Synergism of alveolar endotoxin "priming" and intravascular exotoxin challenge in lung injury

Both endotoxin (lipopolysaccharides of gram-negative bacteria; LPS) and bacterial exotoxins may induce pulmonary microcirculatory disturbances when infused into the lung vasculature, and synergism between these types of microbial challenge has recently been noted. We now asked whether a bronchoalveolar LPS load in perfused rabbit lungs alters the responsiveness to a subsequent intravascular challenge with Escherichia coli hemolysin (ECH). In control lungs (sham aerosolization) and lungs undergoing LPS nebulization (alveolar deposition of approximately 22 micrograms), normal pulmonary artery pressure (PAP), lung weight, and ventilation/perfusion (V/Q) matching were observed. Intravascular ECH (0.013 hemolytic units/ml buffer fluid) increased PAP by approximately 10 mm Hg and lung weight by approximately 4 g within 10 min, paralleled by V/Q mismatch and a shunt flow of approximately 15%. In lungs "primed" for 3 h by a preceding bronchoalveolar LPS deposition, the same ECH dose provoked a dramatic increase in PAP to 40 to 50 mm Hg, a weight gain of approximately 10 g, and shunt flow of 60%. Both vasoconstrictor response and V/Q mismatch were completely suppressed by preadministration and "rescue" application of the thromboxane receptor antagonist BM13.505. We conclude that a bronchoalveolar endotoxin load, though effecting no changes in pulmonary function by itself and showing no spillover into the vascular compartment, primes the lungs for a manifold increased vascular response to a subsequently infused exotoxin. Enhanced thromboxane-mediated vasoconstriction, largely redistributing perfusate flow from normally ventilated to shunt areas, is suggested as the predominant underlying event.