Thromboxane-mediated hypertension and vascular leakage evoked by low doses of Escherichia coli hemolysin in rabbit lungs.

Escherichia coli hemolysin has been implicated as a pathoge- nicity factor in extraintestinal E. coli infections including sepsis. In the present study the effects of intravascular administration of hemolysin were investigated in isolated blood-free perfused rabbit lungs. Low concentrations of the toxin in the perfusate (0.05-5 hemolytic units/ml, corresponding to 5-500 ng/ml), caused a dose-and time-dependent release of potassium, thromboxane A2, and prostaglandin I2, but not of lactate dehydrogenase, into the recirculating medium, as well as a dose-dependent liberation of the prostanoids into the bronchoalveolar space. These events were paralleled by a dose-dependent pulmonary hypertension, and studies with dif- ferent inhibitors collectively indicated that the vasoconstrictor response was mediated predominantly by pulmonary throm- boxane generation. In addition, E. coli hemolysin elicited a protracted, dose-dependent increase in the lung capillary fil- tration coefficient, which was independent of the prostanoidmediated pressor response and resulted in severe pulmonary edema formation. We conclude that E. coli hemolysin can elicit thromboxane-mediated pulmonary hypertension combined with severe vascular leakage in isolated lungs in the absence of circulating inflammatory cells and humoral mediator systems, mimicking the key events in the development of acute respiratory failure in states of septicemia. lung injury of different etiology is often complicated by noso- comial pneumonia (6, 7). In experimental models septic lung failure can be mimicked by the intravenous infusion of live bacteria, e.g., live Escherichia coli (8-1 1). The key pathogenetic events, including acute pulmonary hypertension, delayed increase in vascular permeability, formation of protein-rich edema, and subsequent severe disturbances of gas exchange, can also be evoked by the administration oflipopolysaccharide