Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Member of the German Center of Lung Research (DZL), 81377 Munich, Germany.
ACS Nano. 2023 Nov 14;17(21):21056-21072. doi: 10.1021/acsnano.3c04111. Epub 2023 Oct 19.
Nanoparticles (NPs) released from engineered materials or combustion processes as well as persistent herpesvirus infection are omnipresent and are associated with chronic lung diseases. Previously, we showed that pulmonary exposure of a single dose of soot-like carbonaceous NPs (CNPs) or fiber-shaped double-walled carbon nanotubes (DWCNTs) induced an increase of lytic virus protein expression in mouse lungs latently infected with murine γ-herpesvirus 68 (MHV-68), with a similar pattern to acute infection suggesting virus reactivation. Here we investigate the effects of a more relevant repeated NP exposure on lung disease development as well as herpesvirus reactivation mechanistically and suggest an avenue for therapeutic prevention. In the MHV-68 mouse model, progressive lung inflammation and emphysema-like injury were detected 1 week after repetitive CNP and DWCNT exposure. NPs reactivated the latent herpesvirus mainly in CD11b+ macrophages in the lungs. , in persistently MHV-68 infected bone marrow-derived macrophages, ERK1/2, JNK, and p38 MAPK were rapidly activated after CNP and DWCNT exposure, followed by viral gene expression and increased viral titer but without generating a pro-inflammatory signature. Pharmacological inhibition of p38 activation abrogated CNP- but not DWCNT-triggered virus reactivation , and inhibitor pretreatment of latently infected mice attenuated CNP-exposure-induced pulmonary MHV-68 reactivation. Our findings suggest a crucial contribution of particle-exposure-triggered herpesvirus reactivation for nanomaterial exposure or air pollution related lung emphysema development, and pharmacological p38 inhibition might serve as a protective target to alleviate air pollution related chronic lung disease exacerbations. Because of the required precondition of latent infection described here, the use of single hit models might have severe limitations when assessing the respiratory toxicity of nanoparticle exposure.
纳米颗粒（NPs）可由工程材料或燃烧过程释放，也可由持续性疱疹病毒感染产生，它们普遍存在，并与慢性肺部疾病相关。先前，我们发现，单剂量类似烟尘的碳质纳米颗粒（CNPs）或纤维状双层碳纳米管（DWCNTs）经肺部暴露后，可导致潜伏感染鼠γ疱疹病毒 68（MHV-68）的小鼠肺部裂解病毒蛋白表达增加，其模式与急性感染相似，表明病毒重新激活。在此，我们研究了更相关的重复 NP 暴露对肺部疾病发展以及疱疹病毒重新激活的影响，并提出了一种治疗性预防的途径。在 MHV-68 小鼠模型中，反复 CNP 和 DWCNT 暴露 1 周后，检测到肺部炎症和肺气肿样损伤进展。NPs 主要在肺部的 CD11b+巨噬细胞中重新激活潜伏的疱疹病毒。在持续感染 MHV-68 的骨髓来源巨噬细胞中，CNP 和 DWCNT 暴露后 ERK1/2、JNK 和 p38 MAPK 迅速激活，随后病毒基因表达和病毒滴度增加，但没有产生促炎特征。p38 激活的药理学抑制消除了 CNP 但没有 DWCNT 触发的病毒重新激活，潜伏感染小鼠的抑制剂预处理减轻了 CNP 暴露引起的肺部 MHV-68 重新激活。我们的研究结果表明，颗粒暴露触发的疱疹病毒重新激活对纳米材料暴露或与空气污染相关的肺气肿发展具有重要贡献，药理学抑制 p38 可能作为一种保护靶点，以减轻与空气污染相关的慢性肺部疾病恶化。由于这里描述的潜伏感染的先决条件，在评估纳米颗粒暴露的呼吸毒性时，单次打击模型的使用可能具有严重的局限性。
