title: Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our data provide molecular insight into PAMAM nanoparticle-induced lung injury and suggest potential therapeutic and screening strategies to address the safety of nanomaterials.
authors.affiliation: 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. biosuny@gmail.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 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. guofengsd@gmail.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: 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. zouzhenat9t@gmail.com.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zou
authors.affiliation: 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. lichenggang1981@gmail.com.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: 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. Hongxx2000@sina.com.|Institute of Medical Biology, Chinese Academy of Medical Sciences, No. 379, Jiaoling Road, Kunming, Yunnan, 650118, China. Hongxx2000@sina.com.|Chinese Pharmacopeia Commission, No. 11 Building Fahuananli Chongwen District, Beijing, 100060, China. Hongxx2000@sina.com.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Hong
authors.affiliation: 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. zhaoyanray@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: National Center for Nanoscience and Technology, Beijing, 100190, China. wangcx@nanoctr.cn.
authors.forename: Chenxuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: 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. whl2468@aliyun.com.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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. LiuH2@njhealth.org.
authors.forename: Haolin
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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. yangp459@126.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: 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. hanzongsheng.com@163.com.
authors.forename: Zongsheng
authors.initials: Z
authors.lastname: Han
authors.affiliation: 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. liukangtai_001@163.com.
authors.forename: Kangtai
authors.initials: K
authors.lastname: Liu
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse3, A-1030, Vienna, Austria. kuba.mtt@mri.tmd.ac.jp.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
authors.affiliation: 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. songbinbj@gmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.affiliation: Center for Translational Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, PR China. gaojm@pumch.cn.
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Rd, Guangzhou, Guangdong, 510120, China. moziyao@163.net.
authors.forename: Ziyao
authors.initials: Z
authors.lastname: Mo
authors.affiliation: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. dsli@sibs.ac.cn.
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.affiliation: National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Hongda Middle Street A8, Beijing Economic and Technological Development Area, Beijing, 100176, China. libo@nicpbp.org.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences, No. 379, Jiaoling Road, Kunming, Yunnan, 650118, China. liqihan@imbcams.com.cn.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Rd, Guangzhou, Guangdong, 510120, China. nanshan@vip.163.com.
authors.forename: Nanshan
authors.initials: N
authors.lastname: Zhong
authors.affiliation: National Center for Nanoscience and Technology, Beijing, 100190, China. wangch@nanoctr.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse3, A-1030, Vienna, Austria. josef.penninger@imba.oeaw.ac.at.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: 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. jiang@pumc.edu.cn.|Center for Translational Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, PR China. jiang@pumc.edu.cn.|State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610000, China. jiang@pumc.edu.cn.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Jiang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002412:Cations; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D015536:Down-Regulation; D007322:Instillation, Drug; D019808:Losartan / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016019:Survival Analysis
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002412:Cations; D050091:Dendrimers; C104700:PAMAM Starburst; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D019808:Losartan