The early onset and persistent worsening pulmonary alveolar proteinosis in rats by indium oxide nanoparticles

Abstract

Workplace inhalation exposure to indium compounds has been reported to produce ‘indium lung disease’ characterized by pulmonary alveolar proteinosis (PAP), granulomas, and pulmonary fibrosis. However, there is little information about the pulmonary toxicity of nano-sized indium oxide (In₂O₃), which is widely used in various applications such as liquid crystal displays. In this study, we evaluated the time-course and dose-dependent lung injuries by In₂O₃ nanoparticles (NPs) after a single intratracheal instillation to rats. In₂O₃ NPs were instilled to female Wistar rats at 7.5, 30, and 90 cm²/rat and lung injuries were evaluated at day 1, 3, 7, 14, 30, 90, and 180 after a single intratracheal instillation. Treatment of In₂O₃ NPs induced worsening diverse pathological changes including PAP, persistent neutrophilic inflammation, type II cell hyperplasia, foamy macrophages, and granulomas in a time- and dose-dependent manner. PAP was induced from day 3 and worsened throughout the study. The concentrations of interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in bronchoalveolar lavage fluid (BALF) showed dose- and time-dependent increases and the levels of these inflammatory mediators are consistent with the data of inflammatory cells in BALF and progressive lung damages by In₂O₃ NPs. This study suggests that a single inhalation exposure to In₂O₃ NPs can produce worsening lung damages such as PAP, chronic active inflammation, infiltration of foamy macrophages, and granulomas. The early onset and persistent PAP even at the very low dose (7.5 cm²/rat) implies that the re-evaluation of occupational recommended exposure limit for In₂O₃ NPs is urgently needed to protect workers.

Keywords:

• Indium oxide
• pulmonary alveolar proteinosis
• chronic active inflammation
• intratracheal instillation

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by the BB21+ Project in 2019 and the National Research Foundation of Korea [NRF-2018K1A3A1A74065871 and NRF-2019R1A2C1084489].