Fibrotic gene expression coexists with alveolar proteinosis in early indium lung

Abstract

Occupational inhalation of indium compounds can cause the so-called "indium lung disease". Most affected individuals show pulmonary alveolar proteinosis (PAP) and fibrotic interstitial lung disease. In animal experiments, inhalation of indium tin oxide or indium oxide has been shown to cause lung damage. However, the mechanisms by which indium compounds lead to indium lung disease remain unknown. In this study, we constructed a mouse model of indium lung disease and analyzed gene expression in response to indium exposure. Indium oxide (In2O3, 10 mg/kg, primary particle size <100 nm) was administered intratracheally to C57BL/6 mice (male, 8 weeks of age) twice a week for 8 weeks. Four weeks after the final instillation, histopathological analysis exhibited periodic acid-Schiff positive material in the alveoli, characteristic of PAP. Comprehensive gene expression analysis by RNA-Seq, however, revealed expression of fibrosis-related genes, such as surfactant associated protein D, surfactant associated protein A1, mucin 1, and collagen type I and III, was significantly increased, indicating that fibrotic gene expression progresses in early phase of indium lung. These data supported the latest hypothesis that PAP occurs as an acute phase response and is replaced by fibrosis after long-term latency.

Pulmonary and Systemic Toxicity in a Rat Model of Pulmonary Alveolar Proteinosis Induced by Indium-Tin Oxide Nanoparticles

“…This onset of PAP is contrasted with the previous animal studies, which only required two weeks of repeated inhalation or instillation exposure to induce PAP. 20 , 21 For example, Jeong et al have shown that PAP was induced from day 3 and fully developed at 2 weeks. 22 The higher protein deposition responses in alveoli and earlier onset of pulmonary fibrosis observed in the present study, compared with previous studies, could be attributed to the higher deposition of indium nanoparticles in the alveoli than indium compounds.…”

Histologic factors associated with nintedanib efficacy in patients with idiopathic pulmonary fibrosis

“…It is one of the histological findings in pulmonary edema; the underlying aetiology of permeability edema has been reported in addition to other mechanisms, such as inhalant toxicity, primary alveolar proteinosis, pulmonary veno-occlusive disease, traumatic lung injury, or acute respiratory distress syndrome. Moreover, it is regarded as a manifestation of lymphovascular disorder in the interstitium or alveolar damage [24][25][26][27][28]. If alveolar capillary damage persists, leakage of the protein-rich fluid from the intravascular space into the interstitium may progress and eventually induce pulmonary fibrosis [29].…”