ENDOTOXIN PRIMES PERFUSED RABBIT LUNGS FOR ENHANCED VASOCONSTRICTOR RESPONSE TO STAPHYLOCOCCAL ALPHA-TOXIN

The major pore-forming exotoxin of Staphylococcus aureus, staphylococc al alpha-toxin, causes thromboxane-mediated pulmonary hypertension and prostanoid-independent protracted vascular leakage in perfused rabbit lungs (8, 9). We asked whether lung responsiveness to the staphylococ cal agent would be altered by a preceding period of endotoxin priming. Isolated rabbit lungs were perfused with Krebs-Henseleit buffer in th e presence or absence of 100 ng/ml Salmonella abortus equii endotoxin for up to 5 h. The lipopolysaccharide exposure evoked the release of l arge quantities of tumor necrosis factor into the vascular and alveola r spaces but did not significantly alter pulmonary artery pressure, or gan weight, or the repeatedly assessed capillary filtration coefficien t (Kfc). Two and 4 h after endotoxin administration, alpha-toxin (10 t o 30 ng/ml) was bolus-injected into the pulmonary artery. Toxin-evoked prostanoid generation (TxB(2), 6-keto-PGF(1 alpha)) and presser respo nses were markedly accelerated and enhanced in endotoxin-primed lungs, both for the 2 h and the 4 h priming period. No significant influence of endotoxin was noted when applied simultaneously with alpha-toxin. Cyclooxygenase inhibition suppressed the alpha-toxin-evoked pressure r ise in both endotoxin-primed and nonprimed lungs. Endotoxin priming di d not influence the alpha-toxin-induced protracted increase in Kfc val ues, assessed in the presence of cyclooxygenase inhibition. We conclud e that endotoxin primes rabbit lungs for enhanced prostanoid generatio n and pulmonary hypertension in response to S. aureus alpha-toxin. Suc h cooperativity of endotoxin priming and exotoxin triggering may be re levant in critically ill patients suffering from both endotoxemia and gram-positive sepsis.