@article{dominguez_holmes_bartone_tisch_tighe_bonner_payne_2023, title={House dust mite extract forms a der p 2 corona on multi-walled carbon nanotubes: implications for allergic airway disease}, ISSN={["2051-8161"]}, DOI={10.1039/d3en00666b}, abstractNote={MWCNTs are used in a variety of industrial applications. Inhalation of MWCNTs can occur during manufacturing and handling. We address the interaction of MWCNTs with house dust mite allergens (a source of asthma) and lung fluid proteins.}, journal={ENVIRONMENTAL SCIENCE-NANO}, author={Dominguez, Judith and Holmes, Samantha K. and Bartone, Ryan D. and Tisch, Logan J. and Tighe, Robert M. and Bonner, James C. and Payne, Christine K.}, year={2023}, month={Dec} }
 @article{lee_you_taylor-just_tisch_bartone_atkins_ralph_antoniak_bonner_2023, title={Role of the protease-activated receptor-2 (PAR2) in the exacerbation of house dust mite-induced murine allergic lung disease by multi-walled carbon nanotubes}, volume={20}, ISSN={["1743-8977"]}, DOI={10.1186/s12989-023-00538-6}, abstractNote={Abstract}, number={1}, journal={PARTICLE AND FIBRE TOXICOLOGY}, author={Lee, Ho Young and You, Dorothy J. J. and Taylor-Just, Alexia and Tisch, Logan J. and Bartone, Ryan D. and Atkins, Hannah M. and Ralph, Lauren M. and Antoniak, Silvio and Bonner, James C.}, year={2023}, month={Aug} }
 @article{lee_you_taylor-just_linder_atkins_ralph_cruz_bonner_2022, title={Pulmonary exposure of mice to ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX) suppresses the innate immune response to carbon black nanoparticles and stimulates lung cell proliferation}, ISSN={["1091-7691"]}, DOI={10.1080/08958378.2022.2086651}, abstractNote={Abstract Background Per- and polyfluoroalkyl substances (PFAS) have been associated with respiratory diseases in humans, yet the mechanisms through which PFAS cause susceptibility to inhaled agents is unknown. Herein, we investigated the effects of ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), an emerging PFAS, on the pulmonary immune response of mice to carbon black nanoparticles (CBNP). We hypothesized that pulmonary exposure to GenX would increase susceptibility to CBNP through suppression of innate immunity. Methods Male C57BL/6 mice were exposed to vehicle, 4 mg/kg CBNP, 10 mg/kg GenX, or CBNP and GenX by oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) was collected at 1 and 14 days postexposure for cytokines and total protein. Lung tissue was harvested for histopathology, immunohistochemistry (Ki67 and phosphorylated (p)-STAT3), western blotting (p-STAT3 and p-NF-κB), and qRT-PCR for cytokine mRNAs. Results CBNP increased CXCL-1 and neutrophils in BALF at both time points evaluated. However, GenX/CBNP co-exposure reduced CBNP-induced CXCL-1 and neutrophils in BALF. Moreover, CXCL-1, CXCL-2 and IL-1β mRNAs were increased by CBNP in lung tissue but reduced by GenX. Western blotting showed that CBNP induced p-NF-κB in lung tissue, while the GenX/CBNP co-exposed group displayed decreased p-NF-κB. Furthermore, mice exposed to GenX or GenX/CBNP displayed increased numbers of BALF macrophages undergoing mitosis and increased Ki67 immunostaining. This was correlated with increased p-STAT3 by western blotting and immunohistochemistry in lung tissue from mice co-exposed to GenX/CBNP. Conclusions Pulmonary exposure to GenX suppressed CBNP-induced innate immune response in the lungs of mice yet promoted the proliferation of macrophages and lung epithelial cells.}, journal={INHALATION TOXICOLOGY}, author={Lee, Ho Young and You, Dorothy J. and Taylor-Just, Alexia J. and Linder, Keith E. and Atkins, Hannah M. and Ralph, Lauren M. and Cruz, Gabriela and Bonner, James C.}, year={2022}, month={Jun} }
 @article{you_lee_taylor-just_bonner_2022, title={Synergistic induction of IL-6 production in human bronchial epithelial cells in vitro by nickel nanoparticles and lipopolysaccharide is mediated by eSTAT3 and C/EBP beta}, volume={83}, ISSN={["1879-3177"]}, DOI={10.1016/j.tiv.2022.105394}, abstractNote={We previously reported that delivery of nickel nanoparticles (NiNPs) and bacterial lipopolysaccharide (LPS) into the lungs of mice synergistically increased IL-6 production and inflammation, and male mice were more susceptible than female mice. The primary goal of this study was to utilize an in vitro human lung epithelial cell model (BEAS-2B) to investigate the intracellular signaling mechanisms that mediate IL-6 production by LPS and NiNPs. We also investigated the effect of sex hormones on NiNP and LPS-induced IL-6 production in vitro. LPS and NiNPs synergistically induced IL-6 mRNA and protein in BEAS-2B cells. TPCA-1, a dual inhibitor of IKK-2 and STAT3, blocked the synergistic increase in IL-6 caused by LPS and NiNPs, abolished STAT3 activation, and reduced C/EBPβ. Conversely, SC144, an inhibitor of the gp130 component of the IL-6 receptor, enhanced IL-6 production induced by LPS and NiNPs. Treatment of BEAS-2B cells with sex hormones (17β-estradiol, progesterone, or testosterone) or the anti-oxidant NAC, had no effect on IL-6 induction by LPS and NiNPs. These data suggest that LPS and NiNPs induce IL-6 via STAT3 and C/EBPβ in BEAS-2B cells. While BEAS-2B cells are a suitable model to study mechanisms of IL-6 production, they do not appear to be suitable for studying the effect of sex hormones.}, journal={TOXICOLOGY IN VITRO}, author={You, Dorothy J. and Lee, Ho Young and Taylor-Just, Alexia J. and Bonner, James C.}, year={2022}, month={Sep} }
 @article{lison_ibouraadaten_brule_todea_vulpoi_turcu_ziemann_creutzenberg_bonner_ameloot_et al._2021, title={Femtosecond pulsed laser microscopy: a new tool to assess the in vitro delivered dose of carbon nanotubes in cell culture experiments}, volume={18}, ISSN={["1743-8977"]}, DOI={10.1186/s12989-021-00402-5}, abstractNote={Abstract}, number={1}, journal={PARTICLE AND FIBRE TOXICOLOGY}, author={Lison, Dominique and Ibouraadaten, Saloua and Brule, Sybille and Todea, Milica and Vulpoi, Adriana and Turcu, Flaviu and Ziemann, Christina and Creutzenberg, Otto and Bonner, James C. and Ameloot, Marcel and et al.}, year={2021}, month={Feb} }
 @article{sridharan_taylor-just_bonner_2021, title={Osteopontin mRNA expression by rat mesothelial cells exposed to multi-walled carbon nanotubes as a potential biomarker of chronic neoplastic transformation in vitro}, volume={73}, ISSN={["1879-3177"]}, DOI={10.1016/j.tiv.2021.105126}, abstractNote={Mesothelioma is a cancer of the lung pleura primarily associated with inhalation of asbestos fibers. Multi-walled carbon nanotubes (MWCNTs) are engineered nanomaterials that pose a potential risk for mesothelioma due to properties that are similar to asbestos. Inhaled MWCNTs migrate to the pleura in rodents and some types cause mesothelioma. Like asbestos, there is a diversity of MWCNT types. We investigated the neoplastic potential of tangled (tMWCNT) versus rigid (rMWCNT) after chronic exposure using serial passages of rat mesothelial cells in vitro. Normal rat mesothelial (NRM2) cells were exposed to tMWCNTs or rMWCNTs for 45 weeks over 85 passages to determine if exposure resulted in transformation to a neoplastic phenotype. Rat mesothelioma (ME1) cells were used as a positive control. Osteopontin (OPN) mRNA was assayed as a biomarker of transformation by real time quantitative polymerase chain reaction (qPCR) and transformation was determined by a cell invasion assay. Exposure to rMWCNTs, but not tMWCNTs, resulted in transformation of NRM2 cells into an invasive phenotype that was similar to ME1 cells. Moreover, exposure of NRM2 cells to rMWCNTs increased OPN mRNA that correlated with cellular transformation. These data suggest that OPN is a potential biomarker that should be further investigated to screen the carcinogenicity of MWCNTs in vitro.}, journal={TOXICOLOGY IN VITRO}, author={Sridharan, Sreepradha and Taylor-Just, Alexia and Bonner, James C.}, year={2021}, month={Jun} }
 @article{ihrie_duke_shipkowski_you_lee_taylor-just_bonner_2021, title={STAT6-dependent exacerbation of house dust mite-induced allergic airway disease in mice by multi-walled carbon nanotubes}, volume={22}, ISSN={["2452-0748"]}, DOI={10.1016/j.impact.2021.100309}, abstractNote={There is increasing evidence that inhaled multi-walled carbon nanotubes (MWCNTs) can have harmful effects on the respiratory system. Rodent studies suggest that individuals with asthma may be susceptible to the adverse pulmonary effects of MWCNTs. Asthma is an allergic lung disease characterized by a TH2 immune response that results in chronic airway disease characterized by eosinophilic lung inflammation, airway mucous cell metaplasia, and airway fibrosis. Signal transducer and activator of transcription 6 (STAT6) is a transcription factor with multiple roles in TH2 type inflammation. Herein we sought to examine the role of STAT6 in the exacerbation of house dust mite (HDM) allergen-induced allergic airway disease by MWCNTs. Male wild type (WT) and STAT6 knockout (Stat6 KO) mice were dosed via intranasal aspiration on days 0, 2, 4, 14, 16 and 18 with either vehicle, HDM extract, MWCNTs, or a combination of HDM and MWCNTs. Necropsy was performed on day 21 to collect bronchoalveolar lavage fluid (BALF), serum and lung tissue. MWCNTs exacerbated HDM-induced allergic endpoints, including eosinophilic lung inflammation, mucous cell metaplasia, and serum IgE levels. HDM-induced eosinophilic lung inflammation, mucous cell metaplasia, and serum IgE and exacerbation of these endpoints by MWCNTs were ablated in Stat6 KO mice. In addition, airway fibrosis was significantly increased by the combination of HDM and MWCNTs in WT mice but not in Stat6 KO mice. These findings provide new mechanistic insight by demonstrating a requirement for STAT6 in MWCNT-induced exacerbation of allergic respiratory disease.}, journal={NANOIMPACT}, author={Ihrie, Mark D. and Duke, Katherine S. and Shipkowski, Kelly A. and You, Dorothy J. and Lee, Ho Young and Taylor-Just, Alexia J. and Bonner, James C.}, year={2021}, month={Apr} }
