PULMONARY-EDEMA INDUCED BY PHORBOL-MYRISTATE ACETATE IS ATTENUATED BYCOMPOUNDS THAT INCREASE INTRACELLULAR CAMP

We have investigated the effect of terbutaline, aminophylline and dibu tyryl cyclic AMP (DBcAMP) on phorbol myristate acetate (PMA)-induced a cute lung injury in isolated, blood-perfused rabbit lungs. Pulmonary a rterial pressure and lung weight were measured for 30 min after a bolu s injection of PMA (10 mu g/kg). In the group exposed to PMA alone, th e mean pulmonary arterial pressure (PAP) increased from 16.33+/-1.28 t o 77.30+/-6.40 mmHg (P<0.001), and lung weight increased by 70.69+/-10 .94 g during the 30 min after PMA challenge (P<0.001). Pretreatment wi th terbutaline, aminophylline or DBcAMP prevented the increases in bot h PAP and lung weight (P<0.001). Each of the three drugs also prevente d the increase in pulmonary vascular permeability induced by PMA: terb utaline, aminophylline, and DBcAMP all significantly reduced the pulmo nary capillary filtration coefficient (K-fc) as well as the albumin co ncentration in the lung lavage fluid after PMA exposure. Post-treatmen t with terbutaline 5 min after PMA administration also had a protectiv e effect. The mechanisms responsible for these protective effects may all involve an increase in intracellular cAMP, since all three drugs i ncrease cAMP in the lung (though by different mechanisms). Our data fu rther indicate that the inhibition of tumor necrosis factor production may likewise play an important role in the protective effect exerted by these drugs.