Amiodarone inhibits lung degradation of SP-A and perturbs the distributionof lysosomal enzymes

Amiodarone may induce lung damage by direct toxicity or indirectly through inflammation. To clarify the mechanism of direct toxicity, we briefly expos ed rabbit alveolar macrophages to amiodarone and analyzed their morphology, synthesis, and degradation of dipalmitoylphosphatidylcholine (DPPC); distr ibution of lysosomal enzymes; and uptake of diphtheria toxin and surfactant protein (SP) A used as tracers of the endocytic pathway. Furthermore, in n ewborn rabbits, we studied the clearance of DPPC and SP-A instilled into th e trachea together with increasing amounts of amiodarone. We found that in vitro amiodarone decreases the surface density of mitochondria and lysosome s while increasing the surface density of inclusion bodies, increases the i ncorporation of choline into DPPC, modifies the distribution of lysosomal e nzymes, and does not affect the uptake and processing of diphtheria toxin b ut inhibits the degradation of SP-A. In vivo amiodarone inhibits the degrad ation of SP-A but not of DPPC. We conclude that the acute exposure to amiod arone perturbs the endocytic pathway acting after the early endosomes, alte rs the traffic of lysosomal enzymes, and interferes with the turnover of SP -A.