@article{lin_degan_theriot_fischer_strachan_liang_pierce_sunday_noble_kraft_et al._2012, title={Chronic treatment in vivo with beta-adrenoceptor agonists induces dysfunction of airway beta(2)-adrenoceptors and exacerbates lung inflammation in mice}, volume={165}, ISSN={["1476-5381"]}, DOI={10.1111/j.1476-5381.2011.01725.x}, abstractNote={BACKGROUND AND PURPOSE Inhalation of a β‐adrenoceptor agonist (β‐agonist) is first‐line asthma therapy, used for both prophylaxis against, and acute relief of, bronchoconstriction. However, repeated clinical use of β‐agonists leads to impaired bronchoprotection and, in some cases, adverse patient outcomes. Mechanisms underlying this β2‐adrenoceptor dysfunction are not well understood, due largely to the lack of a comprehensive animal model and the uncertainty as to whether or not bronchorelaxation in mice is mediated by β2‐adrenoceptors. Thus, we aimed to develop a mouse model that demonstrated functional β‐agonist‐induced β2‐adrenoceptor desensitization in the context of allergic inflammatory airway disease.}, number={7}, journal={BRITISH JOURNAL OF PHARMACOLOGY}, author={Lin, Rui and Degan, Simone and Theriot, Barbara S. and Fischer, Bernard M. and Strachan, Ryan T. and Liang, Jiurong and Pierce, Richard A. and Sunday, Mary E. and Noble, Paul W. and Kraft, Monica and et al.}, year={2012}, month={Apr}, pages={2365–2377} }
 @article{krunkosky_fischer_martin_jones_akley_adler_2000, title={Effects of TNF-alpha on expression of ICAM-1 in human airway epithelial cells in vitro - Signaling pathways controlling surface and gene expression}, volume={22}, ISSN={["1535-4989"]}, DOI={10.1165/ajrcmb.22.6.3925}, abstractNote={Signaling pathways associated with tumor necrosis factor (TNF)- α –induced intercellular adhesion molecule 1 (ICAM-1) surface and gene expression were investigated in well differentiated normal human bronchial epithelial (NHBE) cells in air–liquid interface primary culture. Cells were exposed to human recombinant TNF- α (hrTNF- α ; 0.015 to 150 ng/ml [specific activity, 2.86 × 107 U/mg]). TNF- α enhanced ICAM-1 surface expression (measured by flow cytometry) and steady-state messenger RNA (mRNA) levels (assessed by Northern hybridization) in concentration- and time-dependent manners. TNF- α –induced ICAM-1 surface and gene expression were both blocked by the RNA polymerase II inhibitor actinomycin D (0.1 μ g/ml), and surface expression was attenuated by a neutralizing monoclonal antibody directed against the TNF- α receptor p55 (TNF-RI). The intracellular signaling pathway leading to enhanced expression appeared to involve activation of a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC) becaus...}, number={6}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Krunkosky, TM and Fischer, BM and Martin, LD and Jones, N and Akley, NJ and Adler, KB}, year={2000}, month={Jun}, pages={685–692} }
 @article{fischer_rochelle_voynow_akley_adler_1999, title={Tumor necrosis factor-alpha stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cells in vitro}, volume={20}, ISSN={["1044-1549"]}, DOI={10.1165/ajrcmb.20.3.3393}, abstractNote={Tumor necrosis factor (TNF)-alpha, a pluripotent cytokine implicated in the pathogenesis of airway inflammation, has been shown to provoke hypersecretion of mucin by airway epithelial cells in vitro. In this study, we investigated potential signaling pathways mediating TNF-alpha-induced mucin secretion using guinea pig tracheal epithelial (GPTE) cells in air-liquid interface culture. Exogenously applied TNF-alpha (human recombinant) stimulated mucin secretion in a concentration-dependent manner, with maximal effects at 10 to 15 ng/ml (286 to 429 U/ml). The pathway of stimulated secretion appeared to involve generation of intracellular nitric oxide (NO), activation of soluble guanylate cyclase (GC-S), production of cyclic guanosine monophosphate (cGMP), and activation of cGMP-dependent protein kinase (PKG). TNF-alpha increased production of nitrite and nitrate by GPTE cells; both mucin secretion and cGMP production were attenuated by NG-monomethyl-L-arginine (1 mM), a competitive inhibitor of nitric oxide synthase (NOS), or by the GC-S inhibitor LY83583 (50 microM); and mucin secretion in response to TNF-alpha or to the cGMP analogue dibutyryl cGMP (100 and 500 microM) was