 @article{yaeger_reece_kilburg-basnyat_hodge_pal_dunigan-russell_luo_you_bonner_spangenburg_et al._2021, title={Sex Differences in Pulmonary Eicosanoids and Specialized Pro-Resolving Mediators in Response to Ozone Exposure}, volume={183}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfab081}, abstractNote={Abstract}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Yaeger, Michael J. and Reece, Sky W. and Kilburg-Basnyat, Brita and Hodge, Miles X. and Pal, Anandita and Dunigan-Russell, Katelyn and Luo, Bin and You, Dorothy J. and Bonner, James C. and Spangenburg, Espen E. and et al.}, year={2021}, month={Sep}, pages={170–183} }
 @book{bonner_brown_2020, place={Cham, Switzerland}, series={Molecular and Integrative Toxicology}, title={Interaction of Nanomaterials with the Immune System}, ISBN={9783030339616 9783030339623}, ISSN={2168-4219 2168-4235}, url={http://dx.doi.org/10.1007/978-3-030-33962-3}, DOI={10.1007/978-3-030-33962-3}, abstractNote={This book covers the most up-to- date information on our understanding of immune responses to ENMs across a wide range of topics including innate immunity, and allergic immune responses. It also covers Testing strategies for evaluating immunotoxicity of ENMs.}, publisher={Springer International Publishing}, year={2020}, collection={Molecular and Integrative Toxicology} }
 @article{bonner_brown_2020, title={Interaction of Nanomaterials with the Immune System Introduction}, ISBN={["978-3-030-33961-6"]}, ISSN={["2168-4219"]}, DOI={10.1007/978-3-030-33962-3_1}, abstractNote={The rise of nanotechnology, a new industrial revolution, is generating a wealth of novel advanced materials that are dramatically changing the fields of electronics, engineering, and medicine. It is anticipated that these changes will solve important problems in renewable energy, more efficient communication and transportation systems, bioremediation of environmental pollution, and treatment of debilitating diseases. However, the impact of nanomaterials on the immune system is a concern, since manipulation of matter with a size range on par with subcellular structures has the potential to activate or suppress cells of the innate or adaptive immune system. This chapter overviews the topics covered in this book and thereby sets the stage for understanding the complexity of immune responses to a diversity of emerging engineered nanomaterials.}, journal={INTERACTION OF NANOMATERIALS WITH THE IMMUNE SYSTEM}, author={Bonner, James C. and Brown, Jared M.}, year={2020}, pages={1–14} }
 @article{you_lee_bonner_2020, title={Macrophages: First Innate Immune Responders to Nanomaterials}, ISBN={["978-3-030-33961-6"]}, ISSN={["2168-4219"]}, DOI={10.1007/978-3-030-33962-3_2}, abstractNote={Macrophages are professional phagocytes that play key roles in immune surveillance and host defense against a variety of external stimuli, including engineered nanomaterials (ENMs). Physicochemical characteristics of ENMs such as size, shape, and surface charge are factors that determine macrophage recognition and uptake through various endocytotic mechanisms. Moreover, toll-like receptors (TLRs) and scavenger receptors (SRs) on the surface of macrophages facilitate binding, uptake, and intracellular signaling in response to specific types of ENMs. Biocorona formation further modulates the interaction of ENMs with cell-surface receptors. The immune response of macrophages to ENMs, including inflammasome activation and alternative polarization, plays important roles in immune-mediated diseases such as fibrosis, asthma, and cancer.}, journal={INTERACTION OF NANOMATERIALS WITH THE IMMUNE SYSTEM}, author={You, Dorothy J. and Lee, Ho Young and Bonner, James C.}, year={2020}, pages={15–34} }
 @article{you_lee_taylor-just_linder_bonner_2020, title={Sex differences in the acute and subchronic lung inflammatory responses of mice to nickel nanoparticles}, volume={14}, ISSN={["1743-5404"]}, DOI={10.1080/17435390.2020.1808105}, abstractNote={Abstract Nickel nanoparticles (NiNPs) are increasingly used in nanotechnology applications, yet information on sex differences in NiNP-induced lung disease is lacking. The goal of this study was to explore mechanisms of susceptibility between male and female mice after acute or subchronic pulmonary exposure to NiNPs. For acute exposure, male and female mice received a single dose of NiNPs with or without LPS by oropharyngeal aspiration and were necropsied 24 h later. For subchronic exposure, mice received NiNPs with or without LPS six times over 3 weeks prior to necropsy. After acute exposure to NiNPs and LPS, male mice had elevated cytokines (CXCL1 and IL-6) and more neutrophils in bronchoalveolar lavage fluid (BALF), along with greater STAT3 phosphorylation in lung tissue. After subchronic exposure to NiNPs and LPS, male mice exhibited increased monocytes in BALF. Moreover, subchronic exposure of male mice to NiNP only induced higher CXCL1 and CCL2 in BALF along with increased alveolar infiltrates and CCL2 in lung tissue. STAT1 in lung tissue was induced by subchronic exposure to NiNPs in females but not males. Males had a greater induction of IL-6 mRNA in liver after acute exposure to NiNPs and LPS, and greater CCL2 mRNA in liver after subchronic NiNP exposure. These data indicate that susceptibility of males to acute lung inflammation involves enhanced neutrophilia with increased CXCL1 and IL-6/STAT3 signaling, whereas susceptibility to subchronic lung inflammation involves enhanced monocytic infiltration with increased CXCL1 and CCL2. STAT transcription factors appear to play a role in these sex differences. This study demonstrates sex differences in the lung inflammatory response of mice to NiNPs that has implications for human disease.}, number={8}, journal={NANOTOXICOLOGY}, author={You, Dorothy J. and Lee, Ho Young and Taylor-Just, Alexia J. and Linder, Keith E. and Bonner, James C.}, year={2020}, month={Sep}, pages={1058–1081} }
 @misc{you_bonner_2020, title={Susceptibility Factors in Chronic Lung Inflammatory Responses to Engineered Nanomaterials}, volume={21}, ISSN={["1422-0067"]}, DOI={10.3390/ijms21197310}, abstractNote={Engineered nanomaterials (ENMs) are products of the emerging nanotechnology industry and many different types of ENMs have been shown to cause chronic inflammation in the lungs of rodents after inhalation exposure, suggesting a risk to human health. Due to the increasing demand and use of ENMs in a variety of products, a careful evaluation of the risks to human health is urgently needed. An assessment of the immunotoxicity of ENMs should consider susceptibility factors including sex, pre-existing diseases, deficiency of specific genes encoding proteins involved in the innate or adaptive immune response, and co-exposures to other chemicals. This review will address evidence from experimental animal models that highlights some important issues of susceptibility to chronic lung inflammation and systemic immune dysfunction after pulmonary exposure to ENMs.}, number={19}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={You, Dorothy J. and Bonner, James C.}, year={2020}, month={Oct} }
 @article{taylor-just_ihrie_duke_lee_you_hussain_kodali_ziemann_creutzenberg_vulpoi_et al._2020, title={The pulmonary toxicity of carboxylated or aminated multi-walled carbon nanotubes in mice is determined by the prior purification method}, volume={17}, ISSN={["1743-8977"]}, DOI={10.1186/s12989-020-00390-y}, abstractNote={Abstract}, number={1}, journal={PARTICLE AND FIBRE TOXICOLOGY}, author={Taylor-Just, Alexia J. and Ihrie, Mark D. and Duke, Katherine S. and Lee, Ho Young and You, Dorothy J. and Hussain, Salik and Kodali, Vamsi K. and Ziemann, Christina and Creutzenberg, Otto and Vulpoi, Adriana and et al.}, year={2020}, month={Dec} }
