title: Nanoparticles-induced apoptosis of human airway epithelium is mediated by proNGF/p75NTRsignaling.
abstract: Environmental and occupational exposures to respirable ultrafine fractions of particulate matter (PM) have been implicated in the initiation and exacerbation of lung diseases. However, the precise mechanisms underlying production of cell damage and death attributed to nanoparticles (NP) on human airway epithelium are not fully understood. This study examined the role of neurotrophic pathways in NP-induced airway toxicity. Size and agglomeration of TiO2nanoparticles (TiO2-NP) and fine (TiO2-FP) particles were measured by dynamic light scattering. Expression and signaling of key neurotrophic factors and receptors were assessed by real-time polymerase chain reaction, flow cytometry, immunostaining, and Western blot in various respiratory epithelial cells after exposure to TiO2-NP or TiO2-FP. Particle-induced cell death was measured by flow cytometry after annexin V/propidium iodide staining. The role of neurotrophin-dependent apoptotic pathways was analyzed with specific blocking antibodies or siRNAs. Exposure of human epithelial cells to TiO2-NP enhanced interleukin (IL)-1α synthesis, as well as nerve growth factor (NGF) gene expression and protein levels, specifically the precursor form (proNGF). TiO2-NP exposure also increased expression of p75NRFreceptor genes. These neurotropic factor and receptor responses were stimulated by IL-1α and abolished by its specific receptor antagonist (IL-1-ra). TiO2-NP also increased JNK phosphorylation and apoptosis, which was prevented by anti-p75NRFor NGFsiRNA. Data demonstrated that TiO2-NP exerted adverse effects in the respiratory tract by inducing unbalanced overexpression of immature neurotrophins, which led to apoptotic death of epithelial cells signaled through the death receptor p75NTR. This may result in airway inflammation and hyperreactivity after exposure to TiO2-NP.
authors.affiliation: a Department of Pediatrics , West Virginia University School of Medicine , Morgantown , West Virginia , USA.
authors.forename: Sreeparna
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: b Department of Pharmaceutical Science , West Virginia University School of Pharmacy , Morgantown , West Virginia , USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
authors.affiliation: c Pediatric Institute and Children's Hospital, Cleveland Clinic Foundation , Cleveland , Ohio , USA.
authors.forename: Miriam K
authors.initials: MK
authors.lastname: Perez
authors.affiliation: c Pediatric Institute and Children's Hospital, Cleveland Clinic Foundation , Cleveland , Ohio , USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piedimonte
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity*; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects; D014025:Titanium / Q000633:toxicity*
chemical_list: D009414:Nerve Growth Factors; D052638:Particulate Matter; D017475:Receptors, Nerve Growth Factor; C009495:titanium dioxide; D014025:Titanium