Department of Pharmacology and Hubei Province Key Laboratory of Allergy and Immune-related Diseases, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan 430071, China.
Toxicology. 2020 Apr 15;435:152410. doi: 10.1016/j.tox.2020.152410. Epub 2020 Feb 14.
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 μg/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-α, IL-1β 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-α and IL-1β, and thereby exacerbated the effects of MWCNTs. Moreover, IL-1β and TNF-α 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.
流行病学研究表明，空气污染物和颗粒物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，作为一种标准的细颗粒物，多壁碳纳米管（MWCNTs）经气管内滴注会通过改变肠道微生物群以及肺部和结肠巨噬细胞表型来加重多柔比星（DOX）诱导的小鼠心脏毒性。MWCNTs（每天 25μg/kg，每周 5 天，持续 3 周）促进了 DOX（每周两次，每次 2mg/kg，持续 5 周）处理的 C57BL/6 小鼠的心脏毒性和细胞凋亡。MWCNTs 加剧了 DOX 诱导的肠道微生物群失调，其特征是 Helicobacteraceae 和 Coriobacteriaceae 的丰度增加。此外，MWCNTs 促进了 DOX 诱导的结肠巨噬细胞 M1 样极化，导致外周血中 TNF-α、IL-1β 和 CC 趋化因子配体 2 的增加。重要的是，抗生素治疗减轻了 MWCNTs 加 DOX 诱导的心肌细胞凋亡和结肠巨噬细胞 M1 样极化。粪便微生物群移植表明，MWCNTs 通过结肠巨噬细胞的 M1 样极化加剧了 DOX 诱导的心脏毒性。经 MWCNTs 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-1β 的产生，从而加剧了 MWCNTs 的作用。此外，单独或联合使用 IL-1β 和 TNF-α 阻断剂可减轻 MWCNTs 加重的心脏毒性。总之，MWCNTs 通过肠道微生物群和肺部及结肠巨噬细胞的相互作用加剧了 DOX 诱导的小鼠心脏毒性。我们的研究结果确定了吸入颗粒驱动的心脏毒性的一种新作用机制。