 @article{ihrie_taylor-just_walker_stout_gupta_richey_hayden_baker_sparrow_duke_et al._2019, title={Inhalation exposure to multi-walled carbon nanotubes alters the pulmonary allergic response of mice to house dust mite allergen}, volume={31}, ISSN={["1091-7691"]}, DOI={10.1080/08958378.2019.1643955}, abstractNote={Abstract Background: Increasing evidence from rodent studies indicates that inhaled multi-walled carbon nanotubes (MWCNTs) have harmful effects on the lungs. In this study, we examined the effects of inhalation exposure to MWCNTs on allergen-induced airway inflammation and fibrosis. We hypothesized that inhalation pre-exposure to MWCNTs would render mice susceptible to developing allergic lung disease induced by house dust mite (HDM) allergen. Methods: Male B6C3F1/N mice were exposed by whole-body inhalation for 6 h a day, 5 d a week, for 30 d to air control or 0.06, 0.2, and 0.6 mg/m3 of MWCNTs. The exposure atmospheres were agglomerates (1.4–1.8 µm) composed of MWCNTs (average diameter 16 nm; average length 2.4 µm; 0.52% Ni). Mice then received 25 µg of HDM extract by intranasal instillation 6 times over 3 weeks. Necropsy was performed at 3 and 30 d after the final HDM dose to collect serum, bronchoalveolar lavage fluid (BALF), and lung tissue for histopathology. Results: MWCNT exposure at the highest dose inhibited HDM-induced serum IgE levels, IL-13 protein levels in BALF, and airway mucus production. However, perivascular and peribronchiolar inflammatory lesions were observed in the lungs of mice at 3 d with MWCNT and HDM, but not MWCNT or HDM alone. Moreover, combined HDM and MWCNT exposure increased airway fibrosis in the lungs of mice. Conclusions: Inhalation pre-exposure to MWCNTs inhibited HDM-induced TH2 immune responses, yet this combined exposure resulted in vascular inflammation and airway fibrosis, indicating that MWCNT pre-exposure alters the immune response to allergens.}, number={5}, journal={INHALATION TOXICOLOGY}, author={Ihrie, Mark D. and Taylor-Just, Alexia J. and Walker, Nigel J. and Stout, Matthew D. and Gupta, Amit and Richey, Jamie S. and Hayden, Barry K. and Baker, Gregory L. and Sparrow, Barney R. and Duke, Katherine S. and et al.}, year={2019}, month={Apr}, pages={192–202} }
 @article{ziemann_reamon-buettner_lison_bonner_brule_simon_creutzenberg_2018, title={ICONS - Integrated testing strategy for mechanistically assessing the respiratory toxicity of functionalized MWCNTs - Comparative in vitro investigations}, volume={295}, ISSN={["1879-3169"]}, DOI={10.1016/j.toxlet.2018.06.922}, abstractNote={Exposure to environmental toxicants that target ovarian follicles can have long-lasting effects on women’s reproductive health and health of the offspring. Experiments in rodents have contributed knowledge about the effects of individual toxicants on ovarian follicles. However, little is known about the effects of mixtures of toxicants on ovarian follicular health. We studied the combined effects of low, physiologically- and environmentally-relevant concentrations of toxicants on murine secondary ovarian follicles cultured in an encapsulated three-dimensional (3D) system. Exposure to lindane and 7,12-dimenthylbenz(a)anthracene (DMBA) led to decreased follicle survival, impaired development and compromised maturation in a concentration-dependent manner. DMBA showed a greater toxicity to cultured follicles compared to lindane. The mixtures of lindane and DMBA did not produce a synergistic toxic effect on follicles. Rather, ovarian follicles exposed to the mixtures showed survival and growth patterns similar to the follicles exposed to the same concentrations of individual toxicants. Our findings regarding follicle toxicity at such low concentrations help informing what might be overlooked when regulating environmental toxicants. The proposed 3D culture system allowed studying the effects of mixtures of environmental toxicants in a physiological setting, providing much needed information on how simultaneous exposure to multiple toxicants affects complex and sensitive biological structures, such as ovarian follicles.}, journal={TOXICOLOGY LETTERS}, author={Ziemann, C. and Reamon-Buettner, S. M. and Lison, D. and Bonner, J. C. and Brule, S. and Simon, S. and Creutzenberg, O. H.}, year={2018}, month={Oct}, pages={S213–S213} }
 @misc{duke_bonner_2018, title={Mechanisms of carbon nanotube-induced pulmonary fibrosis: A physicochemical characteristic perspective}, volume={10}, number={3}, journal={Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology}, author={Duke, K. S. and Bonner, J. C.}, year={2018} }
 @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_ihrie_shipkowski_needham_bonner_2018, title={Signal transducer and activator of transcription 1 regulates multiwalled carbon nanotube-induced pulmonary fibrosis in mice via suppression of transforming growth factor-beta 1 production and signaling}, volume={15}, journal={Annals of the American Thoracic Society}, author={Duke, K. S. and Taylor, A. J. and Ihrie, M. D. and Shipkowski, K. A. and Needham, E. C. and Bonner, J. C.}, year={2018}, pages={S129–130} }
 @article{ihrie_bonner_2018, title={The Toxicology of Engineered Nanomaterials in Asthma}, volume={5}, ISSN={2196-5412}, url={http://dx.doi.org/10.1007/S40572-018-0181-4}, DOI={10.1007/S40572-018-0181-4}, abstractNote={The explosive growth of the nanotechnology industry has necessitated the examination of engineered nanomaterials (ENMs) for their toxicity. The unique properties that make ENMs useful also make them a health risk, and individuals with pre-existing diseases such as asthma are likely more susceptible. This review summarizes the current literature on the ability of ENMs to both exacerbate and directly cause asthma.Recent studies highlight the ability of metal nanoparticles (NPs) and carbon nanotubes (CNTs) to not only exacerbate pre-existing asthma in animal models but also initiate allergic airway disease directly. CNTs alone are shown to cause airway mucus production, elevated serum IgE levels, and increased TH2 cytokine levels, all key indicators of asthma. The ability of ENMs to modulate the immune response in asthma varies depending on their physicochemical properties and exposure timing. CNTs consistently exacerbate asthma, as do Ni and TiO2 NPs, whereas some NPs like Au attenuate asthma. Evidence is strong that ENMs can contribute to allergic airway disease; however, more work is required to determine their mechanisms, and more epidemiological studies are needed to validate results from animal models.}, number={1}, journal={Current Environmental Health Reports}, publisher={Springer Science and Business Media LLC}, author={Ihrie, Mark D. and Bonner, James C.}, year={2018}, month={Feb}, pages={100–109} }
 @article{hilton_taylor_hussain_dandley_griffith_garantziotis_parsons_bonner_bereman_2017, title={Mapping differential cellular protein response of mouse alveolar epithelial cells to multi-walled carbon nanotubes as a function of atomic layer deposition coating}, volume={11}, ISSN={["1743-5404"]}, DOI={10.1080/17435390.2017.1299888}, abstractNote={Abstract Carbon nanotubes (CNTs), a prototypical engineered nanomaterial, have been increasingly manufactured for a variety of novel applications over the past two decades. However, since CNTs possess fiber-like shape and cause pulmonary fibrosis in rodents, there is concern that mass production of CNTs will lead to occupational exposure and associated pulmonary diseases. The aim of this study was to use contemporary proteomics to investigate the mechanisms of cellular response in E10 mouse alveolar epithelial cells in vitro after exposure to multi-walled CNTs (MWCNTs) that were functionalized by atomic layer deposition (ALD). ALD is a method used to generate highly uniform and conformal nanoscale thin-film coatings of metals to enhance novel conductive properties of CNTs. We hypothesized that specific types of metal oxide coatings applied to the surface of MWCNTs by ALD would determine distinct proteomic profiles in mouse alveolar epithelial cells in vitro that could be used to predict oxidative stress and pulmonary inflammation. Uncoated (U)-MWCNTs were functionalized by ALD with zinc oxide (ZnO) to yield Z-MWCNTs or aluminum oxide (Al2O3) to yield A-MWCNTs. Significant differential protein expression was found in the following critical pathways: mTOR/eIF4/p70S6K signaling and Nrf-2 mediated oxidative stress response increased following exposure to Z-MWCNTs, interleukin-1 signaling increased following U-MWCNT exposure, and inhibition of angiogenesis by thrombospondin-1, oxidative phosphorylation, and mitochondrial dysfunction increased following A-MWCNT exposure. This study demonstrates that specific types of metal oxide thin film coatings applied by ALD produce distinct cellular and biochemical responses related to lung inflammation and fibrosis compared to uncoated MWCNT exposure in vitro.}, number={3}, journal={NANOTOXICOLOGY}, author={Hilton, Gina M. and Taylor, Alexia J. and Hussain, Salik and Dandley, Erinn C. and Griffith, Emily H. and Garantziotis, Stavros and Parsons, Gregory N. and Bonner, James C. and Bereman, Michael S.}, year={2017}, month={Apr}, pages={313–326} }
 @article{duke_bonner_2017, title={Mechanisms of carbon nanotube-induced pulmonary fibrosis: a physicochemical characteristic perspective}, volume={10}, ISSN={1939-5116}, url={http://dx.doi.org/10.1002/WNAN.1498}, DOI={10.1002/WNAN.1498}, abstractNote={Carbon nanotubes (CNTs) are engineered nanomaterials (ENMs) with numerous beneficial applications. However, they could pose a risk to human health from occupational or consumer exposures. Rodent models demonstrate that exposure to CNTs via inhalation, instillation, or aspiration results in pulmonary fibrosis. The severity of the fibrogenic response is determined by various physicochemical properties of the nanomaterial such as residual metal catalyst content, rigidity, length, aggregation status, or surface charge. CNTs are also increasingly functionalized post‐synthesis with organic or inorganic agents to modify or enhance surface properties. The mechanisms of CNT‐induced fibrosis involve oxidative stress, innate immune responses of macrophages, cytokine and growth factor production, epithelial cell injury and death, expansion of the pulmonary myofibroblast population, and consequent extracellular matrix accumulation. A comprehensive understanding of how physicochemical properties affect the fibrogenic potential of various types of CNTs should be considered in combination with genetic variability and gain or loss of function of specific genes encoding secreted cytokines, enzymes, or intracellular cell signaling molecules. Here, we cover the current state of the literature on mechanisms of CNT‐exposed pulmonary fibrosis in rodent models with a focus on physicochemical characteristics as principal drivers of the mechanisms leading to pulmonary fibrosis.}, number={3}, journal={Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology}, publisher={Wiley}, author={Duke, Katherine S. and Bonner, James C.}, year={2017}, month={Oct}, pages={e1498} }
