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A study was made of the development of various forms of local and systemic injury in animals treated with inhibitors of proteolytic activity. The agents used were tosylarginine methyl ester (TAME), epsilon aminocaproic acid (EACA), and soybean trypsin inhibitor (SBTI). 1. Hemorrhagic necrosis in the skin of the rabbit following intradermal epinephrine in combination with bacterial endotoxin (either intravenous or local) was clearly suppressed by EACA, TAME, and SBTI, given systemically. Tosylarginine (TA) was ineffective. 2. No effect was observed on the classical Shwartzman reaction, the local Arthus phenomenon, or inflammation induced by xylene. 3. The lethal effects of systemic anaphylaxis in the mouse, acute endotoxemia in the rat and mouse, and drum shock in the rat are suppressed by EACA and TAME. 4. There was no effect on the generalized Shwartzman phenomenon in the rabbit and on anaphylaxis in the guinea pig. 5. The effects of EACA or TAME on the injury reactions under investigation were not due to a pharmacological or chemical action on vascular behavior per se. 6. The data provide corroborative evidence for a proteolytic step in injury phenomena which may be mediated through some common activation system. 7. The working hypothesis is advanced that local or systemic stress through the release of epinephrine may result in an increase of a circulating activator of proteolysis and that this in turn may give rise to the release of vasoactive substances,-possibly histamine, serotonin, or a polypeptide.

SOME EFFECTS OF PROTEOLYTIC INHIBITORS ON TISSUE INJURY AND SYSTEMIC ANAPHYLAXIS