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Respiratory and systemic impacts following MWCNT inhalation in B6C3F1/N mice
Particle and Fibre Toxicology ( IF 10 ) Pub Date : 2021-03-26 , DOI: 10.1186/s12989-021-00408-z
Christopher T Migliaccio 1 , Raymond F Hamilton 1 , Pamela K Shaw 1 , Joseph F Rhoderick 1 , Sanghamitra Deb 2 , Rohit Bhargava 3 , Jack R Harkema 4 , Andrij Holian 1
Affiliation  

A very pure multi-walled carbon nanotube (MWCNT) that was shown to have very low toxicity in vitro, was evaluated for lung and systemic effects and distribution following inhalation exposure. B6C3F1/N mice were exposed to varying doses (0, 0.06, 0.2, and 0.6 mg/m3) of the (99.1% carbon) MWCNT by inhalation for 30 days (excluding weekends). Ten days following the last exposure, the lungs and spleen were harvested and processed for histology and immune cell population assessment. In addition, lung lavage cells and fluid were analyzed. Stimulated Raman scattering (SRS) was used to identify particles in the lungs, spleen, kidneys, liver, mediastinal and brachial lymph nodes, and olfactory bulb. Splenic tissue sections were stained with hematoxylin and eosin (H&E) for light microscopic histopathology assessment. Blood plasma was analyzed for cytokines and cathepsins. A section of the spleen was processed for RNA isolation and relative gene expression for 84 inflammation-related cytokines/chemokines. Following MWCNT exposure, particles were clearly evident in the lungs, spleens, lymph nodes and olfactory bulbs, (but not livers or kidneys) of exposed mice in a dose-dependent manner. Examination of the lavaged lung cells was unremarkable with no significant inflammation indicated at all particle doses. In contrast, histological examination of the spleen indicated the presence of apoptotic bodies within T cells regions of the white pulp area. Isolated splenic leukocytes had significant changes in various cells including an increased number of proinflammatory CD11b+Ly6C+ splenic cells. The gene expression studies confirmed this observation as several inflammation-related genes were upregulated particularly in the high dose exposure (0.6 mg/m3). Blood plasma evaluations showed a systemic down-regulation of inflammatory cytokines and a dose-dependent up-regulation of lysosomal cathepsins. The findings in the lungs were consistent with our hypothesis that this MWCNT exposure would result in minimal lung inflammation and injury. However, the low toxicity of the MWCNT to lung macrophages may have contributed to enhanced migration of the MWCNT to the spleen through the lymph nodes, resulting in splenic toxicity and systemic changes in inflammatory mediators.

中文翻译:

在 B6C3F1/N 小鼠中吸入 MWCNT 后的呼吸和全身影响

一种非常纯的多壁碳纳米管 (MWCNT) 在体外表现出非常低的毒性,对吸入暴露后的肺和全身效应和分布进行了评估。B6C3F1/N 小鼠通过吸入暴露于不同剂量(0、0.06、0.2 和 0.6 mg/m3)的(99.1% 碳)MWCNT 30 天(不包括周末)。最后一次暴露后 10 天,收集肺和脾脏并进行处理以进行组织学和免疫细胞群评估。此外,还分析了肺灌洗细胞和液体。受激拉曼散射 (SRS) 用于识别肺、脾、肾、肝、纵隔和肱淋巴结以及嗅球中的颗粒。脾组织切片用苏木精和伊红 (H&E) 染色,用于光镜组织病理学评估。分析血浆的细胞因子和组织蛋白酶。脾脏的一部分被处理用于 RNA 分离和 84 种炎症相关细胞因子/趋化因子的相关基因表达。暴露于 MWCNT 后,颗粒在暴露小鼠的肺、脾、淋巴结和嗅球(但不是肝脏或肾脏)中以剂量依赖性方式清晰可见。对灌洗的肺细胞的检查无异常,在所有粒子剂量下均未显示显着炎症。相反,脾脏的组织学检查表明白髓区域的 T 细胞区域内存在凋亡小体。分离的脾白细胞在各种细胞中发生了显着变化,包括促炎性 CD11b+Ly6C+ 脾细胞数量增加。基因表达研究证实了这一观察结果,因为一些炎症相关基因被上调,特别是在高剂量暴露 (0.6 mg/m3) 中。血浆评估显示炎性细胞因子的全身下调和溶酶体组织蛋白酶的剂量依赖性上调。肺部的发现与我们的假设一致,即这种 MWCNT 暴露会导致最小的肺部炎症和损伤。然而,多壁碳纳米管对肺巨噬细胞的低毒性可能有助于增强多壁碳纳米管通过淋巴结向脾脏的迁移,导致脾脏毒性和炎症介质的全身变化。血浆评估显示炎性细胞因子的全身下调和溶酶体组织蛋白酶的剂量依赖性上调。肺部的发现与我们的假设一致,即这种 MWCNT 暴露会导致最小的肺部炎症和损伤。然而,多壁碳纳米管对肺巨噬细胞的低毒性可能有助于增强多壁碳纳米管通过淋巴结向脾脏的迁移,导致脾脏毒性和炎症介质的全身变化。血浆评估显示炎性细胞因子的全身下调和溶酶体组织蛋白酶的剂量依赖性上调。肺部的发现与我们的假设一致,即这种 MWCNT 暴露会导致最小的肺部炎症和损伤。然而,多壁碳纳米管对肺巨噬细胞的低毒性可能有助于增强多壁碳纳米管通过淋巴结向脾脏的迁移,导致脾脏毒性和炎症介质的全身变化。
更新日期:2021-03-26
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