 @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{dandley_taylor_duke_ihrie_shipkowski_parsons_bonner_2016, title={Atomic layer deposition coating of carbon nanotubes with zinc oxide causes acute phase immune responses in human monocytes in vitro and in mice after pulmonary exposure}, volume={13}, ISSN={["1743-8977"]}, url={http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000378430800002&KeyUID=WOS:000378430800002}, DOI={10.1186/s12989-016-0141-9}, abstractNote={Atomic layer deposition (ALD) is a method for applying conformal nanoscale coatings on three-dimensional structures. We hypothesized that surface functionalization of multi-walled carbon nanotubes (MWCNTs) with polycrystalline ZnO by ALD would alter pro-inflammatory cytokine expression by human monocytes in vitro and modulate the lung and systemic immune response following oropharyngeal aspiration in mice.Pristine (U-MWCNTs) were coated with alternating doses of diethyl zinc and water over increasing ALD cycles (10 to 100 ALD cycles) to yield conformal ZnO-coated MWCNTs (Z-MWCNTs). Human THP-1 monocytic cells were exposed to U-MWCNTs or Z-MWCNTs in vitro and cytokine mRNAs measured by Taqman real-time RT-PCR. Male C57BL6 mice were exposed to U- or Z-MWCNTs by oropharyngeal aspiration (OPA) and lung inflammation evaluated at one day post-exposure by histopathology, cytokine expression and differential counting of cells in bronchoalveolar lavage fluid (BALF) cells. Lung fibrosis was evaluated at 28 days. Cytokine mRNAs (IL-6, IL-1β, CXCL10, TNF-α) in lung, heart, spleen, and liver were quantified at one and 28 days. DNA synthesis in lung tissue was measured by bromodeoxyuridine (BrdU) uptake.ALD resulted in a conformal coating of MWCNTs with ZnO that increased proportionally to the number of coating cycles. Z-MWCNTs released Zn(+2) ions in media and increased IL-6, IL-1β, CXCL10, and TNF-α mRNAs in THP-1 cells in vitro. Mice exposed to Z-MWCNTs by OPA had exaggerated lung inflammation and a 3-fold increase in monocytes and neutrophils in BALF compared to U-MWCNTs. Z-MWCNTs, but not U-MWCNTs, induced IL-6 and CXCL10 mRNA and protein in the lungs of mice and increased IL-6 mRNA in heart and liver. U-MWCNTs but not Z-MWCNTs stimulated airway epithelial DNA synthesis in vivo. Lung fibrosis at 28 days was not significantly different between mice treated with U-MWCNT or Z-MWCNT.Pulmonary exposure to ZnO-coated MWCNTs produces a systemic acute phase response that involves the release of Zn(+2), lung epithelial growth arrest, and increased IL-6. ALD functionalization with ZnO generates MWCNTs that possess increased risk for human exposure.}, journal={PARTICLE AND FIBRE TOXICOLOGY}, author={Dandley, Erinn C. and Taylor, Alexia J. and Duke, Katherine S. and Ihrie, Mark D. and Shipkowski, Kelly A. and Parsons, Gregory N. and Bonner, James C.}, year={2016}, month={Jun} }
 @article{clippinger_ahluwalia_allen_bonner_casey_castranova_david_halappanavar_hotchkiss_jarabek_et al._2016, title={Expert consensus on an in vitro approach to assess pulmonary fibrogenic potential of aerosolized nanomaterials}, volume={90}, ISSN={["1432-0738"]}, DOI={10.1007/s00204-016-1717-8}, abstractNote={The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their potential to induce adverse lung effects following inhalation has lead to much interest in better understanding the hazard associated with these nanomaterials (NMs). While the current regulatory requirement for substances of concern, such as MWCNTs, in many jurisdictions is a 90-day rodent inhalation test, the monetary, ethical, and scientific concerns associated with this test led an international expert group to convene in Washington, DC, USA, to discuss alternative approaches to evaluate the inhalation toxicity of MWCNTs. Pulmonary fibrosis was identified as a key adverse outcome linked to MWCNT exposure, and recommendations were made on the design of an in vitro assay that is predictive of the fibrotic potential of MWCNTs. While fibrosis takes weeks or months to develop in vivo, an in vitro test system may more rapidly predict fibrogenic potential by monitoring pro-fibrotic mediators (e.g., cytokines and growth factors). Therefore, the workshop discussions focused on the necessary specifications related to the development and evaluation of such an in vitro system. Recommendations were made for designing a system using lung-relevant cells co-cultured at the air-liquid interface to assess the pro-fibrogenic potential of aerosolized MWCNTs, while considering human-relevant dosimetry and NM life cycle transformations. The workshop discussions provided the fundamental design components of an air-liquid interface in vitro test system that will be subsequently expanded to the development of an alternative testing strategy to predict pulmonary toxicity and to generate data that will enable effective risk assessment of NMs.}, number={7}, journal={ARCHIVES OF TOXICOLOGY}, author={Clippinger, Amy J. and Ahluwalia, Arti and Allen, David and Bonner, James C. and Casey, Warren and Castranova, Vincent and David, Raymond M. and Halappanavar, Sabina and Hotchkiss, Jon A. and Jarabek, Annie M. and et al.}, year={2016}, month={Jul}, pages={1769–1783} }
 @article{hussain_ji_taylor_degraff_george_tucker_chang_li_bonner_garantziotis_2016, title={Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury}, volume={10}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.6b03013}, abstractNote={Commercialization of multiwalled carbon nanotubes (MWCNT)-based applications has been hampered by concerns regarding their lung toxicity potential. Hyaluronic acid (HA) is a ubiquitously found polysaccharide, which is anti-inflammatory in its native high molecular weight form. HA-functionalized smart MWCNTs have shown promise as tumor-targeting drug delivery agents and can enhance bone repair and regeneration. However, it is unclear whether HA functionalization could reduce the pulmonary toxicity potential of MWCNTs. Using in vivo and in vitro approaches, we investigated the effectiveness of MWCNT functionalization with HA in increasing nanotube biocompatibility and reducing lung inflammatory and fibrotic effects. We utilized three-dimensional cultures of differentiated primary human bronchial epithelia to translate findings from rodent assays to humans. We found that HA functionalization increased stability and dispersion of MWCNTs and reduced postexposure lung inflammation, fibrosis, and mucus cell metaplasia compared with nonfunctionalized MWCNTs. Cocultures of fully differentiated bronchial epithelial cells (cultivated at air-liquid interface) and human lung fibroblasts (submerged) displayed significant reduction in injury, oxidative stress, as well as pro-inflammatory gene and protein expression after exposure to HA-functionalized MWCNTs compared with MWCNTs alone. In contrast, neither type of nanotubes stimulated cytokine production in primary human alveolar macrophages. In aggregate, our results demonstrate the effectiveness of HA functionalization as a safer design approach to eliminate MWCNT-induced lung injury and suggest that HA functionalization works by reducing MWCNT-induced epithelial injury.}, number={8}, journal={ACS NANO}, author={Hussain, Salik and Ji, Zhaoxia and Taylor, Alexia J. and DeGraff, Laura M. and George, Margaret and Tucker, Charles J. and Chang, Chong Hyun and Li, Ruibin and Bonner, James C. and Garantziotis, Stavros}, year={2016}, month={Aug}, pages={7675–7688} }
 @article{shipkowski_taylor_thompson_glista-baker_sayers_messenger_bauer_jaspers_bonner_2015, title={An allergic lung microenvironment suppresses carbon nanotube-induced inflammasome activation via STAT6-dependent inhibition of caspase-1}, volume={10}, number={6}, journal={PLoS One}, author={Shipkowski, K. A. and Taylor, A. J. and Thompson, E. A. and Glista-Baker, E. E. and Sayers, B. C. and Messenger, Z. J. and Bauer, R. N. and Jaspers, I. and Bonner, J. C.}, year={2015} }
