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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

      105,621 Monthly downloads/views I 7.033 Impact Factor I 10.9 CiteScore I 1.22 Source Normalized Impact per Paper (SNIP) I 1.032 Scimago Journal & Country Rank (SJR)

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

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          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.

          Most cited references23

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          Pulmonary alveolar proteinosis in workers at an indium processing facility.

          K. Cummings, W Donat, D Ettensohn … (2010)
          Two cases of pulmonary alveolar proteinosis, including one death, occurred in workers at a facility producing indium-tin oxide (ITO), a compound used in recent years to make flat panel displays. Both workers were exposed to airborne ITO dust and had indium in lung tissue specimens. One worker was tested for autoantibodies to granulocytemacrophage-colonystimulating factor (GM-CSF) and found to have an elevated level. These cases suggest that inhalational exposure to ITO causes pulmonary alveolar proteinosis, which may occur via an autoimmune mechanism.
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            Indium lung disease.

            Kristin Cummings, Makiko Nakano, Kazuyuki Omae … (2012)
            Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases. To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken. Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers. Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies.
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              Interstitial pulmonary disorders in indium-processing workers.

              K Omae, T Chonan, O Taguchi (2007)
              The production of indium-tin oxide has increased, owing to the increased manufacture of liquid-crystal panels. It has been reported that interstitial pneumonia occurred in two indium-processing workers; therefore, the present study aimed to evaluate whether interstitial pulmonary disorders were prevalent among indium workers. The study was carried out in 108 male workers in the indium plant where the two interstitial pneumonia patients mentioned above were employed, and included high-resolution computed tomography (HRCT) of the lungs, pulmonary function tests and analysis of serum sialylated carbohydrate antigen KL-6 and the serum indium concentration. Significant interstitial changes were observed in 23 indium workers on HRCT and serum KL-6 was abnormally high (>500 U x mL(-1)) in 40 workers. Workers with serum indium concentrations in the highest quartile had significantly longer exposure periods, greater HRCT changes, lower diffusing capacity of the lung for carbon monoxide and higher KL-6 levels compared with those in the lowest quartile. The serum indium concentration was positively correlated with the KL-6 level and with the degree of HRCT changes. In conclusion, the results of the present study indicated that serum KL-6 and high-resolution computed tomography abnormalities were prevalent among indium workers and that these abnormalities increased with the indium burden, suggesting that inhaled indium could be a potential cause of occupational lung disease.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Nanomedicine
                Journal ID (iso-abbrev): Int J Nanomedicine
                Journal ID (publisher-id): ijn
                Title: International Journal of Nanomedicine
                Publisher: Dove
                ISSN (Print): 1176-9114
                ISSN (Electronic): 1178-2013
                Publication date (Electronic): 17 February 2022
                Publication date Collection: 2022
                Volume: 17
                Pages: 713-731
                Affiliations
                [1 ]School of Public Health, North China University of Science and Technology , Tangshan, 063210, Hebei, People’s Republic of China
                [2 ]Baoding Center for Disease Control and Prevention , Baoding, 071030, Hebei, People’s Republic of China
                [3 ]Institute of Industrial Hygiene of Ordnance Industry , Xian, 710065, Shanxi, People’s Republic of China
                [4 ]XinXiang Medical University , Xinxiang, 453003, Henan, People’s Republic of China
                Author notes
                Correspondence: Sanqiao Yao, North China University of Science and Technology , Bohai Avenue 21, Tangshan, 063210, Hebei, People’s Republic of China, Fax +86-315-8805583, Email sanqiaoyao@xxmu.edu.cn
                Article
                Publisher ID: 338955
                DOI: 10.2147/IJN.S338955
                PMC ID: 8860399
                PubMed ID: 35210771
                SO-VID: 863055e9-7fbf-4fd9-acd9-1dbf201ab7c5
                Copyright © © 2022 Liu et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 12 September 2021
                Date accepted : 01 February 2022
                Page count
                Figures: 11, References: 23, Pages: 19
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Molecular medicine
                Keywords: indium-tin oxide nanoparticles,pulmonary fibrosis,pulmonary alveolar proteinosis
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: indium-tin oxide nanoparticles, pulmonary fibrosis, pulmonary alveolar proteinosis

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