While exposure to ambient air contaminants is clearly associated with adverse health outcomes, disentangling mechanisms of pollutant interactions remains a challenge. We aimed at characterizing free radical pathways and the endothelinergic system in rats after inhalation of urban particulate matter, ozone, and a combination of particles plus ozone to gain insight into pollutant-specific toxicity mechanisms and any effect modification due to air pollutant mixtures. Fischer 344 rats were exposed for 4 h to a 3 × 3 concentration matrix of ozone (0, 0.4, 0.8 ppm) and EHC-93 particles (0, 5, 50 mg/m3). Bronchoalveolar lavage fluid (BALF), BAL cells, blood and plasma were analysed for biomarkers of effects immediately and 24 h post-exposure. Inhalation of ozone increased (p < 0.05) lipid oxidation products in BAL cells immediately post-exposure, and increased (p < 0.05) total protein, neutrophils and mature macrophages in the BALF 24 h post-exposure. Ozone increased (p < 0.05) the formation of reactive oxygen species (ROS), assessed by m-, p-, o-tyrosines in BALF (Ozone main effects, p < 0.05), while formation of reactive nitrogen species (RNS), indicated by 3-nitrotyrosine, correlated with dose of urban particles (EHC-93 main effects or EHC-93 × Ozone interactions, p < 0.05). Carboxyhemoglobin levels in blood exhibited particle exposure-related increase (p < 0.05) 24 h post recovery. Plasma 3-nitrotyrosine and o-tyrosine were increased (p < 0.05) after inhalation of particles; the effect on 3-nitrotyrosine was abrogated after exposure to ozone plus particles (EHC-93 × Ozone, p < 0.05). Big endothelin-1 (BET-1) and ET-1 were increased in plasma after inhalation of particles or ozone alone, but the effects appeared to be attenuated by co-exposure to contaminants (EHC-93 × Ozone, p < 0.05). Plasma ET levels were positively correlated (p < 0.05) with BALF m- and o-tyrosine levels. Pollutant-specific changes can be amplified or abrogated following multi-pollutant exposures. Oxidative and nitrative stress in the lung compartment may contribute to secondary extra-pulmonary ROS/RNS formation. Nitrative stress and endothelinergic imbalance emerge as potential key pathways of air pollutant health effects, notably of ambient particulate matter.

中文翻译：

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吸入颗粒物和臭氧后的硝化应激，氧化应激和血浆内皮素水平。

虽然暴露于环境空气污染物中显然与不良健康后果相关，但消除污染物相互作用的机制仍然是一个挑战。我们旨在表征大鼠吸入城市颗粒物，臭氧以及颗粒与臭氧的混合物后的自由基途径和内皮素能系统，以深入了解特定污染物的毒性机理以及由于空气污染物混合物引起的任何效应改变。将Fischer 344大鼠暴露于3×3浓度的臭氧（0、0.4、0.8 ppm）和EHC-93颗粒（0、5、50 mg / m3）的基质中4 h。立即和暴露后24小时分析支气管肺泡灌洗液（BALF），BAL细胞，血液和血浆的生物标志物。暴露后立即在BAL细胞中吸入臭氧增加（p <0.05）脂质氧化产物，暴露后24小时内BALF中的总蛋白，中性粒细胞和成熟巨噬细胞的含量增加（p <0.05）。通过BALF中的m-，p-，o-酪氨酸评估，臭氧增加了（p <0.05）活性氧物种（ROS）的形成（臭氧主要作用，p <0.05），而活性氮物种（RNS）的形成，由3-硝基酪氨酸指示，与城市颗粒剂量相关（EHC-93主要作用或EHC-93×臭氧相互作用，p <0.05）。恢复后24小时，血液中的血红蛋白水平显示与颗粒暴露有关的增加（p <0.05）。吸入颗粒后血浆3-硝基酪氨酸和邻酪氨酸增加（p <0.05）；暴露于臭氧加颗粒（EHC-93×臭氧，p <0.05）后，对3-硝基酪氨酸的影响被消除。单独吸入颗粒或臭氧后，血浆中的大内皮素1（BET-1）和ET-1升高，但与污染物的共同暴露似乎减弱了这种效应（EHC-93×臭氧，p <0.05）。血浆ET水平与BALF间酪氨酸和邻酪氨酸水平呈正相关（p <0.05）。暴露于多种污染物后，特定于污染物的变化可以被放大或消除。肺区室中的氧化和硝化应激可能有助于继发性肺外ROS / RNS的形成。硝化应激和内皮素能失衡成为空气污染物健康影响的潜在关键途径，尤其是周围颗粒物的健康影响。05）具有BALF的m-和o-酪氨酸水平。暴露于多种污染物后，特定于污染物的变化可以被放大或消除。肺区室中的氧化和硝化应激可能有助于继发性肺外ROS / RNS的形成。硝化应激和内皮素能失衡成为空气污染物健康影响的潜在关键途径，尤其是周围颗粒物的健康影响。05）具有BALF的m-和o-酪氨酸水平。暴露于多种污染物后，特定于污染物的变化可以被放大或消除。肺区室中的氧化和硝化应激可能有助于继发性肺外ROS / RNS的形成。硝化应激和内皮素能失衡成为空气污染物健康影响的潜在关键途径，尤其是周围颗粒物的健康影响。