ARDS-LIKE LUNG INJURY PRODUCED BY ENDOTOXIN IN PLATELET-ACTIVATING FACTOR-PRIMED RATS

We recently reported that the combined administration of lipopolysacch aride (LPS) and platelet-activating factor (PAF) in rats, at doses tha t are completely devoid of any effect when given alone, caused lung in jury characterized by neutrophil adhesion to lung capillaries and post capillary venules, neutrophil accumulation in the lung parenchyma, pla telet-fibrin deposits in postcapillary venules, and pulmonary edema. A marked increase in lung myeloperoxidase activity and an elevation of serum tumor necrosis factor-alpha and thromboxane B2, along with leuko penia and thrombocytopenia, were also noticed. The present study aimed to examine whether repeated LPS-PAF stimulus can cause progressive lu ng injury reminiscent of adult respiratory distress syndrome (ARDS). A second LPS-PAF challenge, 4 h (n = 11) after the original challenge, induced mortality (69% at 24 h, P < 0.01) and some of the pathological changes seen in clinical ARDS, including severe pulmonary edema, alve olar proteinaceous exudates, monocytic infiltration, and a further inc rease in lung myeloperoxidase activity (700%, P < 0.01). Repeated LPS- PAF dosing also resulted in sustained increased serum tumor necrosis f actor-alpha levels (1,610 +/- 470 pg/ml, P < 0.01) and further exacerb ation of the leukopenia (68 +/- 6%, P < 0.01) and thrombocytopenia (65 +/- 8%, P < 0.01). These data suggest that repeated LPS-PAF actions a re sufficient to elicit pathophysiology of ARDS-like lung injury.