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

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 (InO), 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 InO nanoparticles (NPs) after a single intratracheal instillation to rats. InO NPs were instilled to female Wistar rats at 7.5, 30, and 90 cm/rat and lung injuries were evaluated at day 1, 3, 7, 14, 30, 90, and 180 after a single intratracheal instillation. Treatment of InO 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 InO NPs. This study suggests that a single inhalation exposure to InO 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 cm/rat) implies that the re-evaluation of occupational recommended exposure limit for InO NPs is urgently needed to protect workers.