@article{duke_thompson_ihrie_taylor-just_ash_shipkowski_hall_tokarz_cesta_hubbs_et al._2018, title={Role of p53 in the chronic pulmonary immune response to tangled or rod-like multi-walled carbon nanotubes}, volume={12}, ISSN={["1743-5404"]}, DOI={10.1080/17435390.2018.1502830}, abstractNote={Abstract The fiber-like shape of multi-walled carbon nanotubes (MWCNTs) is reminiscent of asbestos, suggesting they pose similar health hazards when inhaled, including pulmonary fibrosis and mesothelioma. Mice deficient in the tumor suppressor p53 are susceptible to carcinogenesis. However, the chronic pathologic effect of MWCNTs delivered to the lungs of p53 heterozygous (p53+/−) mice has not been investigated. We hypothesized that p53+/− mice would be susceptible to lung tumor development after exposure to either tangled (t-) or rod-like (r-) MWCNTs. Wild-type (p53+/+) or p53+/− mice were exposed to MWCNTs (1 mg/kg) via oropharyngeal aspiration weekly over four consecutive weeks and evaluated for cellular and pathologic outcomes 11-months post-initial exposure. No lung or pleural tumors were observed in p53+/+ or p53+/− mice exposed to either t- or rMWCNTs. In comparison to tMWCNTs, the rMWCNTs induced the formation of larger granulomas, a greater number of lymphoid aggregates and greater epithelial cell hyperplasia in terminal bronchioles in both p53+/− and p53+/+ mice. A constitutively larger area of CD45R+/CD3+ lymphoid tissue was observed in p53+/− mice compared to p53+/+ mice. Importantly, p53+/− mice had larger granulomas induced by rMWCNTs as compared to p53+/+ mice. These findings indicate that a combination of p53 deficiency and physicochemical characteristics including nanotube geometry are factors in susceptibility to MWCNT-induced lymphoid infiltration and granuloma formation.}, number={9}, journal={NANOTOXICOLOGY}, author={Duke, Katherine S. and Thompson, Elizabeth A. and Ihrie, Mark D. and Taylor-Just, Alexia J. and Ash, Elizabeth A. and Shipkowski, Kelly A. and Hall, Jonathan R. and Tokarz, Debra A. and Cesta, Mark F. and Hubbs, Ann F. and et al.}, year={2018}, month={Oct}, pages={975–991} }
 @article{duke_taylor-just_ihrie_shipkowski_thompson_dandley_parsons_bonner_2017, title={STAT1-dependent and -independent pulmonary allergic and fibrogenic responses in mice after exposure to tangled versus rod-like multi-walled carbon nanotubes}, volume={14}, ISSN={["1743-8977"]}, DOI={10.1186/s12989-017-0207-3}, abstractNote={Pulmonary toxicity of multi-walled carbon nanotubes (MWCNTs) is influenced by physicochemical characteristics and genetic susceptibility. We hypothesized that contrasting rigidities of tangled (t) versus rod-like (r) MWCNTs would result in differing immunologic or fibrogenic responses in mice and that these responses would be exaggerated in transgenic mice lacking the signal transducer and activator of transcription-1 (STAT1), a susceptible mouse model of pulmonary fibrosis.Male wild type (Stat1 +/+ ) and STAT1-deficient (Stat1 -/- ) mice were exposed to 4 mg/kg tMWCNTs, rMWCNTs, or vehicle alone via oropharyngeal aspiration and evaluated for inflammation at one and 21 days post-exposure via histopathology, differential cell counts, and cytokine levels in bronchoalveolar lavage fluid (BALF). Granuloma formation, mucous cell metaplasia, and airway fibrosis were evaluated by quantitative morphometry. Airway epithelial cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation. Cytokine protein levels in BALF and serum IgE levels were measured by ELISA. Lung protein Smad2/3 levels and activation were measured by Western blot. Lung mRNAs were measured by PCR.There was a 7-fold difference in rigidity between tMWCNTs and rMWCNTs as determined by static bending ratio. Both MWCNT types resulted in acute inflammation (neutrophils in BALF) after one-day post-exposure, yet only rMWCNTs resulted in chronic inflammation at 21 days as indicated by neutrophil influx and larger granulomas. Both MWCNTs induced BrdU uptake in airway epithelial cells, with the greatest proliferative response observed in rMWCNT-exposed mice after one-day. Only rMWCNTs induced mucous cell metaplasia, but this index was not different between genotypes. Stat1 -/- mice had higher levels of baseline serum IgE than Stat1 +/+ mice. Greater airway fibrosis was observed with rMWCNTs compared to tMWCNTs, and exaggerated airway fibrosis was seen in the Stat1 -/- mouse lungs with rMWCNTs but not tMWCNTs. Increased fibrosis correlated with elevated levels of TGF-β1 protein levels in the BALF of Stat1 -/- mice exposed to rMWCNTs and increased lung Smad2/3 phosphorylation.Rigidity plays a key role in the toxicity of MWCNTs and results in increased inflammatory, immunologic, and fibrogenic effects in the lung. STAT1 is an important protective factor in the fibroproliferative response to rMWCNTs, regulating both induced TGF-β1 production and Smad2/3 phosphorylation status. Therefore, both rigidity and genetic susceptibility should be major considerations for risk assessment of MWCNTs.}, journal={PARTICLE AND FIBRE TOXICOLOGY}, author={Duke, Katherine S. and Taylor-Just, Alexia J. and Ihrie, Mark D. and Shipkowski, Kelly A. and Thompson, Elizabeth A. and Dandley, Erinn C. and Parsons, Gregory N. and Bonner, James C.}, year={2017}, month={Jul} }