 @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{hilton_taylor_mcclure_parsons_bonner_bereman_2015, title={Toxicoproteomic analysis of pulmonary carbon nanotube exposure using LC-MS/MS}, volume={329}, ISSN={["0300-483X"]}, url={http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000350519500009&KeyUID=WOS:000350519500009}, DOI={10.1016/j.tox.2015.01.011}, abstractNote={Toxicoproteomics is a developing field that utilizes global proteomic methodologies to investigate the physiological response as a result of adverse toxicant exposure. The aim of this study was to compare the protein secretion profile in lung bronchoalveolar lavage fluid (BALF) from mice exposed to non-functionalized multi-walled carbon nanotubes (U-MWCNTs) or MWCNTs functionalized by nanoscale Al2O3 coatings (A-MWCNT) formed using atomic layer deposition (ALD). Proteins were identified using liquid chromatography tandem mass spectrometry (LC-MS/MS), and quantified using a combination of two label-free proteomic methods: spectral counting and MS1 peak area analysis. On average 465 protein groups were identified per sample and proteins were first screened using spectral counting and the Fisher’s exact test to determine differentially regulated species. Significant proteins by Fisher’s exact test (p < 0.05) were then verified by integrating the intensity under the extracted ion chromatogram from a single unique peptide for each protein across all runs. A two sample t-test based on integrated peak intensities discovered differences in 27 proteins for control versus U-MWCNT, 13 proteins for control versus A-MWCNT, and 2 proteins for U-MWCNT versus A-MWCNT. Finally, an in-vitro binding experiment was performed yielding 4 common proteins statistically different (p < 0.05) for both the in-vitro and in-vivo study. Several of the proteins found to be significantly different between exposed and control groups are known to play a key role in inflammatory and immune response. A comparison between the in-vitro and in-vivo CNT exposure emphasized a true biological response to CNT exposure.}, journal={TOXICOLOGY}, author={Hilton, Gina M. and Taylor, Alexia J. and McClure, Christina D. and Parsons, Gregory N. and Bonner, James C. and Bereman, Michael S.}, year={2015}, month={Mar}, pages={80–87} }
 @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{walters_white_patel_davis_veluci-marlow_sunkesula_bonner_martin_gladwell_kleeberger_2014, title={Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5)}, volume={28}, ISSN={["1530-6860"]}, DOI={10.1096/fj.13-235044}, abstractNote={Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, and steel alloys. Pulmonary responses to V2O5, including dose‐dependent increases in lung permeability, inflammation, collagen content, and dysfunction, were significantly greater in DBA/2J mice compared to C57BL/6J mice. Inflammatory and fibrotic responses persisted for 4 mo in DBA/2J mice, while limited responses in C57BL/6J mice resolved. We investigated the genetic basis for differential responses through genetic mapping of V2O5‐induced lung collagen content in BXD recombinant inbred (RI) strains and identified significant linkage on chromosome 4 with candidate genes that associate with V2O5‐induced collagen content across the RI strains. Results suggest that V2O5 may induce pulmonary fibrosis through mechanisms distinct from those in other models of pulmonary fibrosis. These findings should further advance our understanding of mechanisms involved in ILD and thereby aid in identification of new therapeutic targets.—Walters, D. M., White, K. M., Patel, U., Davis, M. J., Veluci‐Marlow, R. M., Bhupanapadu Sunkesula, S. R., Bonner, J. C., Martin, J. R., Gladwell, W., Kleeberger, S. R. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5). FASEB J. 28, 1098–1112 (2014). www.fasebj.org}, number={3}, journal={FASEB JOURNAL}, author={Walters, Dianne M. and White, Kevin M. and Patel, Ushma and Davis, Martin J. and Veluci-Marlow, Roberta M. and Sunkesula, Solomon Raju Bhupanapadu and Bonner, James C. and Martin, Jessica R. and Gladwell, Wes and Kleeberger, Steven R.}, year={2014}, month={Mar}, pages={1098–1112} }
 @article{hussain_sangtian_anderson_snyder_marshburn_rice_bonner_garantziotis_2014, title={Inflammasome activation in airway epithelial cells after multi-walled carbon nanotube exposure mediates a profibrotic response in lung fibroblasts}, volume={11}, journal={Particle and Fibre Toxicology}, author={Hussain, S. and Sangtian, S. and Anderson, S. M. and Snyder, R. J. and Marshburn, J. D. and Rice, A. B. and Bonner, J. C. and Garantziotis, S.}, year={2014} }
 @article{glista-baker_taylor_sayers_thompson_bonner_2014, title={Nickel Nanoparticles cause exaggerated lung and airway remodeling in mice lacking the T-box transcription factor, TBX21 (T-bet)}, volume={11}, journal={Particle and Fibre Toxicology}, author={Glista-Baker, E. E. and Taylor, A. J. and Sayers, B. C. and Thompson, E. A. and Bonner, J. C.}, year={2014} }
 @article{meyer_bauer_letang_brighton_thompson_simmen_bonner_jaspers_2014, title={Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers}, volume={306}, ISSN={["1522-1504"]}, DOI={10.1152/ajplung.00290.2013}, abstractNote={A hallmark of cigarette smoking is a shift in the protease/antiprotease balance, in favor of protease activity. However, it has recently been shown that smokers have increased expression of a key antiprotease, secretory leukoprotease inhibitor (SLPI), yet the mechanisms involved in SLPI transcriptional regulation and functional activity of SLPI remain unclear. We examined SLPI mRNA and protein secretion in differentiated nasal epithelial cells (NECs) and nasal lavage fluid (NLF) from nonsmokers and smokers and demonstrated that SLPI expression is increased in NECs and NLF from smokers. Transcriptional regulation of SLPI expression was confirmed using SLPI promoter reporter assays followed by chromatin immunoprecipitation. The role of STAT1 in regulating SLPI expression was further elucidated using WT and stat1−/−mice. Our data demonstrate that STAT1 regulates SLPI transcription in epithelial cells and slpi protein in the lungs of mice. Additionally, we reveal that NECs from smokers have increased STAT1 mRNA/protein expression. Finally, we demonstrate that SLPI contained in the nasal mucosa of smokers is proteolytically cleaved but retains functional activity against neutrophil elastase. These results demonstrate that smoking enhances expression of SLPI in NECs in vitro and in vivo, and that this response is regulated by STAT1. In addition, despite posttranslational cleavage of SLPI, antiprotease activity against neutrophil elastase is enhanced in smokers. Together, our findings show that SLPI regulation and activity is altered in the nasal mucosa of smokers, which could have broad implications in the context of respiratory inflammation and infection.}, number={3}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY}, author={Meyer, Megan and Bauer, Rebecca N. and Letang, Blanche D. and Brighton, Luisa and Thompson, Elizabeth and Simmen, Rosalia C. M. and Bonner, James and Jaspers, Ilona}, year={2014}, month={Feb}, pages={L269–L276} }
 @article{nel_nasser_godwin_avery_bahadori_bergeson_beryt_bonner_boverhof_carter_et al._2013, title={A Multi-Stakeholder Perspective on the Use of Alternative Test Strategies for Nanomaterial Safety Assessment}, volume={7}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/NN4037927}, DOI={10.1021/NN4037927}, abstractNote={There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis.}, number={8}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Nel, Andre E. and Nasser, Elina and Godwin, Hilary and Avery, David and Bahadori, Tina and Bergeson, Lynn and Beryt, Elizabeth and Bonner, James C. and Boverhof, Darrell and Carter, Janet and et al.}, year={2013}, month={Aug}, pages={6422–6433} }
 @article{nel_nasser_godwin_avery_bahadori_bergeson_beryt_bonner_boverhof_carter_et al._2013, title={A multi-stakeholder perspective on the use of alternative test strategies for nanomaterial safety assessment}, volume={7}, number={8}, journal={ACS Nano}, author={Nel, A. E. and Nasser, E. and Godwin, H. and Avery, D. and Bahadori, T. and Bergeson, L. and Beryt, E. and Bonner, J. C. and Boverhof, D. and Carter, J. and et al.}, year={2013}, pages={6422–6433} }
 @article{interlaboratory evaluation of in vitro cytotoxicity and inflammatory responses to engineered n nanomaterials: the niehs nano go consortium_2013, volume={121}, number={6}, journal={Environmental Health Perspectives}, year={2013}, pages={683–690} }
 @article{interlaboratory evaluation of rodent pulmonary responses to engineered nanomaterials: the niehs nano go consortium_2013, volume={121}, number={6}, journal={Environmental Health Perspectives}, year={2013}, pages={676–682} }
 @article{bonner_2013, title={Nanomaterials as a potential cause of lung disease}, volume={221}, ISSN={0378-4274}, url={http://dx.doi.org/10.1016/J.TOXLET.2013.06.019}, DOI={10.1016/J.TOXLET.2013.06.019}, abstractNote={Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is a known human carcinogen. In non-smoking adults greater than 95% of BaP exposure is through diet. The carcinogenicity of BaP is utilized by the U.S. EPA to assess relative potency of complex PAH mixtures. PAH relative potency factors (RPFs, BaP = 1) are determined from high dose animal data. We employed accelerator mass spectrometry (AMS) to determine pharmacokinetics of [14C]-BaP in humans following dosing with 46 ng (an order of magnitude lower than human dietary daily exposure and million-fold lower than animal cancer models). To assess the impact of co-administration of food with a complex PAH mixture, humans were dosed with 46 ng of [14C]-BaP with or without smoked salmon. Subjects were asked to avoid high BaP-containing diets and a 3-day dietary questionnaire given to assess dietary exposure prior to dosing and three days post-dosing with [14C]-BaP. Co-administration of smoked salmon, containing a complex mixture of PAHs with an RPF of 460 ng BaPeq, reduced and delayed absorption. Administration of canned commercial salmon, containing very low amounts of PAHs, showed the impacts on pharmacokinetics were not due to high amounts of PAHs but rather a food matrix effect.}, journal={Toxicology Letters}, publisher={Elsevier BV}, author={Bonner, James C.}, year={2013}, month={Aug}, pages={S5} }
