Staphylococcal alpha-toxin-induced vascular leakage in isolated perfused rabbit lungs.
alpha-Toxin, the major, pore-forming exotoxin of Staphylococcus aureus, caused acute hypertension when perfused through blood-free rabbit lungs (21). This reaction is mediated by pulmonary thromboxane generation, for which toxin-induced calcium flux into target cells with subsequent stimulation of arachidonic acid metabolism is predominantly responsible. In the present study, we investigated the effects of alpha-toxin on the integrity of the lung microvasculature. Thromboxane generation was inhibited in all experiments to suppress the development of pulmonary hypertension. Application of low alpha-toxin concentrations (5 to 40 ng/ml) induced protracted, severe vascular leakage in a dose-dependent manner. After a lag period of 40 to 120 minutes, gravimetrically determined capillary filtration coefficients progressively increased to greater than 10-fold values, and this was followed by pronounced weight gain of the isolated organs. These physiologic alterations were paralleled by dose- and time-dependent structural changes documented by electron microscopic examination of perfusion-fixed lungs. Increasing electron density of microvascular endothelial cell nuclei and subsequently of their cytoplasma was noted, followed by detachment of these cells from the mutual endoepithelial basal lamina. Edema was localized in the blood-gas exchange area, in contrast to hydrostatically induced lung fluid accumulation. These results identify pulmonary microvascular endothelium cells as highly susceptible targets for attack by alpha-toxin. Given a similar sensitivity of human endothelial cells, alpha-toxin might directly contribute to the pathogenesis of acute respiratory failure under conditions of severe infection with Staphylococcus aureus.
Department of Internal Medicine, Justus-Liebig-University Giessen, Federal Republic of Germany.
W
W
Seeger
R G
RG
Birkemeyer
L
L
Ermert
N
N
Suttorp
S
S
Bhakdi
H R
HR
Duncker
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002199:Capillary Permeability / Q000187:drug effects*; D005260:Female; D006460:Hemolysin Proteins / Q000633:toxicity*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D009929:Organ Size / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D014690:Venous Pressure / Q000187:drug effects
D001427:Bacterial Toxins; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; D011188:Potassium