Scieszka David, Jin Yan, Noor Shahani, Barr Ed, Garcia Marcus, Begay Jessica, Herbert Guy, Hunter Russell P, Bhaskar Kiran, Kumar Rahul, Gullapalli Rama, Bolt Alicia, McCormick Mark A, Bleske Barry, Gu Haiwei, Campen Matthew
University of New Mexico, College of Pharmacy.
Florida International University, Center for Translational Sciences.
Res Sq. 2023 Jun 5:rs.3.rs-3002040. doi: 10.21203/rs.3.rs-3002040/v1.
Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the neuroinflammatory and metabolomic temporal dynamics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6J mice were exposed to wood smoke every other day for two weeks at an average exposure concentration of 0.5mg/m . Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-days post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of PECAM (CD31), high and medium expressors, with wood smoke inhalation causing an increased proportion of PECAM . These populations of PECAM and PECAM were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b /CD45 ) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules like glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD abundance at day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated wtith wildfire smoke exposure.
在临床前模型中，野火烟雾已被证明会引发神经炎症，其特征是中性粒细胞和单核细胞的神经浸润，以及神经血管内皮表型的改变。为了研究这些结果的持续时间，本研究检测了生物质烟雾吸入暴露后神经炎症和代谢组学的时间动态变化。2个月大的雌性C57BL/6J小鼠每隔一天暴露于木烟中，持续两周，平均暴露浓度为0.5mg/m 。在暴露后的第1、3、7、14和28天进行后续的系列安乐死。右半球的流式细胞术显示了两种PECAM（CD31）内皮细胞群体，即高表达和中等表达群体，吸入木烟导致PECAM 的比例增加。这些PECAM 和PECAM 群体分别与抗炎和促炎反应相关，并且它们的炎症特征在第28天基本消退。然而，在第28天，木烟暴露小鼠中活化的小胶质细胞群体（CD11b /CD45 ）仍高于对照组。到第28天，浸润的中性粒细胞群体减少到低于对照组的水平。然而，外周免疫浸润细胞的MHC-II表达仍然很高，中性粒细胞群体中CD45、Ly6C和MHC-II的表达持续增加。通过采用无偏倚方法检测代谢组学变化，我们观察到海马体中神经递质和信号分子如谷氨酸、喹啉酸和5-α-二氢孕酮出现显著紊乱。利用一个旨在探索与衰老相关的NAD 代谢途径的靶向检测板，木烟暴露在28天的时间进程中引发了波动和代偿，最终在第28天导致海马体中NAD 丰度降低。总之，这些结果表明存在一个高度动态的神经炎症环境，其潜在的消退时间超过28天，这可能意味着长期行为改变、与野火烟雾暴露直接相关的全身和神经后遗症。
