HYDROLYSIS OF A BROAD-SPECTRUM OF EXTRACELLULAR-MATRIX PROTEINS BY HUMAN MACROPHAGE ELASTASE

Macrophage elastase (ME) was originally named when metal-dependent ela stolytic activity was detected in conditioned media of murine macropha ges. Subsequent cDNA cloning of the mouse and human enzyme demonstrate d that ME is a distinct member of the matrix metalloproteinase family. To date, the catalytic parameters that describe the hydrolysis of ela stin by ME have not been quantified and its activity against other mat rix proteins have not been described. In this report, we have examined the action of purified recombinant human ME (rHME), produced in Esche richia coli, on elastin and other extracellular matrix proteins. On a molar basis, rHME is approximately 30% as active as human leukocyte el astase in solubilizing elastin, rHME also efficiently degrades alpha(1 )-antitrypsin (alpha(1)-AT), the primary physiological inhibitor of hu man leukocyte elastase. In addition, rHME efficiently degrades fibrone ctin, laminin, entactin, type TV collagen, chondroitan sulfate, and he paran sulfate. These results suggest that HME may be required for macr ophages to penetrate basement membranes and remodel injured tissue dur ing inflammation, Moreover, abnormal expression of HME may contribute to destructive processes such as pulmonary emphysema and vascular aneu rysm formation. To further understand the specificity of HME, the init ial cleavage sites in alpha(1)-AT have been determined. In addition, t he hydrolysis of a series of synthetic peptides with different P'(1), residues has been determined, rHME can accept large and small amino ac ids at the P', site, but has a preference for leucine.