Diesel exhaust (DE) induces neutrophilia and lymphocytosis in experimentally exposed humans. These responses occur in parallel to nuclear migration of NF-κB and c-Jun, activation of mitogen activated protein kinases and increased production of inflammatory mediators. There remains uncertainty regarding the impact of DE on endogenous antioxidant and xenobiotic defences, mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) respectively, and the extent to which cellular antioxidant adaptations protect against the adverse effects of DE. Using immunohistochemistry we investigated the nuclear localization of Nrf2 and AhR in the epithelium of endobronchial mucosal biopsies from healthy subjects six-hours post exposure to DE (PM10, 300 µg/m3) versus post-filtered air in a randomized double blind study, as a marker of activation. Cytoplasmic expression of cytochrome P450s, family 1, subfamily A, polypeptide 1 (CYP1A1) and subfamily B, Polypeptide 1 (CYP1B1) were examined to confirm AhR activation; with the expression of aldo–keto reductases (AKR1A1, AKR1C1 and AKR1C3), epoxide hydrolase and NAD(P)H dehydrogenase quinone 1 (NQO1) also quantified. Inflammatory and oxidative stress markers were examined to contextualize the responses observed. DE exposure caused an influx of neutrophils to the bronchial airway surface (p = 0.013), as well as increased bronchial submucosal neutrophil (p < 0.001), lymphocyte (p = 0.007) and mast cell (p = 0.002) numbers. In addition, DE exposure enhanced the nuclear translocation of the AhR and increased the CYP1A1 expression in the bronchial epithelium (p = 0.001 and p = 0.028, respectively). Nuclear translocation of AhR was also increased in the submucosal leukocytes (p < 0.001). Epithelial nuclear AhR expression was negatively associated with bronchial submucosal CD3 numbers post DE (r = −0.706, p = 0.002). In contrast, DE did not increase nuclear translocation of Nrf2 and was associated with decreased NQO1 in bronchial epithelial cells (p = 0.02), without affecting CYP1B1, aldo–keto reductases, or epoxide hydrolase protein expression. These in vivo human data confirm earlier cell and animal-based observations of the induction of the AhR and CYP1A1 by diesel exhaust. The induction of phase I xenobiotic response occurred in the absence of the induction of antioxidant or phase II xenobiotic defences at the investigated time point 6 h post-exposures. This suggests DE-associated compounds, such as polycyclic aromatic hydrocarbons (PAHs), may induce acute inflammation and alter detoxification enzymes without concomitant protective cellular adaptations in human airways.

中文翻译：

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人体接触柴油机尾气会诱导 CYP1A1 表达和 AhR 激活，但没有协调的抗氧化反应

柴油机尾气 (DE) 会在实验暴露的人体中引起中性粒细胞增多和淋巴细胞增多。这些反应与 NF-κB 和 c-Jun 的核迁移、丝裂原活化蛋白激酶的激活以及炎症介质的产生增加同时发生。DE 对分别由核因子红细胞 2 相关因子 2 (Nrf2) 和芳烃受体 (AhR) 介导的内源性抗氧化剂和外源性防御的影响，以及细胞抗氧化剂适应在多大程度上防止不利影响仍存在不确定性。 DE 的影响。在一项随机双盲研究中，我们使用免疫组织化学研究了健康受试者暴露于 DE（PM10，300 µg/m3）后 6 小时与过滤后空气中的支气管内粘膜活检上皮细胞中 Nrf2 和 AhR 的核定位，作为激活标记。检查细胞色素 P450、家族 1、亚家族 A、多肽 1 (CYP1A1) 和亚家族 B、多肽 1 (CYP1B1) 的细胞质表达，以确认 AhR 激活；醛酮还原酶（AKR1A1、AKR1C1 和 AKR1C3）、环氧化物水解酶和 NAD(P)H 脱氢酶醌 1 (NQO1) 的表达也进行了定量。检查炎症和氧化应激标记物以了解观察到的反应。DE 暴露导致中性粒细胞涌入支气管气道表面 (p = 0.013)，以及支气管粘膜下中性粒细胞 (p < 0.001)、淋巴细胞 (p = 0.007) 和肥大细胞 (p = 0.002) 数量增加。此外，DE 暴露增强了 AhR 的核转位并增加了支气管上皮中 CYP1A1 的表达（分别为 p = 0.001 和 p = 0.028）。AhR 的核转位在粘膜下白细胞中也增加 (p < 0.001)。DE 后上皮细胞核 AhR 表达与支气管粘膜下 CD3 数量呈负相关（r = -0.706，p = 0.002）。相比之下，DE 不会增加 Nrf2 的核转位，并与支气管上皮细胞中 NQO1 的减少相关 (p = 0.02)，而不影响 CYP1B1、醛酮还原酶或环氧化物水解酶蛋白的表达。这些人体体内数据证实了早期基于细胞和动物的柴油废气诱导 AhR 和 CYP1A1 的观察结果。在暴露后 6 小时的研究时间点，在没有诱导抗氧化剂或 II 期外源防御的情况下，发生了 I 期外源反应的诱导。这表明与 DE 相关的化合物，如多环芳烃 (PAH)，可能会诱发急性炎症并改变解毒酶，而不会伴随人体呼吸道中的保护性细胞适应。