Multi-walled carbon nanotubes exacerbate doxorubicin-induced cardiotoxicity by altering gut microbiota and pulmonary and colonic macrophage phenotype in mice
Multi-walled carbon nanotubes exacerbate doxorubicin-induced cardiotoxicity by altering gut microbiota and pulmonary and colonic macrophage phenotype in mice
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多壁碳纳米管通过改变小鼠肠道微生物群以及肺和结肠巨噬细胞表型加剧阿霉素诱导的心脏毒性
DOI：
10.1016/j.tox.2020.152410
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发表时间：
2020-04-15
期刊：
影响因子：
4.5
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Liu, Xiaoxiao;Liu, Yanzhuo;Yang, Jing
流行病学研究表明，空气污染物和颗粒物的水平与心血管疾病的发病率和死亡率呈正相关。在这里，我们证明了多壁碳纳米管（MWCNTs），一种标准的细颗粒，通过改变肠道微生物群和肺和结肠巨噬细胞表型，加剧阿霉素（DOX）诱导的小鼠心脏毒性。多壁碳纳米管（25 μ g/kg/天，每周5天，持续3周）促进DOX（2 mg/kg，每周两次，持续5周）治疗的C57 BL/6小鼠的心脏毒性和细胞凋亡。多壁碳纳米管夸大了DOX诱导的肠道微生物群生态失调，其特征在于Helicobacteraceae和Coriobacteraceae的丰度增加。此外，多壁碳纳米管促进DOX诱导的结肠巨噬细胞M1样极化，外周血中TNF-α、IL-1 β和CC趋化因子配体2增加。重要的是，用抗生素治疗减弱了多壁碳纳米管加阿霉素诱导的心肌细胞凋亡和结肠巨噬细胞的M1样极化。粪便微生物群移植表明，多壁碳纳米管加剧了阿霉素诱导的心脏毒性与M1样极化的结肠巨噬细胞。来自MWCNT处理的肺巨噬细胞的条件培养基促进了DOX诱导的肠道微生物群生态失调和结肠巨噬细胞极化。此外，巨噬细胞和粪便细菌的共培养促进了M1样巨噬细胞极化及其TNF-α和IL-1 β的产生，从而加剧了MWCNT的作用。此外，IL-1 β和TNF-α阻断，无论是单独或联合减弱MWCNT加重心脏毒性。总之，MWCNT通过肠道微生物群和肺及结肠巨噬细胞相互作用加剧小鼠中DOX诱导的心脏毒性。我们的研究结果确定了吸入颗粒驱动心脏毒性的一种新的作用机制。
Epidemiologic studies show that the levels of air pollutants and particulate matter are positively associated with the morbidity and mortality of cardiovascular diseases. Here we demonstrate that the intratracheal instillation of multi-walled carbon nanotubes (MWCNTs), a standard fine particle, exacerbate doxorubicin (DOX)-induced cardiotoxicity in mice through altering gut microbiota and pulmonary and colonic macrophage phenotype. MWCNTs (25 mu g/kg per day, 5 days a week for 3 weeks) promoted cardiotoxicity and apoptosis in the DOX (2 mg/kg, twice a week for 5 weeks)-treated C57BL/6 mice. MWCNTs exaggerated DOX-induced gut microbiota dysbiosis characterized by the increased abundances of Helicobacteraceae and Coriobacteriaceae. In addition, MWCNTs promoted DOX-induced M1-like polarization of colonic macrophages with an increase in TNF-alpha, IL-1 beta and CC chemokine ligand 2 in peripheral blood. Importantly, treatment with the antibiotics attenuated MWCNTs plus DOX-induced apoptosis of cardiomyocytes and M1-like polarization of colonic macrophages. The fecal microbiota transplantation demonstrated that MWCNTs exaggerated DOX-induced cardiotoxicity with M1-like polarization of colonic macrophages. The conditioned medium from MWCNTs-treated pulmonary macrophages promoted DOX-induced gut microbiota dysbiosis and colonic macrophage polarization. Furthermore, the co-culture of macrophages and fecal bacteria promoted M1-like macrophage polarization and their production of TNF-alpha and IL-1 beta, and thereby exacerbated the effects of MWCNTs. Moreover, IL-1 beta and TNF-alpha blockade, either alone or in combination attenuated MWCNTs-exacerbated cardiotoxicity. In summary, MWCNTs exacerbate DOX-induced cardiotoxicity in mice through gut microbiota and pulmonary and colonic macrophage interaction. Our findings identify a novel mechanism of action of inhaled particle-driven cardiotoxicity.