Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854.
Laboratory of Environmental Research, Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland.
Toxicol Sci. 2020 Dec 1;178(2):358-374. doi: 10.1093/toxsci/kfaa150.
Sulfur mustard (SM) inhalation causes debilitating pulmonary injury in humans which progresses to fibrosis. Herein, we developed a rat model of SM toxicity which parallels pathological changes in the respiratory tract observed in humans. SM vapor inhalation caused dose (0.2-0.6 mg/kg)-related damage to the respiratory tract within 3 days of exposure. At 0.4-0.6 mg/kg, ulceration of the proximal bronchioles, edema and inflammation were observed, along with a proteinaceous exudate containing inflammatory cells in alveolar regions. Time course studies revealed that the pathologic response was biphasic. Thus, changes observed at 3 days post-SM were reduced at 7-16 days; this was followed by more robust aberrations at 28 days, including epithelial necrosis and hyperplasia in the distal bronchioles, thickened alveolar walls, enlarged vacuolated macrophages, and interstitial fibrosis. Histopathologic changes were correlated with biphasic increases in bronchoalveolar lavage (BAL) cell and protein content and proliferating cell nuclear antigen expression. Proinflammatory proteins receptor for advanced glycation end product (RAGE), high-mobility group box protein (HMGB)-1, and matrix metalloproteinase (MMP)-9 also increased in a biphasic manner following SM inhalation, along with surfactant protein-D (SP-D). Tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS), inflammatory proteins implicated in mustard lung toxicity, and the proinflammatory/profibrotic protein, galectin (Gal)-3, were upregulated in alveolar macrophages and in bronchiolar regions at 3 and 28 days post-SM. Inflammatory changes in the lung were associated with oxidative stress, as reflected by increased expression of heme oxygenase (HO)-1. These data demonstrate a similar pathologic response to inhaled SM in rats and humans suggesting that this rodent model can be used for mechanistic studies and for the identification of efficacious therapeutics for mitigating toxicity.
芥子气（SM）吸入会导致人体肺部严重损伤，并逐渐发展为纤维化。在此，我们建立了一个大鼠 SM 毒性模型，该模型与人类呼吸道的病理变化相似。SM 蒸气吸入会导致暴露后 3 天内呼吸道出现剂量（0.2-0.6mg/kg）相关损伤。在 0.4-0.6mg/kg 时，近端细支气管出现溃疡、水肿和炎症，肺泡区域含有炎性细胞的蛋白性渗出物。时程研究表明，病理反应呈双相性。因此，暴露后 3 天观察到的变化在 7-16 天减少；随后在 28 天出现更强烈的异常，包括远端细支气管上皮坏死和增生、肺泡壁增厚、空泡化巨噬细胞增大和间质纤维化。组织病理学变化与支气管肺泡灌洗液（BAL）细胞和蛋白含量以及增殖细胞核抗原表达的双相增加相关。受体晚期糖基化终产物（RAGE）、高迁移率族蛋白（HMGB）-1 和基质金属蛋白酶（MMP）-9 等促炎蛋白也呈双相增加，表面活性蛋白-D（SP-D）也是如此。肿瘤坏死因子（TNF）-α和诱导型一氧化氮合酶（iNOS）、与芥子气肺毒性相关的促炎蛋白、以及促炎/致纤维化蛋白半乳糖凝集素（Gal）-3，在 SM 暴露后 3 天和 28 天的肺泡巨噬细胞和细支气管区域上调。肺部炎症变化与氧化应激相关，血红素加氧酶（HO）-1 的表达增加反映了这一点。这些数据表明，大鼠和人类对吸入 SM 的病理反应相似，表明该啮齿动物模型可用于机制研究和确定减轻毒性的有效治疗方法。
