentration of the alpha(1)-protease inhibitor for elastase [PI(E)], which is the major serum inhibitor of elastase and cathepsin G. In addition, neutrophil lysosomal dysfunctions charac terized by abnormally high contents of elastase and cathepsin G, or de fective lysosomal secretion are observed in tight-skin and pallid mice respectively. Another C57 B1/6J mutant with lysosomal abnormalities i s the beige mouse. Negligible amounts of elastase and cathepsin G, as well as defective neutrophil degranulation, have been described previo usly in this strain. We found, however, discrete amounts of a latent f orm of neutrophil elastase that undergoes a spontaneous activation by a protease-dependent mechanism. We also report that neutrophil catheps in G in this mouse is tightly bound to lysosomal membranes, but is rel eased in near normal quantities during exocytosis. Cytosolic elastase and cathepsin G inhibitors, which were previously reported as being sp ecific for the beige neutrophils, have also been detected in all the e xamined strains. Neutrophil functions, lysosomal enzyme content and se rum antiprotease screening may represent key elements in the protease- antiprotease balance and may explain the different interstrain suscept ibility to developing lesions in which an elastolytic activity has bee n implicated.