Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects

There is increasing evidence that antiproteases are able to affect the infl ammatory response. To further examine this question, we administered human ce-l-antitrypsin (al AT) or a synthetic metalloprotease inhibitor (RS113456 ) to C57 mice followed by a single intratracheal dose of quartz, a dust tha t evokes a marked, lasting, polymorphonuclear leukocyte (PMN) infiltrate. A t 2 hours after dust administration, both antiproteases completely suppress ed silica-induced PMN influx into the lung and macrophage inflammatory prot ein-2 (MIP-2)/monocyte chemotactic protein-1 (MCP-1) (neutrophil/macrophage chemoattractant) gene expression, partially suppressed nuclear transcripti on factor kappaB (NF-kappaB) translocation, and increased inhibitor of NF-k appaB (I kappaB) levels. By 24 hours, PMN influx and connective tissue brea kdown measured as lavage desmosine or hydroxyproline were still at, or clos e to, control levels after antiprotease treatment, and increases in NF-kapp aB translocation and MIP-2/MCP-1 gene expression were variably suppressed. At both time points, neither agent prevented silica-induced increases in am ount of whole lung MIP-2 or MCP-1 protein, but both did prevent increases i n whole lung intercellular adhesion molecule-1 (ICAM-1) at 24 hours. Inacti vating the alpha 1AT by oxidation to the point that it no longer possessed antiproteolytic properties did not affect its ability to suppress inflammat ion. Both antiproteases also prevented the silica-induced acute inflammator y response in mice with knocked out genes for macrophage metalloelastase (M ME -/-), mice that develop inflammation, but not connective tissue breakdow n, and the pattern of alpha 1AT breakdown fragments was identical in contro l and MME -/- animals. These findings suggest that, in this model of acute PMN mediated inflammation, a serine protease inhibitor and a metalloproteas e inhibitor have similar anti-inflammatory properties, that inflammation is not mediated by proteolysis with generation of chemotactic matrix fragment s, and that classic antiproteolysis (complexing of protease to antiprotease ) probably does not play a role in suppression of inflammation. The antipro teolytic effects of these agents do not seem to be mediated by protection o f endogenous alpha 1AT.