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E xtracellular mobilization of Group IIA 14-kD phospholipase A2 (PLA2) in glycogen-induced rabbit inflammatory peritoneal exudates is responsible for the potent bactericidal activity of the inflammatory fluid toward Staphylococcus aureus (1996. J. Clin. Invest. 97:250-257). Because similar levels of PLA2 are induced in plasma during systemic inflammation, we have tested whether this gives rise to plasma bactericidal activity not present in resting animals. Baboons were injected intravenously (i.v.) with a lethal dose of Escherichia coli and plasma or serum was collected before and at hourly intervals after injection. After infusion of bacteria, PLA2 levels in plasma and serum rose > 100-fold over 24 h to approximately 1 microg PLA2/ml. Serum collected at 24 h possessed potent bactericidal activity toward S. aureus, Streptococcus pyogenes, and encapsulated E. coli not exhibited by serum collected from unchallenged animals. Bactericidal activity toward S. aureus and S. pyogenes was nearly completely blocked by a monoclonal antibody to human Group IIA PLA2 and addition of purified human Group IIA PLA2 to prechallenge serum conferred potent antistaphylococcal and antistreptococcal activity equal to that of the 24 h post-challenge serum. PLA2-dependent bactericidal activity was enhanced approximately 10x by factor(s) present constitutively in serum or plasma. Bactericidal activity toward encapsulated E. coli was accompanied by extensive bacterial phospholipid degradation mediated, at least in part, by the mobilized Group IIA PLA2 but depended on the action of other bactericidal factors in the 24-h serum. These findings further demonstrate the contribution of Group IIA PLA2 to the antibacterial potency of biological fluids and suggest that mobilization of this enzyme during inflammation may play an important role in host defense against invading bacteria.