INHIBITION OF LIPOPOLYSACCHARIDE-INDUCED PULMONARY-EDEMA BY ISOZYME-SELECTIVE PHOSPHODIESTERASE INHIBITORS IN GUINEA-PIGS

There is a need for pharmacological agents for the treatment of pulmon ary edema associated with the adult respiratory distress syndrome. The refore, we examined the effects of isozyme-selective cyclic AMP phosph odiesterase (cAMP PDE) inhibitors, as well as aminophylline and dexame thasone, on the pulmonary edema, protein leakage into the airways and airway neutrophilia induced by aerosolized lipopolysaccharide (LPS) in intact guinea pigs. Twenty-four hours after LPS exposure lung wet/dry weight ratios increased from 4.9 +/- 0.004 to 5.8 +/- 0.02. Rolipram (PDE4 selective), CI-930 (PDE3 selective), aminophylline and dexametha sone (given p.o. 1 hr before and 4 hr after LPS exposure) inhibited pu lmonary edema formation with ED,, values of 1.7, 0.5, 31 and 2.8 mg/kg , respectively. Maximum inhibition occurred with rolipram at 10 mg/kg (70 +/- 17%), CI-930 at 10 mg/kg (101 +/- 4%), aminophylline at 50 mg/ kg (88 +/- 14%) and dexamethasone at 3 mg/kg (64 +/- 6%). Denbufylline and milrinone also inhibited pulmonary edema formation at 10 mg/kg i. p., supporting the inhibition of PDE4 and PDE3 as the mechanisms of ac tion of rolipram and CI-930, respectively. Rolipram, CI-930, aminophyl line and dexamethasone (at maximum doses for inhibiting pulmonary edem a) inhibited the 3-fold increase in bronchoalveolar lavage albumin con centration 24 hr after LPS exposure (42 +/- 14%, 98 +/- 2%, 70 +/- 9% and 53 +/- 13%, respectively). However, none of these compounds (at ma ximum doses for inhibiting pulmonary edema) inhibited the correspondin g 400-fold increase in lavage neutrophil counts. In conclusion, inhibi tors of either cAMP PDE3 or cAMP PDE4 inhibited the pulmonary edema an d protein leakage into the airways produced by LPS aerosols in guinea pigs by mechanisms other than inhibiting neutrophil influx into the ai rways. These results suggest that selective inhibitors of one or both forms of cAMP PDE may be useful for treating pulmonary edema associate d with the adult respiratory distress syndrome.