Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response.
Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response.
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人体暴露于柴油废气诱导CYP1A1表达和AhR激活，没有协调的抗氧化反应。
DOI：
10.1186/s12989-023-00559-1
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发表时间：
2023-12-08
影响因子：
10
通讯作者：
中科院分区：
文献类型：
--
作者：
柴油机废气（DE）在实验暴露的人体中诱导嗜中性粒细胞和淋巴细胞增多。这些反应与NF-κB和c-Jun的核迁移、有丝分裂原活化蛋白激酶的活化和炎症介质的产生增加平行发生。DE对内源性抗氧化剂和外源性防御的影响仍然不确定，分别由核因子红细胞2相关因子2（Nrf 2）和芳香烃受体（AhR）介导，以及细胞抗氧化适应保护免受DE不良影响的程度。在一项随机双盲研究中，我们使用免疫组织化学研究了暴露于DE（PM10，300 µg/m3）与过滤后空气6小时后健康受试者支气管内粘膜活检上皮中Nrf 2和AhR的核定位，作为激活的标志物。检查了细胞色素P450家族1、亚家族A多肽1（CYP 1A 1）和亚家族B多肽1（CYP 1B 1）的细胞质表达，以确认AhR活化;还定量了醛酮还原酶（AKR 1A 1、AKR 1C 1和AKR 1C 3）、环氧化物水解酶和NAD（P）H脱氢酶醌1（NQO 1）的表达。检查炎症和氧化应激标志物，以了解观察到的反应。DE暴露导致中性粒细胞流入支气管气道表面（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的CYP 1A 1表达（分别为p = 0.001和p = 0.028）。粘膜下白细胞AhR核转位也增加（p < 0.001）。DE后上皮细胞核AhR表达与支气管粘膜下CD 3数量呈负相关（r =-0.706，p = 0.002）。相比之下，DE没有增加Nrf 2的核转位，并且与支气管上皮细胞中NQO 1的降低相关（p = 0.02），而不影响CYP 1B 1、醛酮还原酶或环氧化物水解酶蛋白的表达。这些体内人体数据证实了早期基于细胞和动物的观察结果，即柴油机尾气诱导AhR和CYP 1A 1。I期异生物质反应的诱导发生在没有诱导的抗氧化剂或II期异生物质防御在调查的时间点6小时后曝光。这表明DE相关化合物，如多环芳烃（PAH），可能会诱导急性炎症，并改变解毒酶，而不会伴随人类气道中的保护性细胞适应。在线版本包含补充材料，可通过10.1186/s12989-023-00559-1获得。
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. The online version contains supplementary material available at 10.1186/s12989-023-00559-1.
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影响因子：
10
作者：
Barath S;Mills NL;Lundbäck M;Törnqvist H;Lucking AJ;Langrish JP;Söderberg S;Boman C;Westerholm R;Löndahl J;Donaldson K;Mudway IS;Sandström T;Newby DE;Blomberg A
通讯作者：
Blomberg A
影响因子：
4.9
作者：
Kelly, FJ
通讯作者：
Kelly, FJ
DOI：
10.1165/ajrcmb.25.4.4515
发表时间：
2001-10-01
影响因子：
6.4
作者：
Bonvallot, V;Baeza-Squiban, A;Marano, F
通讯作者：
Marano, F
影响因子：
168.9
作者：
Kelly, FK;Mudway, J;Sandström, T
通讯作者：
Sandström, T
影响因子：
3.5
作者：
Kumar, Abhinav;Dailey, Lea Ann;Forbes, Ben
通讯作者：
Forbes, Ben