@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{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{cesta_baty_keene_smoak_malarkey_2005, title={Pathology of end-stage remodeling in a family of cats with hypertrophic cardiomyopathy}, volume={42}, ISSN={["1544-2217"]}, DOI={10.1354/vp.42-4-458}, abstractNote={ End-stage hypertrophic cardiomyopathy (ES-HCM), affecting 5-10% of human hypertrophic cardiomyopathy (HCM) patients, is characterized by relative thinning of the ventricular walls and septum with dilation of the ventricular lumen, decreased fractional shortening, and progression to heart failure. C. J. Baty and others recently documented similar progressive changes to ES-HCM in a family of four cats through serial echocardiograms. At the time of heart failure, these cats exhibited changes similar to those exhibited by human ES-HCM patients. Our objectives were to describe the pathologic alterations associated with ES-HCM and investigate the pathogenesis in three of the four cats. Grossly, there was left atrial dilation with relative thinning of the interventricular septum (IVS) and left ventricular free wall (LVFW). The left atrium contained large thrombi in two of the three cats, and all three cats died following thromboembolization of the aortic bifurcation. Histologically, all three cats had subendocardial and myocardial fibrosis, predominantly of the IVS and LVFW, and one cat had acute, multifocal, myocardial infarcts with mononuclear inflammatory cell infiltrates. The pathogenesis of ES-HCM is uncertain, but theories implicate occlusion of the coronary blood flow by thickening of the coronary vessels, coronary vascular thromboembolism or coronary vessel spasm, apoptosis of myocytes, and myocardial hypertrophy beyond the ability of the vasculature to supply blood. Apoptosis assays did not reveal any apoptotic myocytes. Considering the hypercoagulative state of these cats, coronary vascular thromboembolism could be a major contributing factor. We cannot exclude apoptosis or coronary vessel spasm on the basis of the data presented. }, number={4}, journal={VETERINARY PATHOLOGY}, author={Cesta, MF and Baty, CJ and Keene, BW and Smoak, IW and Malarkey, DE}, year={2005}, month={Jul}, pages={458–467} }
 @article{ellinwood_wang_skeen_sharp_cesta_decker_edwards_bublot_thompson_bush_et al._2003, title={A model of mucopolysaccharidosis IIIB (Sanfilippo syndrome type IIIB): N-acetyl-alpha-D-glucosaminidase deficiency in Schipperke dogs}, volume={26}, ISSN={["0141-8955"]}, DOI={10.1023/A:1025177411938}, abstractNote={Abstract}, number={5}, journal={JOURNAL OF INHERITED METABOLIC DISEASE}, author={Ellinwood, NM and Wang, P and Skeen, T and Sharp, NJH and Cesta, M and Decker, S and Edwards, NJ and Bublot, I and Thompson, JN and Bush, W and et al.}, year={2003}, pages={489–504} }
 @article{li_newman_cesta_tompkins_khosla_sannes_2003, title={Modulation of fibroblast growth factor expression and signal transduction in type II cells}, volume={123}, ISSN={["0012-3692"]}, DOI={10.1378/chest.123.3_suppl.429S}, abstractNote={repair and wound healing. PDGFs are synthesized and secreted by most inflammatory cell types present within the milieu of the asthmatic airway. We have previously reported that airway fibroblasts from severe asthmatics produce more type I procollagen in response to PDGF stimulation as compared to patients with mild asthma and normal control subjects; therefore, we hypothesized that the enhanced responsiveness to PDGFs in patients with severe asthma is linked to an increased expression of PDGF receptors. In an ongoing study, 5 subjects with severe asthma, 10 subjects with mild-to-moderate asthma, and 6 normal control subjects underwent bronchoscopy with endobronchial biopsy. Biopsies were placed in Dulbecco’s modified Eagle’s serum supplemented with fetal bovine serum (10%), streptomycin (100 g/mL), penicillin (10,000 U/mL), and gentamicin (100 g/mL), and cultured until fibroblast growth was established at 50% confluency (approximately 8 to 20 days). Immunostaining with vimentin (Dako; Carpenteria, CA), Ab-1 (Calbiochem; San Diego, CA) and -smooth muscle actin (Dako) confirmed fibroblast identity. To determine baseline fibroblast expression of PDGF receptors (PDGFRs) [PDGFRand PDGFR], we developed a sandwich enzyme-linked immunosorbent assay for these receptors that quantifies receptor protein levels in fibroblast cell lysates. Receptor protein levels were expressed in nanograms per 100 g of total cell protein. There were no significant differences in baseline expression of PDGFRbetween the groups (severe, 7.6 ng/100 g protein; mild to moderate, 12.50 ng/100 g protein; normal control, 11.33 ng/100 g protein; p 0.35). However, there was a significantly greater baseline expression of PDGFRin the severe asthmatic group, as compared to both the mild/moderate asthmatic and normal control groups (severe, 15.20 ng/100 g protein; mild-to-moderate, 13.30 ng/100 g protein; normal control, 3.67 ng/100 g protein; p 0.0024). Our data suggests that airway fibroblasts from severe asthmatics may be of a synthetic phenotype, with altered capabilities in collagen production, as compared to those from patients with mild-to-moderate asthma and normal control subjects, and this may be driven by an increased expression of PDGFR. Modulation of Fibroblast Growth Factor Expression and Signal Transduction in Type II Cells*}, number={3}, journal={CHEST}, author={Li, CM and Newman, D and Cesta, M and Tompkins, L and Khosla, J and Sannes, PL}, year={2003}, month={Mar}, pages={429S–429S} }