柴油废气颗粒改变人支气管上皮细胞线粒体生物能和 cAMP 生成能力

IF 3.6 Q2 TOXICOLOGY Frontiers in toxicology Pub Date : 2024-07-25 DOI:10.3389/ftox.2024.1412864
I. Cattani-Cavalieri, Marina Trombetta-Lima, Hong Yan, Ana L. Manzano-Covarrubias, H. Baarsma, Asmaa Oun, Melissa Mol van der Veen, Emily Oosterhout, Amalia M. Dolga, R. Ostrom, S. Valença, Martina Schmidt
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引用次数: 0

摘要

导言:柴油燃烧造成的空气污染部分与柴油废气微粒(DEP)的产生有关。接触柴油机废气微粒会诱发各种过程,包括炎症和氧化应激,最终导致肺功能下降。环磷酸腺苷(cAMP)信号传导对肺的平衡至关重要。DEP对cAMP信号转导的影响尚不清楚:我们将人支气管上皮细胞(BEAS-2B)暴露于 DEP 24-72 小时,并评估了线粒体生物能、氧化应激和炎症指标以及 cAMP 信号转导的成分。线粒体生物能在 72 小时后进行测量,以捕捉长期暴露于 DEP 对线粒体功能的潜在和累积效应:结果:DEP 严重改变了线粒体的形态和网络完整性,降低了线粒体的基础呼吸和 ATP 链接呼吸以及糖酵解能力。暴露于DEP会增加氧化应激和炎症标志物(如白细胞介素-8和白细胞介素-6)的基因表达。DEP明显影响了由cAMP直接激活的交换蛋白-1和-2(Epac1和Epac2)的mRNA水平,似乎增加了Epac1蛋白,但磷酸-PKA水平未受影响。暴露于 DEP 会增加 A 激酶锚定蛋白 1、β2-肾上腺素受体和前列腺素 E 受体亚型 4 的 mRNA 水平。有趣的是,在福斯可林(AC 激活剂)、非诺特罗(β2-AR 激动剂)或 PGE2(EPR 激动剂)的刺激下,DEP 降低了腺苷酸环化酶 9 的 mRNA 水平,并降低了 cAMP 水平:我们的研究结果表明,DEP 会诱导线粒体功能障碍,这一过程伴随着氧化应激和炎症,并广泛抑制 cAMP 信号传导。这些上皮反应可能是空气污染暴露诱发肺功能障碍的原因之一。
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Diesel exhaust particles alter mitochondrial bioenergetics and cAMP producing capacity in human bronchial epithelial cells
Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown.Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24–72 h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72 h to capture the potential and accumulative effects of prolonged DEP exposure on mitochondrial function.Results: DEP profoundly altered mitochondrial morphology and network integrity, reduced both basal and ATP-linked respiration as well as the glycolytic capacity of mitochondria. DEP exposure increased gene expression of oxidative stress and inflammation markers such as interleukin-8 and interleukin-6. DEP significantly affected mRNA levels of exchange protein directly activated by cAMP-1 and -2 (Epac1, Epac2), appeared to increase Epac1 protein, but left phospho-PKA levels unhanged. DEP exposure increased A-kinase anchoring protein 1, β2‐adrenoceptor and prostanoid E receptor subtype 4 mRNA levels. Interestingly, DEP decreased mRNA levels of adenylyl cyclase 9 and reduced cAMP levels stimulated by forskolin (AC activator), fenoterol (β2-AR agonist) or PGE2 (EPR agonist).Discussion: Our findings suggest that DEP induces mitochondrial dysfunction, a process accompanied by oxidative stress and inflammation, and broadly dampens cAMP signaling. These epithelial responses may contribute to lung dysfunction induced by air pollution exposure.
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CiteScore
3.80
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审稿时长
13 weeks
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