Sun Yang, Guo Feng, Zou Zhen, Li Chenggang, Hong Xiaoxu, Zhao Yan, Wang Chenxuan, Wang Hongliang, Liu Haolin, Yang Peng, Han Zongsheng, Liu Kangtai, Kuba Keiji, Song Bin, Gao Jinming, Mo Ziyao, Li Dangsheng, Li Bo, Li Qihan, Zhong Nanshan, Wang Chen, Penninger Josef M, Jiang Chengyu
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, 100005, China.
Institute of Medical Biology, Chinese Academy of Medical Sciences, No. 379, Jiaoling Road, Kunming, Yunnan, 650118, China.
Part Fibre Toxicol. 2015 Mar 7;12:4. doi: 10.1186/s12989-015-0080-x.
Nanoparticles have become a key technology in multiple industries. However, there are growing reports of the toxicity of nanomaterials to humans. In particular, nanomaterials have been linked to lung diseases. The molecular mechanisms of nanoparticle toxicity are largely unexplored.
Acute lung injury was induced in wild-type mice and angiotensin-coverting enzyme 2 (ACE2) knockout mice by the intratracheal instillation of cationic polyamidoamine dendrimer (PAMAM) nanoparticles. For rescue experiments, losartan (15 mg/kg in PBS) was injected intraperitoneally 30 min before nanoparticle administration.
Some PAMAM nanoparticles, but not anionic PAMAM nanoparticles or carbon nanotubes, triggered acute lung failure in mice. Mechanistically, cationic nanoparticles can directly bind ACE2, decrease its activity and down-regulate its expression level in lung tissue, resulting in deregulation of the renin-angiotensin system. Gene inactivation of Ace2 can exacerbate lung injury. Importantly, the administration of losartan, which is an angiotensin II type I receptor antagonist, can ameliorate PAMAM nanoparticle-induced lung injury.
Our data provide molecular insight into PAMAM nanoparticle-induced lung injury and suggest potential therapeutic and screening strategies to address the safety of nanomaterials.
纳米颗粒已成为多个行业的关键技术。然而，关于纳米材料对人类毒性的报道越来越多。特别是，纳米材料与肺部疾病有关。纳米颗粒毒性的分子机制在很大程度上尚未得到探索。
通过气管内滴注阳离子聚酰胺胺树枝状大分子（PAMAM）纳米颗粒，在野生型小鼠和血管紧张素转换酶2（ACE2）基因敲除小鼠中诱导急性肺损伤。在救援实验中，在纳米颗粒给药前30分钟腹腔注射氯沙坦（在PBS中为15mg/kg）。
一些PAMAM纳米颗粒，而非阴离子PAMAM纳米颗粒或碳纳米管，引发了小鼠的急性肺衰竭。从机制上讲，阳离子纳米颗粒可直接结合ACE2，降低其活性并下调其在肺组织中的表达水平，导致肾素-血管紧张素系统失调。Ace2基因失活会加重肺损伤。重要的是，作为血管紧张素II 1型受体拮抗剂的氯沙坦给药可改善PAMAM纳米颗粒诱导的肺损伤。
我们的数据为PAMAM纳米颗粒诱导的肺损伤提供了分子层面的见解，并提出了应对纳米材料安全性的潜在治疗和筛选策略。
