The role of surfactant protein-A (SP-A) in pulmonary uptake and metabolism of [(3)H]dipalmitoylphosphatidylcholine ([(3)H]DPPC) was studied in SP-A gene-targeted mice (SP-A -/-). Unilamellar liposomes were instilled into the trachea of anesthetized mice. Uptake was measured as dpm in lungs plus liver and kidney for in vivo experiments and in lungs and perfusate for isolated lung experiments. [(3)H]DPPC uptake increased with CO(2)-induced hyperventilation in wild-type mice (SP-A +/+) but was unchanged in SP-A -/-. Secretagogue treatment approximately doubled the uptake of [(3)H]DPPC in isolated lungs from SP-A +/+ but had no effect in SP-A -/-. Lungs degraded 23 +/- 1.2% of internalized [(3)H]DPPC in SP-A +/+ and 36 +/- 0.6% in SP-A -/-; degradation increased with 8-bromoadenosine 3',5'-cyclic monophosphate in SP-A +/+ but was unchanged in SP-A -/-. Activity of lysosomal-type phospholipase A(2) (PLA(2)) was significantly greater in lungs from SP-A -/- compared with SP-A +/+. Thus SP-A is necessary for lungs to respond to hyperventilation or secretagogues with increased DPPC uptake and also modulates the PLA(2)-mediated degradation of internalized DPPC.