attenuated by the specific PKG inhibitor KT5823 (1 microM). Increased mucin secretion and increased cGMP production in response to TNF-alpha both appeared to be mediated by a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC), and by protein kinase C (PKC), since both responses were attenuated by either D609 (10 and 20 microg/ml), a specific PC-PLC inhibitor, or by each of three PKC inhibitors: Calphostin C (0.3 and 0.5 microM), bisindoylmaleimide (GF 109203X, Go 6850; 20 nM), or Ro31-8220 (10 microM). Collectively, the results suggest that TNF-alpha stimulates secretion of mucin by GPTE cells via a mechanism(s) dependent on PC-PLC and PKC, and involving activation of NOS, generation of NO, production of cGMP, and activation of PKG.}, number={3}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Fischer, BM and Rochelle, LG and Voynow, JA and Akley, NJ and Adler, KB}, year={1999}, month={Mar}, pages={413–422} }
 @article{rochelle_fischer_adler_1998, title={Concurrent production of reactive oxygen and nitrogen species by airway epithelial cells in vitro}, volume={24}, ISSN={["0891-5849"]}, DOI={10.1016/S0891-5849(97)00375-4}, abstractNote={Intracellularly generated reactive species of both oxygen (ROS) and nitrogen (RNS) have been implicated in signaling responses in airway epithelial cells, but these radicals have not been measured directly in such cells. In this study, intracellular production of both ROS and RNS were measured in the same cell lysates of guinea pig tracheal epithelial (GPTE) cells maintained in primary culture. ROS and RNS were quantified under basal (constitutive) conditions and in response to different stimuli: LPS and TNFα [activators of inducible nitric oxide synthase (iNOS)]; several activators of calcium-dependent cNOS (ATP, bradykinin, ionophore A23187, and thapsigargin); and exogenous oxidant stress generated by addition of xanthine oxidase to purine (p + XO). Studies with LPS and TNFα also were performed using the murine macrophage cell line, RAW 264.7, as a positive control. Intracellular oxidant production was detected from oxidation of dihydrorhodamine to rhodamine. NOx was quantified by either chemiluminescent or fluorescent detection. NOS activity was measured as citrulline production from arginine. Basal production of oxidants by GPTE cells (0.08 + 0.00 nmol rhodamine) was less than 10% that of RAW.267 cells (0.91 + 0.03 nmol rhodamine). TNFα and LPS significantly increased intracellular oxidant production in GPTE cells, as did p + XO, but none of the cNOS activators affected production of oxidants in these cells. Concentrations of NO2 after 4 h in unstimulated RAW 264.7 and GPTE cells were similar and comprised 63% of total NOx in GPTE and 62% in RAW cells. TNFα and LPS both increased NO2 in GPTE cells, but none of the Ca++-mobilizing agents nor p + XO significantly affected intracellular RNS. The results suggest both ROS and RNS can be measured in the same lysates from airway epithelial cells, and that both ROS and RNS are produced in these cells in response to different stimuli.}, number={5}, journal={FREE RADICAL BIOLOGY AND MEDICINE}, author={Rochelle, LG and Fischer, BM and Adler, KB}, year={1998}, month={Mar}, pages={863–868} }
 @misc{martin_rochelle_fischer_krunkosky_adler_1997, title={Airway epithelium as an effector of inflammation: molecular regulation of secondary mediators}, volume={10}, ISSN={["0903-1936"]}, DOI={10.1183/09031936.97.10092139}, abstractNote={Deleterious environmental stimuli cause the airway epithelium to respond with increased secretions of mucus, reaction of oxygen/nitrogen species, changes in ciliary beating, and the influx of inflammatory cells. The epithelium is a target for factors released by infiltrating inflammatory cells, and has recently been shown to serve as an effector of such inflammation. Molecular mechanisms regulating production of secondary inflammatory mediators (cytokines, lipid mediators, and reactive oxygen/nitrogen species) have yet to be fully described. This report reviews the production of secondary mediators by epithelial cells and by airway epithelium. Lipid mediators are enzymatically produced by the airway epithelium in response to primary mediators. Molecular mechanisms regulating the production of cyclo-oxygenase, lipoxygenase and prostaglandin synthase are discussed, along with the potential of lipid mediators to produce inflammation. The molecular regulation of nitric oxide production is also described in the context of its role as a signalling molecule in pathways regulating secretion of mucus, ciliary motion, and intercellular adhesion molecule-1 (ICAM-1) expression. The production of cytokines by the airway epithelium is shown to play a role in causing inflammation associated with respiratory diseases. Particular attention is paid to molecular mechanisms governing the expression of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL-8).