title: Role of signal transducer and activator of transcription 1 in murine allergen-induced airway remodeling and exacerbation by carbon nanotubes.
abstract: Asthma is characterized by a T helper type 2 phenotype and by chronic allergen-induced airway inflammation (AAI). Environmental exposure to air pollution ultrafine particles (i.e., nanoparticles) exacerbates AAI, and a concern is possible exacerbation posed by engineered nanoparticles generated by emerging nanotechnologies. Signal transducer and activator of transcription (STAT) 1 is a transcription factor that maintains T helper type 1 cell development. However, the role of STAT1 in regulating AAI or exacerbation by nanoparticles has not been explored. In this study, mice with whole-body knockout of the Stat1 gene (Stat1(-/-)) or wild-type (WT) mice were sensitized to ovalbumin (OVA) allergen and then exposed to multiwalled carbon nanotubes (MWCNTs) by oropharygneal aspiration. In Stat1(-/-) and WT mice, OVA increased eosinophils in bronchoalveolar lavage fluid, whereas MWCNTs increased neutrophils. Interestingly, OVA sensitization prevented MWCNT-induced neutrophilia and caused only eosinophilic inflammation. Stat1(-/-) mice displayed increased IL-13 in bronchoalveolar lavage fluid at 1 day compared with WT mice after treatment with OVA or OVA and MWCNTs. At 21 days, the lungs of OVA-sensitized Stat1(-/-) mice displayed increased eosinophilia, goblet cell hyperplasia, airway fibrosis, and subepithelial apoptosis. MWCNTs further increased OVA-induced goblet cell hyperplasia, airway fibrosis, and apoptosis in Stat1(-/-) mice at 21 days. These changes corresponded to increased levels of profibrogenic mediators (transforming growth factor-β1, TNF-α, osteopontin) but decreased IL-10 in Stat1(-/-) mice. Finally, fibroblasts isolated from the lungs of Stat1(-/-) mice produced significantly more collagen mRNA and protein in response to transforming growth factor-β1 compared with WT lung fibroblasts. Our results support a protective role for STAT1 in chronic AAI and exacerbation of remodeling caused by MWCNTs.
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: Elizabeth A
authors: EA
authors: Thompson
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: Brian C
authors: BC
authors: Sayers
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: Ellen E
authors: EE
authors: Glista-Baker
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: Kelly A
authors: KA
authors: Shipkowski
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: Mark D
authors: MD
authors: Ihrie
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: Katherine S
authors: KS
authors: Duke
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: Alexia J
authors: AJ
authors: Taylor
authors: Environmental and Molecular Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors: James C
authors: JC
authors: Bonner
mesh_terms: D000485:Allergens / Q000494:pharmacology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043942:Nanotubes / Q000009:adverse effects*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053495:Osteopontin / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000485:Allergens; C556062:IL10 protein, mouse; D018793:Interleukin-13; D050794:STAT1 Transcription Factor; C506896:Spp1 protein, mouse; C494080:Stat1 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; D016753:Interleukin-10; D010047:Ovalbumin
keywords: airway remodeling; allergen; asthma; carbon nanotubes; nanomaterials