许多研究表明，职业接触铟及其化合物可能诱发肺部疾病。尽管动物毒理学研究和人类流行病学研究表明铟接触可能导致肺损伤、炎症、肺纤维化、肺气肿、肺泡蛋白病甚至肺癌，但目前从人获得的相关数据仅限于单个工作场所，并且对肺部接触的早期影响不太了解。本研究结合了人群研究和动物实验，以检查铟与肺部损伤及其作用机制之间的联系。对中国铟暴露工人进行了一项横断面流行病学研究，以评估职业铟暴露与早期影响血清生物标志物之间的关联。本研究还比较和分析了铟化合物暴露引起的人类血清生物标志物改变和铟暴露相关的大鼠肺病理生物学的因果视角，并讨论了它们识别和预防的可能途径。 本研究对铟锭生产厂的57名暴露工人（每天至少6小时，持续一年）和63名对照进行了研究。利用电感耦合等离子体质谱法测量了血清、尿液和空气中铟的浓度作为暴露指标。采用ELISA测量了肺部损伤、炎症和氧化应激的16种血清生物标志物。分析了血清铟和16种血清生物标志物之间的关联，以探讨铟对铟暴露工人肺部损伤的作用机制。进行了动物实验，测量了大鼠支气管肺泡灌洗液（BALF）中的炎症因子水平和肺组织蛋白质表达水平。建立了四种不同形式的铟化合物暴露大鼠模型（每周两次气管内滴注，持续8周，8周恢复）。模型I：铟锡氧化物组0、1.2、3和6 mg/kg bw；模型II：铟氧化物（In2O3）组0、1.2、3和6 mg/kg bw；模型III：硫酸铟（In2（SO4）3）组0、0.523、1.046和2.614 mg/kg bw；模型IV：氯化铟（InCl3）组0、0.065、0.65和1.3 mg/kg bw。采用苏木精-伊红染色、周期性酸- Schiff染色和Masson's染色、透射电镜评估肺部病理变化，并通过免疫组化确定蛋白质变化。 在生产车间，空气中铟浓度为78.4 μg/m3。铟暴露工人的血清铟和尿铟水平分别为39.3 μg/L和11.0 ng/g肌酐。铟暴露工人中发现了肺部损伤标志物、氧化应激标志物和炎症标志物的增加。铟暴露工人的血清铟水平与SP-A、IL-1β、IL-6的血清水平存在统计学上的正相关。其中，SP-A表现出持续反应的模式。动物实验结果表明，随着剂量的增加，铟暴露显著增加了所有大鼠模型组的血清铟和肺铟、BALF中IL-1β、IL-6、IL-10和TNF-α水平，并上调了所有大鼠模型组中SP-A、SP-D、KL-6、GM-CSF、NF-κBp65和HO-1的蛋白质表达。透射电镜显示In2（SO4）3和InCl3是可溶的，肺组织中没有发现颗粒物，与不溶的化合物（ITO和In2O3）形成对比。在In2（SO4）3和InCl3暴露组的肺组织中未发现PAS染色阳性物质，而ITO和In2O3大鼠模型则支持了铟肺病所见的肺泡蛋白病和间质纤维化的结果。ITO和InCl3可以加速间质纤维化。我们的体内实验结果表明，肺泡内表面活性物质的积聚（免疫组化）和铟肺病特有的胆固醇裂隙肉芽肿（PAS染色）是由特定形式的铟（ITO和In2O3）引起的。 在铟暴露工人中，生物标志物的发现表明肺部损伤、氧化应激和炎症反应。在四种铟形式的大鼠模型中，总体而言，所有化合物的生物标志物反应与人类相符。此外，在铟锡氧化物和铟氧化物的大鼠模型中发现了肺泡蛋白病，在铟锡氧化物和铟三氯化物暴露的大鼠模型中发现了间质纤维化，支持了先前的人类疾病报告。血清SP-A水平与铟暴露呈正相关，可能被视为受暴露工人潜在的生物标志物。 © 2022. The Author(s).