 @article{thompson_sayers_glista-baker_shipkowski_ihrie_duke_taylor_bonner_2015, title={Role of Signal Transducer and Activator of Transcription 1 in Murine Allergen-Induced Airway Remodeling and Exacerbation by Carbon Nanotubes}, volume={53}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2014-0221oc}, abstractNote={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.}, number={5}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Thompson, Elizabeth A. and Sayers, Brian C. and Glista-Baker, Ellen E. and Shipkowski, Kelly A. and Ihrie, Mark D. and Duke, Katherine S. and Taylor, Alexia J. and Bonner, James C.}, year={2015}, month={Nov}, pages={625–636} }
 @article{taylor_mcclure_shipkowski_thompson_hussain_garantziotis_parsons_bonner_2014, title={Atomic Layer Deposition Coating of Carbon Nanotubes with Aluminum Oxide Alters Pro-Fibrogenic Cytokine Expression by Human Mononuclear Phagocytes In Vitro and Reduces Lung Fibrosis in Mice In Vivo}, volume={9}, ISSN={["1932-6203"]}, url={http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000341774300028&KeyUID=WOS:000341774300028}, DOI={10.1371/journal.pone.0106870}, abstractNote={Background Multi-walled carbon nanotubes (MWCNTs) pose a possible human health risk for lung disease as a result of inhalation exposure. Mice exposed to MWCNTs develop pulmonary fibrosis. Lung macrophages engulf MWCNTs and produce pro-fibrogenic cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and osteopontin (OPN). Atomic layer deposition (ALD) is a novel process used to enhance functional properties of MWCNTs, yet the consequence of ALD-modified MWCNTs on macrophage biology and fibrosis is unknown. Methods The purpose of this study was to determine whether ALD coating with aluminum oxide (Al2O3) would alter the fibrogenic response to MWCNTs and whether cytokine expression in human macrophage/monocytes exposed to MWCNTs in vitro would predict the severity of lung fibrosis in mice. Uncoated (U)-MWCNTs or ALD-coated (A)-MWCNTs were incubated with THP-1 macrophages or human peripheral blood mononuclear cells (PBMC) and cell supernatants assayed for cytokines by ELISA. C57BL6 mice were exposed to a single dose of A- or U-MWCNTs by oropharyngeal aspiration (4 mg/kg) followed by evaluation of histopathology, lung inflammatory cell counts, and cytokine levels at day 1 and 28 post-exposure. Results ALD coating of MWCNTs with Al2O3 enhanced IL-1β secretion by THP-1 and PBMC in vitro, yet reduced protein levels of IL-6, TNF-α, and OPN production by THP-1 cells. Moreover, Al2O3 nanoparticles, but not carbon black NPs, increased IL-1β but decreased OPN and IL-6 in THP-1 and PBMC. Mice exposed to U-MWCNT had increased levels of all four cytokines assayed and developed pulmonary fibrosis by 28 days, whereas ALD-coating significantly reduced fibrosis and cytokine levels at the mRNA or protein level. Conclusion These findings indicate that ALD thin film coating of MWCNTs with Al2O3 reduces fibrosis in mice and that in vitro phagocyte expression of IL-6, TNF-α, and OPN, but not IL-1β, predict MWCNT-induced fibrosis in the lungs of mice in vivo.}, number={9}, journal={PLOS ONE}, author={Taylor, Alexia J. and McClure, Christina D. and Shipkowski, Kelly A. and Thompson, Elizabeth A. and Hussain, Salik and Garantziotis, Stavros and Parsons, Gregory N. and Bonner, James C.}, year={2014}, month={Sep} }
 @article{glista-baker_taylor_sayers_thompson_bonner_2012, title={Nickel Nanoparticles Enhance Platelet-Derived Growth Factor-Induced Chemokine Expression by Mesothelial Cells via Prolonged Mitogen-Activated Protein Kinase Activation}, volume={47}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2012-0023oc}, abstractNote={Pleural diseases (fibrosis and mesothelioma) are a major concern for individuals exposed by inhalation to certain types of particles, metals, and fibers. Increasing attention has focused on the possibility that certain types of engineered nanoparticles (NPs), especially those containing nickel, might also pose a risk for pleural diseases. Platelet-derived growth factor (PDGF) is an important mediator of fibrosis and cancer that has been implicated in the pathogenesis of pleural diseases. In this study, we discovered that PDGF synergistically enhanced nickel NP (NiNP)-induced increases in mRNA and protein levels of the profibrogenic chemokine monocyte chemoattractant protein-1 (MCP-1 or CCL2), and the antifibrogenic