Objective: To study the dynamic pathological characteristics of lung tissue in a Nano-ITO induced rat model of indium lung disease and to guide clinical and basic scientific research to further explore the mechanisms of pulmonary interstitial injury and pulmonary alveolar proteinosis (PAP). Methods: Dose-response (three divided doses) and time-course studies (six exposure periods) were performed to investigate the pulmonary toxicity induced by Nano-ITO. At the end of the experiment, cytokine levels and oxidative stress were analyzed in the bronchoalveolar lavage fluid. Rat lung tissues were also collected for staining with H&E, PAS, Masson's, Oil Red O, and Sirius Red. Ultrastructure of lung tissue cells was observed by transmission electron microscopy. Expression of IL-1β, HO-1, SP-A was observed by immunohistochemistry, and the expression of α-SMA was observed by immunofluorescence. Results: Nano-ITO intratracheal instillation caused pulmonary toxicity by inducing acute inflammation at 3 days, granuloma (nodule) formation and collagen hyperplasia at 14 days, and alveolar proteinosis at 56 days post-exposure. Pathological features of lung tissue included typical alveolar exudates, cellular fibrous nodules, enlarged alveolar fat droplet fusion, cholesterol crystal granuloma and pulmonary alveolar proteinosis. The intra-alveolar eosinophilic material (multilamellated, lattice-shaped, and myelin-like structure) showed abnormal lamellar bodies (features of alveolar type Ⅱ epithelial cells) and abundant rough endoplasmic reticulum and mitochondria (features of fibroblasts) on transmission electron microscopy of the lung tissue from rats exposed to Nano-ITO on the 84th day. Cellular pathology revealed that a large amount of amorphous PAS stain-positive substances appear in BALF at 28 days post-exposure, and pink granular protein-like substances can be seen in alveolar macrophages. Conclusions: There are three characteristic developmental stages in Nano-ITO induced pulmonary injury in rats, acute inflammation, granuloma (nodule) formation and collagen proliferation, and pulmonary alveolar proteinosis, which provide a reference feature model for the pathogenesis of indium lung disease.
目的： 研究纳米氧化铟锡（Nano-ITO）致大鼠肺损伤模型中的动态病理学特征，指导临床和基础科研进一步探索肺间质损伤和肺泡蛋白沉积症（PAP）的机制。 方法： 建立大鼠非暴露式气管灌注染毒Nano-ITO模型，进行剂量反应（1.2、3、6 mg·kg-1·bw-1）和时间效应（3、7、14、28、56、84 d）研究，分析支气管肺泡灌洗液（BALF）中炎症因子和氧化应激指标水平，HE、PAS、Masson、油红O、天狼星红染色观察肺组织病理形态的改变，透射电镜观察肺组织细胞超微结构，免疫组化测定IL-1β、HO-1、SP-A蛋白变化，免疫荧光检测α-SMA蛋白表达情况，PAS染色BALF细胞蜡块切片。 结果： 气管内灌注Nano-ITO，通过在暴露后第3天诱发急性炎症、第14天诱发肉芽肿（结节）形成和胶原增生、第56天诱发PAP和脂滴积累引起肺毒性。肺组织病理学特征包括典型的肺泡内渗出物、纤维细胞性结节、肺泡脂肪滴融合变大、胆固醇结晶肉芽肿和肺泡蛋白沉积症。Nano-ITO暴露第84天组大鼠肺组织的透射电镜发现，肺泡内嗜酸性物质（多层、格子状和髓鞘样结构）显示异常的板层体（肺泡Ⅱ型上皮细胞的特征）和丰富的粗面内质网和线粒体（成纤维细胞的特征）。细胞病理学光镜观察可见，Nano-ITO暴露28 d后，BALF中出现大量无定形 PAS 染色阳性物质，肺泡巨噬细胞内可见粉红色颗粒蛋白样物质。 结论： 急性炎症、肉芽肿（结节）形成和胶原增生、肺泡蛋白沉积是Nano-ITO诱导大鼠肺损伤过程中的3个特征性发展阶段，为铟肺病的致病机理研究提供了可参考的特征模型。.