Badding Melissa A, Schwegler-Berry Diane, Park Ju-Hyeong, Fix Natalie R, Cummings Kristin J, Leonard Stephen S
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
PLoS One. 2015 Apr 13;10(4):e0124368. doi: 10.1371/journal.pone.0124368. eCollection 2015.
Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. As the demand for consumer electronics continues to increase, so does the concern for occupational exposures to particles containing these potentially toxic metal oxides. Indium-containing particles have been shown to be cytotoxic in cultured cells and pro-inflammatory in pulmonary animal models. In humans, pulmonary alveolar proteinosis and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which ITO production materials may be the most toxic to workers and how they initiate pulmonary inflammation remain poorly understood. Here we examined four different particle samples collected from an ITO production facility for their ability to induce pro-inflammatory responses in vitro. Tin oxide, sintered ITO (SITO), and ventilation dust particles activated nuclear factor kappa B (NFκB) within 3 h of treatment. However, only SITO induced robust cytokine production (IL-1β, IL-6, TNFα, and IL-8) within 24 h in both RAW 264.7 mouse macrophages and BEAS-2B human bronchial epithelial cells. Our lab and others have previously demonstrated SITO-induced cytotoxicity as well. These findings suggest that SITO particles activate the NLRP3 inflammasome, which has been implicated in several immune-mediated diseases via its ability to induce IL-1β release and cause subsequent cell death. Inflammasome activation by SITO was confirmed, but it required the presence of endotoxin. Further, a phagocytosis assay revealed that pre-uptake of SITO or ventilation dust impaired proper macrophage phagocytosis of E. coli. Our results suggest that adverse inflammatory responses to SITO particles by both macrophage and epithelial cells may initiate and propagate indium lung disease. These findings will provide a better understanding of the molecular mechanisms behind an emerging occupational health issue.
氧化铟锡（ITO）用于制造触摸屏和液晶显示电子产品的透明导电涂层。随着消费电子产品需求的持续增长，人们对职业接触含有这些潜在有毒金属氧化物的颗粒也越来越关注。含铟颗粒已被证明在培养细胞中具有细胞毒性，在肺部动物模型中具有促炎作用。在人类中，已在ITO生产设施的工人中观察到肺泡蛋白沉积症和纤维化间质性肺病。然而，哪些ITO生产材料对工人毒性最大以及它们如何引发肺部炎症仍知之甚少。在这里，我们检测了从ITO生产设施收集的四种不同颗粒样品在体外诱导促炎反应的能力。氧化锡、烧结ITO（SITO）和通风灰尘颗粒在处理后3小时内激活了核因子κB（NFκB）。然而，只有SITO在RAW 264.7小鼠巨噬细胞和BEAS-2B人支气管上皮细胞中在24小时内诱导了强大的细胞因子产生（IL-1β、IL-6、TNFα和IL-8）。我们实验室和其他实验室之前也证明了SITO诱导的细胞毒性。这些发现表明，SITO颗粒激活了NLRP3炎性小体，该炎性小体通过诱导IL-1β释放并导致随后的细胞死亡，与几种免疫介导的疾病有关。SITO对炎性小体的激活得到了证实，但这需要内毒素的存在。此外，吞噬试验表明，预先摄取SITO或通风灰尘会损害巨噬细胞对大肠杆菌的正常吞噬作用。我们的结果表明，巨噬细胞和上皮细胞对SITO颗粒的不良炎症反应可能引发并传播铟肺病。这些发现将有助于更好地理解一个新出现的职业健康问题背后的分子机制。
