PSEUDOMONAS-AERUGINOSA EXOTOXIN-A INDUCES PULMONARY ENDOTHELIAL CYTOTOXICITY - PROTECTION BY DIBUTYRYL-CAMP

In pseudomonal septicaemia, serum levels of antibody to exotoxin A hav e been demonstrated to be an important independent predictor of surviv al. Previously, we have demonstrated that exotoxin A directly injures pulmonary endothelial cells, and that dibutyryl-cyclic adenosine monop hosphate (Db-cAMP) can attenuate this injury. The object of this study was to examine the mechanisms of this pulmonary endothelial cell inju ry and the mechanism of Db-cAMP protection. The effects of differing d uration of exposure to exotoxin A and a reduction in temperature on en dothelial cell injury were examined. In addition, the effect of post-t reatment with Db-cAMP on exotoxin A-induced endothelial cell injury wa s studied. A brief, 5 min, exposure to exotoxin resulted in maximum in jury comparable to that produced by 18 h exposure. This injury did not occur at low temperatures, which would inhibit receptor-mediated endo cytosis. Db-cAMP protected endothelial cells, even when added up to on e hour after exotoxin exposure. These results suggest that, in this mo del, exotoxin A-induced injury of endothelial cells is receptor-mediat ed. Furthermore, this injury may be attenuated even after exotoxin A i nternalization has taken place.