LAUSR

Pulmonary alveolar proteinosis (PAP) is rare disease that accumulates alveolar surfactant. PAP can be induced by nanoparticles (NPs), but there is little information about PAP-producing NPs and their mechanism. Here, we evaluated PAP-producing NPs including 6 of rare earth oxide (REO) NPs and NiO NPs and investigated the magnitude and related gene expression (ATP-binding cassette, ATP) of PAP at 1 and 6 months after single intratracheal instillation to Wistar rats. Furthermore, we evaluated morphological change of REO NPs because biotransformation is critical to understand the toxicity. The 6 REO NPs (Dy2O3, Eu2O3, In2O3, Pr6O11, Sm2O3, and Tb4O7) and NiO NPs caused PAP at 1 month, while only In2O3 NPs showed a persistent PAP at 6 months. All the REO NPs transformed sea urchin-shaped within the alveolar macrophage up to 6 months. The levels of phospholipids, indicators of PAP, showed good correlation with gene expression of five ABC transporters (ABCA1, ABCB4, ABCB8, ABCG1, and ABCG4), which effluxing phospholipids in PAP. Among them, ABCG1 and ABCG4 might be key transporters involved in PAP development because both showed negative correlation with the magnitude of PAP, while others might be compensatory transporters for PAP recovery, as they showed a positive correlation. In conclusion, the identification of seven PAP-producing NPs implies that PAP may be an emerging occupational disease and that ABCG1 and ABCG4 may be therapeutic targets for PAP. In this regard, we are studying therapeutic agent for PAP induced by NPs using medicine related PPAR-gamma, which is upstream mechanism of ABCG1 and ABCG4.