LAZAROID U-74389F ATTENUATES PHORBOL ESTER-INDUCED LUNG INJURY IN RABBITS

We examined the effect of the antioxidant lazaroid U-74389F on acute l ung injury induced in rabbits by phorbol myristate acetate (PMA). Thir ty minutes after receiving either U-74389F (15 mg . kg(-1) i.v.) or U- 74389F vehicle, rabbits (n = 60) were given PMA (60 mu g . kg(-1) i.v. ), PMA vehicle injected rabbits (n = 20) served as controls, Over a 5 h period after PMA or PMA vehicle injection, we measured arterial pH, arterial oxygen tension (Pa,O-2), arterial carbon dioxide tension (Pa, CO2), and the plasma concentration of the neutrophil chemoattractant i nterleukin-8 (IL-8). At postmortem, lungs were inspected for macroscop ic injury and examined histologically. Malondialdehyde levels were ass ayed in lung tissue as an index of lipid peroxidation, In bronchoalveo lar lavage (BAL), total and differential cell counts, protein and IL-8 concentrations were measured. Compared to normal controls, rabbits ch allenged with PMA alone developed arterial acidosis, hypercapnia and h ypoxaemia, accompanied by significant rise in plasma IL-8 concentratio n, U-74389F pretreated animals did not develop significant arterial bl ood gas abnormalities and had significantly lower IL-8 concentration i n plasma U-74389F did not prevent PMA-induced lipid peroxidation. Howe ver, macroscopic signs of lung injury and the degree of alveolar haemo rrhage and protein extravasation were significantly less severe in pre treated rabbits than in those given PMA alone. In addition, U-74389F s ignificantly reduced IL-8 concentration and neutrophil number in BAL, By histological assessment, 80% of lung neutrophils were localized in alveolar spaces of animals receiving PMA alone. Conversely, in U-74389 F pretreated animals, 75% of neutrophils were distributed within extra alveolar blood vessels and alveolar septa. We conclude that lazaroid U -74389F attenuates lung injury in rabbits given PMA by preventing neut rophil migration into pulmonary alveoli. This effect may, in part, be related to downregulation of IL-8 production.