Many studies have shown that occupational exposure to indium and its compounds could induce lung disease. Although animal toxicological studies and human epidemiological studies suggest indium exposure may cause lung injury, inflammation, pulmonary fibrosis, emphysema, pulmonary alveolar proteinosis, and even lung cancer, related data collected from humans is currently limited and confined to single workplaces, and the early effects of exposure on the lungs are not well understood.This study combined population studies and animal experiments to examine the links of indium with pulmonary injury, as well as its mechanism of action. A cross-sectional epidemiological study of indium-exposed workers from China was conducted to evaluate associations between occupational indium exposure and serum biomarkers of early effect. This study also compares and analyzes the causal perspectives of changes in human serum biomarkers induced by indium compound exposure and indium exposure-related rat lung pathobiology, and discusses possible avenues for their recognition and prevention.This is a study of 57 exposed (at least 6 h per day for one year) workers from an indium ingot production plant, and 63 controls. Indium concentration in serum, urine, and airborne as exposure indices were measured by inductively coupled plasma-mass spectrometry. Sixteen serum biomarkers of pulmonary injury, inflammation, and oxidative stress were measured using ELISA. The associations between serum indium and 16 serum biomarkers were analyzed to explore the mechanism of action of indium on pulmonary injury in indium-exposed workers. Animal experiments were conducted to measure inflammatory factors levels in bronchoalveolar lavage fluid (BALF) and lung tissue protein expressions in rats. Four different forms of indium compound-exposed rat models were established (intratracheal instillation twice per week, 8 week exposure, 8 week recovery). Model I: 0, 1.2, 3, and 6 mg/kg bw indium tin oxide group; Model II: 0, 1.2, 3, and 6 mg/kg bw indium oxide (In2O3) group; Model III: 0, 0.523, 1.046, and 2.614 mg/kg bw indium sulfate (In2(SO4)3) group; Model IV: 0, 0.065, 0.65, and 1.3 mg/kg bw indium trichloride (InCl3) group. Lung pathological changes were assessed by hematoxylin & eosin, periodic acid Schiff, and Masson's staining, transmission electron microscopy, and the protein changes were determined by immunohistochemistry.In the production workshop, the airborne indium concentration was 78.4 μg/m3. The levels of serum indium and urine indium in indium-exposed workers were 39.3 μg/L and 11.0 ng/g creatinine. Increased lung damage markers, oxidative stress markers, and inflammation markers were found in indium-exposed workers. Serum indium levels were statistically and positively associated with the serum levels of SP-A, IL-1β, IL-6 in indium-exposed workers. Among them, SP-A showed a duration-response pattern. The results of animal experiments showed that, with an increase in dosage, indium exposure significantly increased the levels of serum indium and lung indium, as well as the BALF levels of IL‑1β, IL‑6, IL‑10, and TNF‑α and up-regulated the protein expression of SP-A, SP-D, KL-6, GM-CSF, NF-κB p65, and HO-1 in all rat models groups. TEM revealed that In2(SO4)3 and InCl3 are soluble and that no particles were found in lung tissue, in contrast to the non-soluble compounds (ITO and In2O3). No PAS-staining positive substance was found in the lung tissue of In2(SO4)3 and InCl3 exposure groups, whereas ITO and In2O3 rat models supported findings of pulmonary alveolar proteinosis and interstitial fibrosis seen in human indium lung disease. ITO and InCl3 can accelerate interstitial fibrosis. Findings from our in vivo studies demonstrated that intra-alveolar accumulation of surfactant (immunohistochemistry) and characteristic cholesterol clefts granulomas of indium lung disease (PAS staining) were triggered by a specific form of indium (ITO and In2O3).In indium-exposed workers, biomarker findings indicated lung damage, oxidative stress and an inflammatory response. In rat models of the four forms of indium encountered in a workplace, the biomarkers response to all compounds overall corresponded to that in humans. In addition, pulmonary alveolar proteinosis was found following exposure to indium tin oxide and indium oxide in the rat models, and interstitial fibrosis was found following exposure to indium tin oxide and indium trichloride, supporting previous report of human disease. Serum SP-A levels were positively associated with indium exposure and may be considered a potential biomarker of exposure and effect in exposed workers.© 2022. The Author(s).