ALPHA-2-MACROGLOBULIN AS THE MAJOR DEFENSE IN ACUTE PSEUDOMONAL SEPTIC SHOCK IN THE GUINEA-PIG MODEL

An intravenous injection of 1.2 mg/kg of Pseudomonas aeruginosa elasta se induces immediate lethal shock in guinea-pigs. In the present study , alpha-2-macroglobulin (alpha(2)M) was shown to be the major factor i n guinea-pig plasma that inhibits the enzymatic activity of elastase i n vitro. Depletion of circulating alpha(2)M by injecting anti-guinea-p ig alpha(2)M rabbit IgG F(ab')(2) rendered the animals sensitive to a dose of elastase of 0.05 mg/kg. When the alpha(2)M-depleted guinea-pig s were reconstituted with human alpha(2)M, this sensitivity was revers ed. Lethal shock did not occur in alpha(2)M-depleted animals even at a n elastase dose of 0.2 mg/kg when Hageman factor was simultaneously de pleted, indicating that elastase induces shock through activation of t he Hageman factor-dependent system. Similar results were obtained when the culture supernatants of an elastase-producing strain, IFO-3455, w ere used instead of the purified elastase, whereas no cardiovascular c hanges occurred, even in the alpha(2)M-depleted guinea-pigs, when the culture supernatants were pretreated with an elastase specific inhibit or (zincov) or when the culture supernatants of an elastase nonproduci ng strain, PA-103 were used.