 @article{sayers_taylor_glista-baker_shipley-phillips_dackor_edin_lih_tomer_zeldin_langenbach_et al._2013, title={Role of Cyclooxygenase-2 in Exacerbation of Allergen-Induced Airway Remodeling by Multiwalled Carbon Nanotubes}, volume={49}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2013-0019oc}, abstractNote={The emergence of nanotechnology has produced a multitude of engineered nanomaterials such as carbon nanotubes (CNTs), and concerns have been raised about their effects on human health, especially for susceptible populations such as individuals with asthma. Multiwalled CNTs (MWCNTs) have been shown to exacerbate ovalbumin (OVA)-induced airway remodeling in mice. Moreover, cyclooxygenase-2 (COX-2) has been described as a protective factor in asthma. We postulated that COX-2-deficient (COX-2(-/-)) mice would be susceptible to MWCNT-induced exacerbations of allergen-induced airway remodeling, including airway inflammation, fibrosis, and mucus-cell metaplasia (i.e., the formation of goblet cells). Wild-type (WT) or COX-2(-/-) mice were sensitized to OVA to induce allergic airway inflammation before a single dose of MWCNTs (4 mg/kg) delivered to the lungs by oropharyngeal aspiration. MWCNTs significantly increased OVA-induced lung inflammation and mucus-cell metaplasia in COX-2(-/-) mice compared with WT mice. However, airway fibrosis after exposure to allergen and MWCNTs was no different between WT and COX-2(-/-) mice. Concentrations of certain prostanoids (prostaglandin D2 and thromboxane B2) were enhanced by OVA or MWCNTs in COX-2(-/-) mice. No differences in COX-1 mRNA concentrations were evident between WT and COX-2(-/-) mice treated with OVA and MWCNTs. Interestingly, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13 and IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2(-/-) mice, but not in WT mice. We conclude that exacerbations of allergen-induced airway inflammation and mucus-cell metaplasia by MWCNTs are enhanced by deficiencies in COX-2, and are associated with the activation of a mixed Th1/Th2/Th17 immune response.}, number={4}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Sayers, Brian C. and Taylor, Alexia J. and Glista-Baker, Ellen E. and Shipley-Phillips, Jeanette K. and Dackor, Ryan T. and Edin, Matthew L. and Lih, Fred B. and Tomer, Kenneth B. and Zeldin, Darryl C. and Langenbach, Robert and et al.}, year={2013}, month={Oct}, pages={525–535} }
 @article{lee_sayers_chun_lao_shipley-phillips_bonner_langenbach_2012, title={Multi-walled carbon nanotubes induce COX-2 and iNOS expression via MAP Kinase-dependent and -independent mechanisms in mouse RAW264.7 macrophages}, volume={9}, journal={Particle and Fibre Toxicology}, author={Lee, J. K. and Sayers, B. C. and Chun, K. S. and Lao, H. C. and Shipley-Phillips, J. K. and Bonner, J. C. and Langenbach, R.}, year={2012} }
 @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{zhang_newman_bonner_sannes_2012, title={Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro}, volume={265}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2012.09.008}, abstractNote={Environmental exposure to cadmium is known to cause damage to alveolar epithelial cells of the lung, impair their capacity to repair, and result in permanent structural alterations. Cell surface heparan sulfate proteoglycans (HSPGs) can modulate cell responses to injury through their interactions with soluble effector molecules. These interactions are often sulfate specific, and the removal of sulfate groups from HS side chains could be expected to influence cellular injury, such as that caused by exposure to cadmium. The goal of this study was to define the role 6-O-sulfate plays in cellular responses to cadmium exposure in two pulmonary epithelial cancer cell lines (H292 and A549) and in normal human primary alveolar type II (hAT2) cells. Sulfate levels were modified by transduced transient over-expression of 6-O-endosulfatase (HSulf-1), a membrane-bound enzyme which specifically removes 6-O-sulfate groups from HSPG side chains. Results showed that cadmium decreased cell viability and activated apoptosis pathways at low concentrations in hAT2 cells but not in the cancer cells. HSulf-1 over-expression, on the contrary, decreased cell viability and activated apoptosis pathways in H292 and A549 cells but not in hAT2 cells. When combined with cadmium, HSulf-1 over-expression further decreased cell viability and exacerbated the activation of apoptosis pathways in the transformed cells but did not add to the toxicity in hAT2 cells. The finding that HSulf-1 sensitizes these cancer cells and intensifies the injury induced by cadmium suggests that 6-O-sulfate groups on HSPGs may play important roles in protection against certain environmental toxicants, such as heavy metals.}, number={1}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Zhang, Huiying and Newman, Donna R. and Bonner, James C. and Sannes, Philip L.}, year={2012}, month={Nov}, pages={27–42} }
 @article{wang_xia_ntim_ji_lin_meng_chung_george_zhang_wang_et al._2011, title={Dispersal State of Multiwalled Carbon Nanotubes Elicits Profibrogenic Cellular Responses That Correlate with Fibrogenesis Biomarkers and Fibrosis in the Murine Lung}, volume={5}, ISSN={["1936-086X"]}, DOI={10.1021/nn2033055}, abstractNote={We developed a dispersal method for multiwalled carbon nanotubes (MWCNTs) that allows quantitative assessment of dispersion on profibrogenic responses in tissue culture cells and in mouse lung. We demonstrate that the dispersal of as-prepared (AP), purified (PD), and carboxylated (COOH) MWCNTs by bovine serum albumin (BSA) and dipalmitoylphosphatidylcholine (DPPC) influences TGF-β1, PDGF-AA, and IL-1β production in vitro and in vivo. These biomarkers were chosen based on their synergy in promoting fibrogenesis and cellular communication in the epithelial-mesenchymal cell trophic unit in the lung. The effect of dispersal was most noticeable in AP- and PD-MWCNTs, which are more hydrophobic and unstable in aqueous buffers than hydrophilic COOH-MWCNTs. Well-dispersed AP- and PD-MWCNTs were readily taken up by BEAS-2B, THP-1 cells, and alveolar macrophages (AM) and induced more prominent TGF-β1 and IL-1β production in vitro and TGF-β1, IL-1β, and PDGF-AA production in vivo than nondispersed tubes. Moreover, there was good agreement between the profibrogenic responses in vitro and in vivo as well as the ability of dispersed tubes to generate granulomatous inflammation and fibrosis in airways. Tube dispersal also elicited more robust IL-1β production in THP-1 cells. While COOH-MWCNTs were poorly taken up in BEAS-2B and induced little TGF-β1 production, they were bioprocessed by AM and induced less prominent collagen deposition at sites of nongranulomatous inflammation in the alveolar region. Taken together, these results indicate that the dispersal state of MWCNTs affects profibrogenic cellular responses that correlate with the extent of pulmonary fibrosis and are of potential use to predict pulmonary toxicity.}, number={12}, journal={ACS NANO}, author={Wang, Xiang and Xia, Tian and Ntim, Susana Addo and Ji, Zhaoxia and Lin, Sijie and Meng, Huan and Chung, Choong-Heui and George, Saji and Zhang, Haiyuan and Wang, Meiying and et al.}, year={2011}, month={Dec}, pages={9772–9787} }
 @misc{mossman_lippmann_hesterberg_kelsey_barchowsky_bonner_2011, title={PULMONARY ENDPOINTS (LUNG CARCINOMAS AND ASBESTOSIS) FOLLOWING INHALATION EXPOSURE TO ASBESTOS}, volume={14}, ISSN={["1521-6950"]}, DOI={10.1080/10937404.2011.556047}, abstractNote={Lung carcinomas and pulmonary fibrosis (asbestosis) occur in asbestos workers. Understanding the pathogenesis of these diseases is complicated because of potential confounding factors, such as smoking, which is not a risk factor in mesothelioma. The modes of action (MOA) of various types of asbestos in the development of lung cancers, asbestosis, and mesotheliomas appear to be different. Moreover, asbestos fibers may act differentially at various stages of these diseases, and have different potencies as compared to other naturally occurring and synthetic fibers. This literature review describes patterns of deposition and retention of various types of asbestos and other fibers after inhalation, methods of translocation within the lung, and dissolution of various fiber types in lung compartments and cells in vitro. Comprehensive dose-response studies at fiber concentrations inhaled by humans as well as bivariate size distributions (lengths and widths), types, and sources of fibers are rarely defined in published studies and are needed. Species-specific responses may occur. Mechanistic studies have some of these limitations, but have suggested that changes in gene expression (either fiber-catalyzed directly or by cell elaboration of oxidants), epigenetic changes, and receptor-mediated or other intracellular signaling cascades may play roles in various stages of the development of lung cancers or asbestosis.}, number={1-4}, journal={JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS}, author={Mossman, Brooke T. and Lippmann, Morton and Hesterberg, Thomas W. and Kelsey, Karl T. and Barchowsky, Aaron and Bonner, James C.}, year={2011}, pages={76–121} }
