Amiodarone inhibits lung degradation of SP-A and perturbs the distribution of lysosomal enzymes.
Amiodarone may induce lung damage by direct toxicity or indirectly through inflammation. To clarify the mechanism of direct toxicity, we briefly exposed rabbit alveolar macrophages to amiodarone and analyzed their morphology, synthesis, and degradation of dipalmitoylphosphatidylcholine (DPPC); distribution of lysosomal enzymes; and uptake of diphtheria toxin and surfactant protein (SP) A used as tracers of the endocytic pathway. Furthermore, in newborn rabbits, we studied the clearance of DPPC and SP-A instilled into the trachea together with increasing amounts of amiodarone. We found that in vitro amiodarone decreases the surface density of mitochondria and lysosomes while increasing the surface density of inclusion bodies, increases the incorporation of choline into DPPC, modifies the distribution of lysosomal enzymes, and does not affect the uptake and processing of diphtheria toxin but inhibits the degradation of SP-A. In vivo amiodarone inhibits the degradation of SP-A but not of DPPC. We conclude that the acute exposure to amiodarone perturbs the endocytic pathway acting after the early endosomes, alters the traffic of lysosomal enzymes, and interferes with the turnover of SP-A.
Baritussio
A
A
Department of Medical and Surgical Sciences, University of Padua, 35128 Padua. aldo.baritussio@unipd.it
Marzini
S
S
Agostini
M
M
Alberti
A
A
Cimenti
C
C
Bruttomesso
D
D
Manzato
E
E
Quaglino
D
D
Pettenazzo
A
A
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism / Q000494:pharmacology; D000638:Amiodarone / Q000633:toxicity*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D048429:Cell Size; D002470:Cell Survival; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D004167:Diphtheria Toxin / Q000494:pharmacology; D004705:Endocytosis / Q000502:physiology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D011510:Proteolipids / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000378:metabolism*; D011817:Rabbits; D011868:Radioisotopes / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D004167:Diphtheria Toxin; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D011868:Radioisotopes; D015060:1,2-Dipalmitoylphosphatidylcholine; D001619:beta-N-Acetylhexosaminidases; D000638:Amiodarone; D002794:Choline