Pulmonary edema induced by phorbol myristate acetate is attenuated by compounds that increase intracellular cAMP.
We have investigated the effect of terbutaline, aminophylline and dibutyryl cyclic AMP (DBcAMP) on phorbol myristate acetate (PMA)-induced acute lung injury in isolated, blood-perfused rabbit lungs. Pulmonary arterial pressure and lung weight were measured for 30 min after a bolus injection of PMA (10 mu g/kg). In the group exposed to PMA alone, the mean pulmonary arterial pressure (PAP) increased from 16.33 + or - 1.28 to 77.30 + or - 6.40 mmHg (P <0.001), and lung weight increased by 70.69 + or - 10.94 g during the 30 min after PMA challenge (P<0.001). Pretreatment with terbutaline, aminophylline or DBcAMP prevented the increases in both PAP and lung weight (P <0.001). Each of the three drugs also prevented the increase in pulmonary vascular permeability induced by PMA: terbutaline, aminophylline, and DBcAMP all significantly reduced the pulmonary capillary filtration coefficient (KfC) as well as the albumin concentration in the lung lavage fluid after PMA exposure. Post-treatment with terbutaline 5 min after PMA administration also had a protective effect. The mechanisms responsible for these protectivp3 effects may all involve an increase in intracellular cAMP, since all three drugs increase cAMP in the lung (though by different mechanisms). Our data further indicate that the inhibition of tumor necrosis factor production may likewise play an important role in the protective effect exerted by these drugs.
Hsu
K
K
Department of Medicine, Tri-service General Hospital, Taiwan.
Wang
D
D
Chang
M L
ML
Wu
C P
CP
Chen
H I
HI
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D055370:Lung Injury; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000188:drug therapy; D013726:Terbutaline / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000628:Aminophylline; D003994:Bucladesine; D000242:Cyclic AMP; D013726:Terbutaline; D013755:Tetradecanoylphorbol Acetate