 @article{cesta_ryman-rasmussen_wallace_masinde_hurlburt_taylor_bonner_2010, title={Bacterial Lipopolysaccharide Enhances PDGF Signaling and Pulmonary Fibrosis in Rats Exposed to Carbon Nanotubes}, volume={43}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2009-0113oc}, abstractNote={Engineered multi-walled carbon nanotubes (MWCNT) represent a possible health risk for pulmonary fibrosis due to their fiber-like shape and potential for persistence in the lung. We postulated that bacterial lipopolysaccharide (LPS), a ubiquitous agent in the environment that causes lung inflammation, would enhance fibrosis caused by MWCNT. Rats were exposed to LPS and then intratracheally instilled with MWCNT or carbon black (CB) nanoparticles 24 hours later. Pulmonary fibrosis was observed 21 days after MWCNT exposure, but not with CB. LPS alone caused no fibrosis but enhanced MWCNT-induced fibrosis. LPS plus CB did not significantly increase fibrosis. MWCNT increased platelet-derived growth factor-AA (PDGF-AA), a major mediator of fibrosis. PDGF-AA production in response to MWCNT, but not CB, was synergistically enhanced by LPS. Immunostaining showed PDGF-AA in bronchiolar epithelial cells and macrophages. Since macrophages engulfed MWCNT, were positive for PDGF-AA, and mediate fibroblast responses, experiments were performed with rat lung macrophages (NR8383 cells) and rat lung fibroblasts in vitro. LPS exposure increased PDGF-A mRNA levels in NR8383 cells and enhanced MWCNT-induced PDGF-A mRNA levels. Moreover, LPS increased MWCNT- or CB-induced PDGF receptor-alpha (PDGF-Ralpha) mRNA in fibroblasts. Our data suggest that LPS exacerbates MWCNT-induced lung fibrosis by amplifying production of PDGF-AA in macrophages and epithelial cells, and by increasing PDGF-Ralpha on pulmonary fibroblasts. Our findings also suggest that individuals with pre-existing pulmonary inflammation are at greater risk for the potential adverse effects of MWCNT.}, number={2}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Cesta, Mark F. and Ryman-Rasmussen, Jessica P. and Wallace, Duncan G. and Masinde, Tiwanda and Hurlburt, Geoffrey and Taylor, Alexia J. and Bonner, James C.}, year={2010}, month={Aug}, pages={142–151} }
 @article{turpin_antao-menezes_cesta_mangum_wallace_bermudez_bonner_2010, title={Respiratory syncytial virus infection reduces lung inflammation and fibrosis in mice exposed to vanadium pentoxide}, volume={11}, ISSN={["1465-993X"]}, DOI={10.1186/1465-9921-11-20}, abstractNote={Vanadium pentoxide (V2O5) exposure is a cause of occupational bronchitis and airway fibrosis. Respiratory syncytial virus (RSV) is a ubiquitous pathogen that causes airway inflammation. It is unknown whether individuals with pre-existing respiratory viral infection are susceptible to V2O5-induced bronchitis. We hypothesized that respiratory viral infection will exacerbate vanadium-induced lung fibrosis.In this study we investigated the effect of RSV pre- or post-exposure to V2O5 in male AKR mice. Mice were pre-exposed by intranasal aspiration to RSV or media vehicle prior to intranasal aspiration of V2O5 or saline vehicle at day 1 or day 7. A parallel group of mice were treated first with V2O5 or saline vehicle at day 1 and day 7 then post-exposed to RSV or media vehicle at day 8.V2O5-induced airway inflammation and fibrosis were decreased by RSV pre- or post-exposure. Real time quantitative RT-PCR showed that V2O5 significantly increased lung mRNAs encoding pro-fibrogenic growth factors (TGF-beta1, CTGF, PDGF-C) and collagen (Col1A2), but also increased mRNAs encoding anti-fibrogenic type I interferons (IFN-alpha, -beta) and IFN-inducible chemokines (CXCL9 and CXCL10). RSV pre- or post-exposure caused a significantly reduced mRNAs of pro-fibrogenic growth factors and collagen, yet reduced RNA levels of anti-fibrogenic interferons and CXC chemokines.Collectively these data suggest that RSV infection reduces the severity of V2O5-induced fibrosis by suppressing growth factors and collagen genes. However, RSV suppression of V2O5-induced IFNs and IFN-inducible chemokines suggests that viral infection also suppresses the innate immune response that normally serves to resolve V2O5-induced fibrosis.}, journal={RESPIRATORY RESEARCH}, author={Turpin, Elizabeth A. and Antao-Menezes, Aurita and Cesta, Mark F. and Mangum, James B. and Wallace, Duncan G. and Bermudez, Edilberto and Bonner, James C.}, year={2010}, month={Feb} }
 @article{ryman-rasmussen_tewksbury_moss_cesta_wong_bonner_2009, title={Inhaled Multiwalled Carbon Nanotubes Potentiate Airway Fibrosis in Murine Allergic Asthma}, volume={40}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2008-0276OC}, abstractNote={Carbon nanotubes are gaining increasing attention due to possible health risks from occupational or environmental exposures. This study tested the hypothesis that inhaled multiwalled carbon nanotubes (MWCNT) would increase airway fibrosis in mice with allergic asthma. Normal and ovalbumin-sensitized mice were exposed to a MWCNT aerosol (100 mg/m(3)) or saline aerosol for 6 hours. Lung injury, inflammation, and fibrosis were examined by histopathology, clinical chemistry, ELISA, or RT-PCR for cytokines/chemokines, growth factors, and collagen at 1 and 14 days after inhalation. Inhaled MWCNT were distributed throughout the lung and found in macrophages by light microscopy, but were also evident in epithelial cells by electron microscopy. Quantitative morphometry showed significant airway fibrosis at 14 days in mice that received a combination of ovalbumin and MWCNT, but not in mice that received ovalbumin or MWCNT only. Ovalbumin-sensitized mice that did not inhale MWCNT had elevated levels IL-13 and transforming growth factor (TGF)-beta1 in lung lavage fluid, but not platelet-derived growth factor (PDGF)-AA. In contrast, unsensitized mice that inhaled MWCNT had elevated PDGF-AA, but not increased levels of TGF-beta1 and IL-13. This suggested that airway fibrosis resulting from combined ovalbumin sensitization and MWCNT inhalation requires PDGF, a potent fibroblast mitogen, and TGF-beta1, which stimulates collagen production. Combined ovalbumin sensitization and MWCNT inhalation also synergistically increased IL-5 mRNA levels, which could further contribute to airway fibrosis. These data indicate that inhaled MWCNT require pre-existing inflammation to cause airway fibrosis. Our findings suggest that individuals with pre-existing allergic inflammation may be susceptible to airway fibrosis from inhaled MWCNT.}, number={3}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Ryman-Rasmussen, Jessica P. and Tewksbury, Earl W. and Moss, Owen R. and Cesta, Mark F. and Wong, Brian A. and Bonner, James C.}, year={2009}, month={Mar}, pages={349–358} }
 @article{ryman-rasmussen_cesta_brody_shipley-phillips_everitt_tewksbury_moss_wong_dodd_andersen_et al._2009, title={Inhaled carbon nanotubes reach the subpleural tissue in mice}, volume={4}, ISSN={["1748-3395"]}, DOI={10.1038/NNANO.2009.305}, abstractNote={Carbon nanotubes are shaped like fibres and can stimulate inflammation at the surface of the peritoneum when injected into the abdominal cavity of mice, raising concerns that inhaled nanotubes may cause pleural fibrosis and/or mesothelioma. Here, we show that multiwalled carbon nanotubes reach the subpleura in mice after a single inhalation exposure of 30 mg m(-3) for 6 h. Nanotubes were embedded in the subpleural wall and within subpleural macrophages. Mononuclear cell aggregates on the pleural surface increased in number and size after 1 day and nanotube-containing macrophages were observed within these foci. Subpleural fibrosis unique to this form of nanotubes increased after 2 and 6 weeks following inhalation. None of these effects was seen in mice that inhaled carbon black nanoparticles or a lower dose of nanotubes (1 mg m(-3)). This work suggests that minimizing inhalation of nanotubes during handling is prudent until further long-term assessments are conducted.}, number={11}, journal={NATURE NANOTECHNOLOGY}, author={Ryman-Rasmussen, Jessica P. and Cesta, Mark F. and Brody, Arnold R. and Shipley-Phillips, Jeanette K. and Everitt, Jeffrey I. and Tewksbury, Earl W. and Moss, Owen R. and Wong, Brian A. and Dodd, Darol E. and Andersen, Melvin E. and et al.}, year={2009}, month={Nov}, pages={747–751} }
 @article{bonner_card_zeldin_2009, title={Nanoparticle-Mediated Drug Delivery and Pulmonary Hypertension}, volume={53}, ISSN={["1524-4563"]}, DOI={10.1161/hypertensionaha.108.122846}, abstractNote={Nanotechnology offers great potential benefits for drug delivery and therapy of respiratory and systemic diseases. Nanoparticles (NPs) have been of significant interest for some time because they can be designed to simultaneously carry a drug payload, specifically target features of diseased tissues, and carry an imaging molecule to track drug accumulation and clearance in tissues. Moreover, they can be engineered to tailor drug delivery and improve pharmacokinetics. A variety of NPs have been investigated in experimental animal models as tools to improve the delivery and therapeutic efficacy of drugs or genes delivered to the lung or other organ systems.1 The nanotechnology platform for drug delivery contains a number of very different types of nanostructures with widely varying properties. Examples of these NPs include dendrimers, fullerenes, carbon nanotubes, and polymeric NPs.