IFN-inducible CXC chemokine (CXCL10) in normal rat pleural mesothelial 2 (NRM2) cells in vitro. Carbon black NPs (CBNPs), used as a negative control NP, did not cause a significant increase in CCL2 or CXCL10 in the absence or presence of PDGF. NiNPs prolonged PDGF-induced phosphorylation of the mitogen-activated protein kinase family termed extracellular signal-regulated kinases (ERK)-1 and -2 for up to 24 hours, and NiNPs also synergistically increased PDGF-induced hypoxia-inducible factor (HIF)-1α protein levels in NRM2 cells. Inhibition of ERK-1,2 phosphorylation with the mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, blocked the synergistic increase in CCL2, CXCL10, and HIF-1α levels induced by PDGF and NiNPs. Moreover, the antioxidant, N-acetyl-L-cysteine (NAC), significantly reduced HIF-1α, ERK-1,2 phosphorylation, and CCL2 protein levels that were synergistically increased by the combination of PDGF and NiNPs. These data indicate that NiNPs enhance the activity of PDGF in regulating chemokine production in NRM2 cells through a mechanism involving reactive oxygen species generation and prolonged activation of ERK-1,2.}, number={4}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Glista-Baker, Ellen E. and Taylor, Alexia J. and Sayers, Brian C. and Thompson, Elizabeth A. and Bonner, James C.}, year={2012}, month={Oct}, pages={552–561} }
 @article{thompson_zhu_hall_house_ranjan_burr_he_owens_smart_2011, title={C/EBP alpha Expression Is Downregulated in Human Nonmelanoma Skin Cancers and Inactivation of C/EBP alpha Confers Susceptibility to UVB-Induced Skin Squamous Cell Carcinomas}, volume={131}, ISSN={["0022-202X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79956039252&partnerID=MN8TOARS}, DOI={10.1038/jid.2011.31}, abstractNote={Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBPα (CCAAT/enhancer-binding protein-α) in the DNA damage response network, where C/EBPα is induced following UVB DNA damage, regulates the G<sub>1</sub> checkpoint, and diminished or ablated expression of C/EBPα results in G<sub>1</sub> checkpoint failure. In the current study we observed that C/EBPα is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBPα expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBPα similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBPα. To determine the significance of C/EBPα in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBPα (CKOα) were exposed to UVB. CKOα mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKOα mice displayed keratinocyte cell cycle checkpoint failure <i>in vivo</i> in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBPα is silenced in human SCC and loss of C/EBPα confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB.}, number={6}, journal={JOURNAL OF INVESTIGATIVE DERMATOLOGY}, author={Thompson, Elizabeth A. and Zhu, Songyun and Hall, Jonathan R. and House, John S. and Ranjan, Rakesh and Burr, Jeanne A. and He, Yu-Ying and Owens, David M. and Smart, Robert C.}, year={2011}, month={Jun}, pages={1339–1346} }
 @article{ranjan_thompson_yoon_smart_2009, title={C/EBP alpha expression is partially regulated by C/EBP beta in response to DNA damage and C/EBP alpha-deficient fibroblasts display an impaired G(1) checkpoint}, volume={28}, ISSN={["1476-5594"]}, DOI={10.1038/onc.2009.176}, abstractNote={We observed that CCAAT/enhancer-binding protein (C/EBP)alpha is highly inducible in primary fibroblasts by DNA-damaging agents that induce strand breaks, alkylate and crosslink DNA as well as those that produce bulky DNA lesions. Fibroblasts deficient in C/EBPalpha (C/EBPalpha(-/-)) display an impaired G1 checkpoint as evidenced by an inappropriate entry into the S-phase in response to DNA damage, and these cells also display an enhanced G1/S transition in response to mitogens. The induction of C/EBPalpha by DNA damage in fibroblasts does not require p53. Electrophoretic mobility shift assay (EMSA) analysis of nuclear extracts prepared from ultraviolet B (UVB)- and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated fibroblasts showed increased binding of C/EBPbeta to a C/EBP consensus sequence and chromatin immunoprecipitation (ChIP) analysis also showed increased C/EBPbeta binding to the C/EBPalpha promoter. To determine whether C/EBPbeta has a function in the regulation of C/EBPalpha, we treated C/EBPbeta(-/-) fibroblasts with UVB or MNNG. We observed that C/EBPalpha induction was impaired in both UVB- and MNNG-treated C/EBPbeta(-/-) fibroblasts. Our study shows a novel function for C/EBPbeta in the regulation of C/EBPalpha in response to DNA damage and provides definitive genetic evidence that C/EBPalpha has a critical role in the DNA damage G1 checkpoint.}, number={36}, journal={ONCOGENE}, author={Ranjan, R. and Thompson, E. A. and Yoon, K. and Smart, R. C.}, year={2009}, month={Sep}, pages={3235–3245} }