Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s).
Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s).
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DOI：
10.1186/s12989-018-0257-1
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发表时间：
2018-05-11
影响因子：
10
通讯作者：
Holme JA
中科院分区：
文献类型：
--
作者：
Brinchmann BC;Skuland T;Rambøl MH;Szoke K;Brinchmann JE;Gutleb AC;Moschini E;Kubátová A;Kukowski K;Le Ferrec E;Lagadic-Gossmann D;Schwarze PE;Låg M;Refsnes M;Øvrevik J;Holme JA
暴露于交通来源的颗粒物（PM），例如柴油机排气颗粒（DEP），是心血管疾病（CVD）的主要环境原因，并且可能导致内皮功能障碍和动脉粥样硬化的发展。DEP和其他吸入性PM如何导致CVD仍有争议。然而，有机化学品（OC）粘附在颗粒表面，被认为是许多生物效应的核心。在本研究中，我们探讨了DEP中OC到达内皮并触发促炎反应的能力，这是动脉粥样硬化途径的核心步骤。暴露相关浓度的DEP（0.12 μg/cm 2）应用于肺泡3D三培养物的上皮侧，快速诱导基底外侧内皮细胞中的促炎和芳烃受体（AhR）调节基因。这些影响似乎是由于可溶性亲脂成分，而不是颗粒易位。接下来，将DEP（DEP-EOM）的可浸提有机材料以增加的极性分级分离，进行化学表征，并检查对来自4名健康供体的人微血管内皮（HMEC-1）细胞和原代人内皮细胞（PHEC）中促炎基因和AhR调节基因的直接影响。暴露相关浓度的亲脂性DEP-EOM（0.15 μg/cm 2）诱导IL-1α、IL-1β、COX 2和MMP-1基因表达轻度至中度增加，MMP-1分泌增加。相比之下，极性更强的EOM即使在更高的浓度下也具有可忽略的影响。药理学抑制剂的使用表明，AhR和蛋白酶激活受体-2（PAR-2）是调节EOM诱导的基因表达的中心。一些影响似乎也归因于氧化还原反应，至少在测试的最高接触浓度下是如此。虽然最亲脂性的EOM，含有大多数的多环芳烃和增塑剂，具有最明显的低浓度效应，但化学成分和生物效应之间没有直接的联系。亲脂性和半亲脂性化学物质似乎与DEP分离，通过肺泡上皮细胞移位，并在内皮细胞中触发促炎反应。这些作用似乎是由AhR激动剂触发的，并且涉及PAR-2信号传导。本文的在线版本（10.1186/s12989-018-0257-1）包含补充材料，可供授权用户使用。
Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis. Exposure-relevant concentrations of DEP (0.12 μg/cm2) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next fractionated with increasing polarity, chemically characterized, and examined for direct effects on pro-inflammatory and AhR-regulated genes in human microvascular endothelial (HMEC-1) cells and primary human endothelial cells (PHEC) from four healthy donors. Exposure-relevant concentrations of lipophilic DEP-EOM (0.15 μg/cm2) induced low to moderate increases in IL-1α, IL-1β, COX2 and MMP-1 gene expression, and the MMP-1 secretion was increased. By contrast, the more polar EOM had negligible effects, even at higher concentrations. Use of pharmacological inhibitors indicated that AhR and protease-activated receptor-2 (PAR-2) were central in regulation of EOM-induced gene expression. Some effects also seemed to be attributed to redox-responses, at least at the highest exposure concentrations tested. Although the most lipophilic EOM, that contained the majority of PAHs and aliphatics, had the clearest low-concentration effects, there was no straight-forward link between chemical composition and biological effects. Lipophilic and semi-lipophilic chemicals seemed to detach from DEP, translocate through alveolar epithelial cells and trigger pro-inflammatory reactions in endothelial cells at exposure-relevant concentrations. These effects appeared to be triggered by AhR agonists, and involve PAR-2 signaling. The online version of this article (10.1186/s12989-018-0257-1) contains supplementary material, which is available to authorized users.
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影响因子：
10
作者：
Klein SG;Serchi T;Hoffmann L;Blömeke B;Gutleb AC
通讯作者：
Gutleb AC
影响因子：
10
作者：
Klein SG;Cambier S;Hennen J;Legay S;Serchi T;Nelissen I;Chary A;Moschini E;Krein A;Blömeke B;Gutleb AC
通讯作者：
Gutleb AC
影响因子：
9.8
作者：
Bouis, Diane;Hospers, Geke A. P.;Mulder, Nanno H.
通讯作者：
Mulder, Nanno H.
影响因子：
2.1
作者：
Cassee FR;Héroux ME;Gerlofs-Nijland ME;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