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

  • ️Sat Jan 01 2022

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

Nan Liu et al. Int J Nanomedicine. 2022.

Abstract

Purpose: The main objective of this study was to clarify the biodistribution and in vivo toxicological effects of indium-tin oxide nanoparticles (Nano-ITO) in male rats.

Methods: Dose-response (three divided doses) and time-course studies (six exposure durations) were performed to examine Nano‑ITO-induced pulmonary and systemic toxicity. At the end of the experiment, hematology and serum biochemical parameters were determined, and cytokines levels and oxidative stress were analyzed in the bronchoalveolar lavage fluid. In addition, indium biodistribution following Nano‑ITO exposure was determined using inductively coupled plasma mass spectrometer to measure indium concentration in the lung, spleen, brain, liver, kidney, and testis. Rat lung tissues were also harvested for staining with hematoxylin and eosin, periodic acid Schiff stain, Masson's trichrome, and Sirius red.

Results: Relative lung weights were significantly increased in all Nano-ITO-exposed groups. All organs exhibited a statistically significant difference in indium levels. Rat exposure to Nano‑ITO resulted in a dose-response increase in acute systemic inflammation and injury. BALF analysis revealed significantly elevated levels of lung oxidative stress, pulmonary injury, and inflammatory markers across most groups. Serum biochemistry results showed that Nano-ITO could affect the liver and renal functions of rats when exposed for 3 days. Compared with the control group, significant inflammatory responses or pathological changes were observed in the liver, kidney, and testis of rats at different sampling times and three doses examined. Histopathologically, foci of slight-to-severe pulmonary inflammatory response along with acute inflammatory, pulmonary fibrosis and alveolar proteinosis were detected, and the severity of these lesions worsened in a dose- and time-dependent manner.

Discussion: These findings provide novel evidence that enhanced progressive massive pulmonary fibrosis, diffuse interstitial fibrosis, and collagen accumulation play a role in the development of pulmonary alveolar proteinosis following Nano-ITO exposure.

Keywords: indium-tin oxide nanoparticles; pulmonary alveolar proteinosis; pulmonary fibrosis.

© 2022 Liu et al.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1

Schematic diagram of male SD rat experimental design. Ten rats were used in each group and two independent experiments were performed accordingly.

Figure 2
Figure 2

The characterization of the Nano-ITO. (A) The SEM images of the Nano-ITO, and the particles were in nearly spherical structure. Scale bar = 500 nm. (B) Nano-ITO bioaccumulate in lung tissues by TEM analysis. Scale bar = 1 μm.

Figure 3
Figure 3

Body weight and organ index in rat. (A) The body weight curve of rat continuously monitored for 12 weeks. (B) The main organ index of rat on Week 12 after exposure to Nano-ITO. *P<0.05 vs control; #P<0.05 vs Nano-ITO 1.2 mg/kg and 3 mg/kg group.

Figure 4
Figure 4

Indium concentration in organs. (A) The indium concentration of six tissues in dose group. The indium concentration of lungs (Ba), spleens (Bb), brains (Bc), livers (Bd), kidneys (Be), and testes (Bf) in time group. *P<0.001 vs control.

Figure 5
Figure 5

Hematology results of experimental rats. (A) Hematology results in dose group. (B) Hematology results in time group; (a) WBC levels; (b) RBC levels; (c) HGB levels; (d) PLT levels; (e) HCT levels; (f) MCV levels; (g) MCH levels; (h) MCHC levels; (i) RDW-SD levels; (j) RDW-CV levels; (k) PDW levels; (l) MPV levels; (m) PCL levels; (n) P-LCR levels; (o) NEUT levels; (p) LYMPH levels. *P<0.05 vs control.

Figure 6
Figure 6

Serum biochemical results of experimental rats. (A) Serum biochemical results in dose group. (B) Serum biochemical results in time group; (a) TP levels; (b) ALB levels; (c) GLB levels; (d) A/G levels; (e) ALT levels; (f) AST levels; (g) CHE levels; (h) TBIL levels; (i) DBIL levels; (j) IBIL levels; (k) BUN levels; (l) UA levels; (m) Cr levels; (n) MDA levels; (o) SOD levels; (p) HYP levels; (q) CAT levels; (r) GSH-px levels. *P<0.05 vs control.

Figure 7
Figure 7

Analysis results of BALF. (A) BALF analysis results in dose group. (B) BALF analysis results in time group; (a) SOD levels; (b) T-AOC levels; (c) MDA levels; (d) TP levels; (e) LDH levels; (f) IL-1β levels; (g) IL-6 levels; (h) IL-10 levels; (i) TNF-α levels. Lung oxidative stress markers (SOD, T-AOC, and MDA); Pulmonary injury markers (TP, LDH); Inflammatory markers in airways (IL-1β, IL-6, IL-10, and TNF-α). *P<0.05 vs control.

Figure 8
Figure 8

Microscopic findings of the serial lung tissue sections stained with H & E (A), PAS (B), Masson’s trichrome (C), and Sirius red (D) in dose-response study. Scale bar = 1000 μm, 100 μm, and 50 μm (the scale of each figure A–C from left to right); Scale bar in figure D represent 100 μm and 50 μm from left to right.

Figure 9
Figure 9

Microscopic findings of the serial lung tissue sections stained with H & E (A), PAS (B), Masson’s trichrome (C), and Sirius red (D) in time-course study. Scale bar = 1000 μm, 100 μm, and 50 μm (the scale of each figure A–C from left to right); Scale bar in figure D represent 100 μm and 50 μm from left to right.

Figure 10
Figure 10

Representative histological images of major organs including spleen, brain, liver, kidney and testis stained with hematoxylin and eosin stain (H & E). Scale bar = 50 μm. Liver: ▲Mild inflammatory cell infiltration, ▲Vacuolation, and ▲Sinusoid dilation. Kidney: ►Vacuolar degeneration in renal tubular epithelial cells, ►Dilated tubules, ►Atrophy of glomeruli, and ♥Cell debris in tubules. Testis: ▼Vacuolization of seminiferous tubules, ⁎Vacuolization of interstitial cells.

Figure 11
Figure 11

Schematic depiction of the mechanism of Nano-ITO involved in pulmonary inflammation, fibrosis, and PAP events.

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References

    1. Homma S, Miyamoto A, Sakamoto S, et al. Pulmonary fibrosis in an individual occupationally exposed to inhaled indium-tin oxide. Eur Respir J. 2005;25(1):200–204. doi:10.1183/09031936.04.10012704 - DOI - PubMed
    1. Chonan T, Taguchi O, Omae K. Interstitial pulmonary disorders in indium-processing workers. Eur Respir J. 2007;29:317–324. doi:10.1183/09031936.00020306 - DOI - PubMed
    1. Cummings KJ, Donat WE, Ettensohn DB, et al. Pulmonary alveolar proteinosis in workers at an indium processing facility. Am J Respir Crit Care Med. 2010;181(5):458–464. doi:10.1164/rccm.200907-1022CR - DOI - PMC - PubMed
    1. Xiao YL, Cai HR, Wang YH, et al. Pulmonary alveolar proteinosis in an indium-processing worker. Chin Med J. 2010;123(10):1347–1350. - PubMed
    1. Omae K, Nakano M, Tanaka A, et al. Indium lung-case reports and epidemiology. Int Arch Occup Environ Health. 2011;84(5):471–477. doi:10.1007/s00420-010-0575-6 - DOI - PubMed

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