In this issue of Hypertension , Kimura et al2 report that nuclear factor κB (NF-κB) decoy oligodeoxynucleotides (ODNs) encapsulated in poly-(ethylene glycol)- block -lactide/glycolide copolymer NPs and delivered to the lungs of rats by intratracheal instillation reduced pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). They showed that NP-encapsulated NF-κB decoy, visualized by fluorescein isothiocyanate labeling, reached the distal regions of the lungs and was present in alveolar macrophages and small pulmonary arteries for ≤14 days after a single instillation. The small pulmonary arteries were also found to be a site of NF-κB activation and NF-κB–dependent inflammatory cytokine production (monocyte chemoattractant protein 1, interleukin 1, and tumor necrosis factor α) in patients with PAH and in rats with MCT-induced PAH. The decoy ODNs, unlike antisense ODNs, which bind specific regions in mRNA, bind directly to the transcription factor and inhibit transcription factor binding to target DNA and initiation of gene transcription (Figure). It was speculated by the authors that cellular uptake of the NPs might slowly release encapsulated …}, number={5}, journal={HYPERTENSION}, author={Bonner, James C. and Card, Jeffrey W. and Zeldin, Darryl C.}, year={2009}, month={May}, pages={751–753} }
 @article{voltz_card_carey_degraff_ferguson_flake_bonner_korach_zeldin_2008, title={Male sex hormones exacerbate lung function impairment after bleomycin-induced pulmonary fibrosis}, volume={39}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2007-0340OC}, abstractNote={The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P < 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P < 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.}, number={1}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Voltz, James W. and Card, Jeffrey W. and Carey, Michelle A. and DeGraff, Laura M. and Ferguson, Catherine D. and Flake, Gordon P. and Bonner, James C. and Korach, Kenneth S. and Zeldin, Darryl C.}, year={2008}, month={Jul}, pages={45–52} }
 @misc{card_zeldin_bonner_nestmann_2008, title={Pulmonary applications and toxicity of engineered nanoparticles}, volume={295}, ISSN={["1522-1504"]}, DOI={10.1152/ajplung.00041.2008}, abstractNote={ Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity. }, number={3}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY}, author={Card, Jeffrey W. and Zeldin, Darryl C. and Bonner, James C. and Nestmann, Earle R.}, year={2008}, month={Sep}, pages={L400–L411} }
 @article{antao-menezes_turpin_bost_ryman-rasmussen_bonner_2008, title={STAT-1 signaling in human lung fibroblasts is induced by vanadium pentoxide through an IFN-beta autocrine loop}, volume={180}, ISSN={["1550-6606"]}, DOI={10.4049/jimmunol.180.6.4200}, abstractNote={Abstract}, number={6}, journal={JOURNAL OF IMMUNOLOGY}, author={Antao-Menezes, Aurita and Turpin, Elizabeth A. and Bost, Phillip C. and Ryman-Rasmussen, Jessica P. and Bonner, James C.}, year={2008}, month={Mar}, pages={4200–4207} }
 @article{bonner_2007, title={Lung Fibrotic Responses to Particle Exposure}, volume={35}, ISSN={0192-6233 1533-1601}, url={http://dx.doi.org/10.1080/01926230601060009}, DOI={10.1080/01926230601060009}, abstractNote={Particles generated from numerous anthropogenic sources have the potential to cause or exacerbate lung diseases, including asthma, bronchitis, and COPD. Fibrotic reactions are a component of all of these pulmonary diseases, and involve the progressive deposition of collagen by pulmonary fibroblasts. The reactivity, toxicity, and fibrogenic potential of particles in the lung depends on a variety of factors including particle size, surface area, and composition. Smaller particles, particularly in the nanosized range, have more toxic and fibrogenic capacity due to a higher surface-to-mass ratio and greater oxidant-generating potential. Composition is also an important determinant in the fibrotic response to particles. Transition metals, bacterial lipopolysaccaride, and polycyclic aromatic hydrocarbons are some of the toxic components of particles that activate intracellular signaling pathways that culminate in the production of profibrotic cytokines and growth factors.}, number={1}, journal={Toxicologic Pathology}, publisher={SAGE Publications}, author={Bonner, James C.}, year={2007}, month={Jan}, pages={148–153} }
 @article{walters_antao-menezes_ingram_rice_nyska_tani_kleeberger_bonner_2005, title={Susceptibility of Signal Transducer and Activator of Transcription-1-Deficient Mice to Pulmonary Fibrogenesis}, volume={167}, ISSN={0002-9440}, url={http://dx.doi.org/10.1016/S0002-9440(10)61210-2}, DOI={10.1016/S0002-9440(10)61210-2}, abstractNote={The signal transducer and activator of transcription (Stat)-1 mediates growth arrest and apoptosis.We postulated that lung fibrosis characterized by excessive proliferation of lung fibroblasts would be enhanced in Stat1-deficient (Stat1 ؊/؊ ) mice.Two weeks after bleomycin aspiration (3 U/kg) , Stat1 ؊/؊ mice exhibited a more severe fibroproliferative response and significantly elevated total lung collagen compared to wild-type mice.Growth factors [epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)] enhanced [ 3 H]thymidine uptake in lung fibroblasts isolated from Stat1 ؊/؊ mice compared to wildtype mice.Interferon (IFN)-␥, which signals growth arrest via Stat1 , inhibited EGF-or PDGF-stimulated mitogenesis in wild-type fibroblasts but enhanced [ 3 H]thymidine uptake in Stat1 ؊/؊ fibroblasts.Moreover , IFN-␥ treatment in the absence of growth factors induced a concentration-dependent increase in [ 3 H]thymidine uptake in Stat1 ؊/؊ but not wild-type fibroblasts.Mitogen-activated protein kinase (ERK-1/2) phosphorylation in response to PDGF or EGF did not differ among Stat1 ؊/؊ and wild-type fibroblasts.However , Stat3 phosphorylation induced by PDGF, EGF , or IFN-␥ increased twofold in Stat1 ؊/؊ fibroblasts compared to wild-type fibroblasts.Our findings indicate that Stat1 ؊/؊ mice are more susceptible to bleomycin-induced lung fibrosis than wild-type mice due to 1) enhanced fibroblast proliferation in response to growth factors (EGF and PDGF) , 2) stimulation of fibroblast growth by a Stat1-independent IFN-␥ signaling pathway, and 3) increased activation of Stat3.}, number={5}, journal={The American Journal of Pathology}, publisher={Elsevier BV}, author={Walters, Dianne M. and Antao-Menezes, Aurita and Ingram, Jennifer L. and Rice, Annette B. and Nyska, Abraham and Tani, Yoshiro and Kleeberger, Steven R. and Bonner, James C.}, year={2005}, month={Nov}, pages={1221–1229} }
 @article{bonner_2004, title={Regulation of PDGF and its receptors in fibrotic diseases}, volume={15}, ISSN={1359-6101}, url={http://dx.doi.org/10.1016/j.cytogfr.2004.03.006}, DOI={10.1016/j.cytogfr.2004.03.006}, abstractNote={Platelet-derived growth factor (PDGF) isoforms play a major role in stimulating the replication, survival, and migration of myofibroblasts during the pathogenesis of fibrotic diseases. During fibrogenesis, PDGF is secreted by a variety of cell types as a response to injury, and many pro-inflammatory cytokines mediate their mitogenic effects via the autocrine release of PDGF. PDGF action is determined by the relative expression of PDGF alpha-receptors (PDGFRalpha) and beta-receptors (PDGFRbeta) on the surface of myofibroblasts. These receptors are induced during fibrogenesis, thereby amplifying biological responses to PDGF isoforms. PDGF action is also modulated by extracellular binding proteins and matrix molecules. This review summarizes the literature on the role of PDGF and its receptors in the development of fibrosis in a variety of organ systems, including lung, liver, kidney, and skin.}, number={4}, journal={Cytokine & Growth Factor Reviews}, publisher={Elsevier BV}, author={Bonner, James C}, year={2004}, month={Aug}, pages={255–273} }
 @article{booth_bonner_adler_martin_2001, title={Autocrine production of TGFa mediates interleukin 13-induced proliferation of human airway epithelial cells during development of a mucous phenotype in vitro.}, volume={163}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Booth, B. and Bonner, J. C. and Adler, K. B. and Martin, L. D.}, year={2001}, pages={A738} }
 @inbook{martin_macchione_bonner_booth_akley_adler_2001, title={Interleukin-13 induced mucous cell hyperplasia in airway epithelium.}, booktitle={Cilia and mucus: from development to respiratory disease.}, author={Martin, L. D. and Macchione, M. and Bonner, J. C. and Booth, B. W. and Akley, N. J. and Adler, K. B.}, year={2001}, pages={253–263} }
 @article{bonner_zhang_sannes_martin_gladwell_koo_gray_adler_2000, title={Induction of heparin-binding epidermal growth factor (HB-EGF) mRNA in normal human bronchial epithelial cells by metal-induced oxidative stress.}, volume={161}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Bonner, J. C. and Zhang, L. and Sannes, P. and Martin, L. and Gladwell, W. and Koo, J.-S. and Gray, T. and Adler, K.}, year={2000}, pages={A149} }
 @article{martin_bonner_macchione_booth_akley_adler_2000, title={Interaction of TGF? and EGF receptor mediates IL-13 induced mucous cell hyperplasia in human airway epithelium in vitro.}, volume={161}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Martin, L. D. and Bonner, J. C. and Macchione, M. and Booth, B. and Akley, N. and Adler, K. B.}, year={2000}, pages={A779} }
 @article{zhang_adler_sannes_bonner_1999, title={Normal human bronchial epithelial cells produce heparin-binding epidermal growth factor (HB-EGF), a mitogen for human lung fibroblasts in vitro.}, volume={159}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Zhang, L. and Adler, K. B. and Sannes, P. and Bonner, J. C.}, year={1999}, pages={A508} }