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

Abstract

Escherichia coli hemolysin has been implicated as a pathogenicity 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 different inhibitors collectively indicated that the vasoconstrictor response was mediated predominantly by pulmonary thromboxane generation. In addition, E. coli hemolysin elicited a protracted, dose-dependent increase in the lung capillary filtration 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.

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

“…Furthermore, severe pulmonary edema was observed, which was independent of thromboxane's vasoconstrictive effect and was caused by increased permeability of the vasculature. These findings mimic events during acute respiratory failure in states of septicemia (417). When in similar experiments the lungs were primed by preexposure to LPS, the effects of HlyA on thromboxane release and blood pressure were 15-fold more severe than those without priming, indicating that the response to LPS, the release of TNF-␣ into the medium, synergizes with the effects of HlyA (418).…”

Effects of Escherichia coli hemolysin on human monocytes. Cytocidal action and stimulation of interleukin 1 release.

“…Toxin production paired with serum resistance thus provides the micro-organisms with uniquely effective mechanisms for counteracting major components of the host immune defence system. The cytocidal action of ECH may extend to several other cell types including endothelial cells (40) and renal tubular epithelial cells (30). Confrontation of monocytes with just a few bacteria will result in rapid production and release of IL-I1f.…”

Escherichia coli hemolysin is a potent inductor of phosphoinositide hydrolysis and related metabolic responses in human neutrophils.

“…coli hemolysin. The hemolysin was prepared as described (2,36). The endotoxin content of the preparation was reduced to -3 ng of lipopolysaccharide (LPS)/Mg protein.…”