title: PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway.
abstract: Nanotechnology is an important and emerging industry with a projected annual market of around one trillion US dollars by 2011-2015. Concerns about the toxicity of nanomaterials in humans, however, have recently been raised. Although studies of nanoparticle toxicity have focused on lung disease the molecular link between nanoparticle exposure and lung injury remained unclear. In this report, we show that cationic Starburst polyamidoamine dendrimer (PAMAM), a class of nanomaterials that are being widely developed for clinical applications can induce acute lung injury in vivo. PAMAM triggers autophagic cell death by deregulating the Akt-TSC2-mTOR signaling pathway. The autophagy inhibitor 3-methyladenine rescued PAMAM dendrimer-induced cell death and ameliorated acute lung injury caused by PAMAM in mice. Our data provide a molecular explanation for nanoparticle-induced lung injury, and suggest potential remedies to address the growing concerns of nanotechnology safety.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.forename: Haolin
authors.initials: H
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Hongliang
authors.initials: H
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Shuan
authors.initials: S
authors.lastname: Rao
authors.forename: Jiejie
authors.initials: J
authors.lastname: Deng
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yufa
authors.initials: Y
authors.lastname: Miao
authors.forename: Chenying
authors.initials: C
authors.lastname: Guo
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.forename: Xiping
authors.initials: X
authors.lastname: Chen
authors.forename: Limin
authors.initials: L
authors.lastname: Li
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Chengyu
authors.initials: C
authors.lastname: Jiang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D050091:Dendrimers; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles / Q000633:toxicity* / Q000648:ultrastructure; D011073:Polyamines / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D050091:Dendrimers; D047908:Intracellular Signaling Peptides and Proteins; C104700:PAMAM Starburst; D011073:Polyamines; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases