SYNERGISM BETWEEN ENDOTOXIN PRIMING AND EXOTOXIN CHALLENGE IN PROVOKING SEVERE VASCULAR LEAKAGE IN RABBIT LUNGS

Lipopolysaccharides (LPS) of gram-negative bacteria prime rabbit lungs for enhanced thromboxane-mediated vasoconstriction upon subsequent ch allenge with the exotoxin Escherichia call hemolysin (HlyA) (Walmrath et al. J. Exp. Med. 1994;180:1437-1443). We investigated the impact of endotoxin priming and subsequent HlyA challenge on lung vascular perm eability while maintaining constancy of capillary pressure. Rabbit lun gs were perfused in a pressure-controlled mode in the presence of the thromboxane receptor antagonist BM 13.505, with continuous monitoring of flow. Perfusion for 180 min with 10 ng/ml LPS did not provoke vasoc onstriction or alteration of capillary filtration coefficient (Kfc) va lues. HlyA (0.021 hemolytic units/mi) induced thromboxane release and a transient decrease in perfusion flow in the absence of significant c hanges in Kfc. Similar results were obtained when LPS and HlyA were co applied simultaneously. However, when the HlyA challenge was undertake n after 180 min of LPS priming, a manifold increase in Kfc values was noted, with concomitant severe lung edema formation, although capillar y pressure remained unchanged. Thus, endotoxin primes the lung vascula ture to respond with a severe increase in vascular permeability to a s ubsequent low-dose application of HlyA. Such synergism between endotox in priming and exotoxin challenge in provoking lung vascular leakage m ay contribute to the pathogenesis of respiratory failure in sepsis and severe lung infection.