}, number={9}, journal={EUROPEAN RESPIRATORY JOURNAL}, author={Martin, LD and Rochelle, LG and Fischer, BM and Krunkosky, TM and Adler, KB}, year={1997}, month={Sep}, pages={2139–2146} }
 @article{martin_krunkosky_dye_fischer_jiang_rochelle_akley_dreher_adler_1997, title={The role of reactive oxygen and nitrogen species in the response of airway epithelium to particulates}, volume={105}, ISSN={["1552-9924"]}, DOI={10.2307/3433551}, abstractNote={Epidemiologic and occupational studies indicate adverse health effects due to inhalation of particulate air pollutants, but precise biologic mechanisms responsible have yet to be fully established.The tracheobronchial epithelium forms the body's first physiologic barrier to such airborne pollutants, where ciliary movement functions to remove the offending substances caught in the overlying mucus layer.Resident and infiltrating phagocytic cells also function in this removal process.In this paper, we examine the role of reactive oxygen and nitrogen species (ROS/RNS) in the response of airway epithelium to particulates.Some particulates themselves can generate ROS, as can the epithelial cells, in response to appropriate stimulation.In addition, resident macrophages in the airways and the alveolar spaces can release ROS/RNS after phagocytosis of inhaled particles.These macrophages also release large amounts of tumor necrosis factor alpha (TNF-a), a cytokine that can generate responses within the airway epithelium dependent upon intracellular generation of ROS/RNS.As a result, signal transduction pathways are set in motion that may contribute to inflammation and other pathobiology in the airway.Such effects include increased expression of intercellular adhesion molecule 1, interleukin-6, cytosolic and inducible nitric oxide synthase, manganese superoxide dismutase, cytosolic phospholipase A2, and hypersecretion of mucus.Ultimately, ROS/RNS may play a role in the global response of the airway epithelium to particulate pollutants via activation of kinases and transcription factors common to many response genes.Thus, defense mechanisms involved in responding to offending particulates may result in a complex cascade of events that can contribute to airway pathology.}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Martin, LD and Krunkosky, TM and Dye, JA and Fischer, BM and Jiang, NF and Rochelle, LG and Akley, NJ and Dreher, KL and Adler, KB}, year={1997}, month={Sep}, pages={1301–1307} }
 @article{price_page_fischer_levine_gerig_1991, title={Efficacy and Toxicity of Doxorubicin/Cyclophosphamide Maintenance Therapy in Dogs with Multicentric Lymphosarcoma}, volume={5}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.1991.tb03131.x}, DOI={10.1111/j.1939-1676.1991.tb03131.x}, abstractNote={Doxorubicin/cyclophosphamide were evaluated as maintenance drugs for dogs with multicentric lymphosarcoma (n = 28). Median remission time of all dogs was 173 days. Remission duration was shorter, however, in dogs with stage IV/V disease, in dogs with pretreatment hypoalbuminemia, and in dogs that had received glucocorticoids before initiation of chemotherapy (P < 0.04). Nineteen dogs were evaluable for toxicity. Dose‐limiting gastrointestinal toxicosis was observed in three dogs, neutropenia was observed in three dogs, and cardiomyopathy was observed in three dogs. The doxorubicin/cyclophosphamide protocol described in this report is safe and effective in treating canine multicentric lymphosarcoma. Clinical stage, pretreatment steroid therapy, and hypoalbuminemia are prognostic factors for response to this protocol}, number={5}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Price, G. Sylvester and Page, Rodney L. and Fischer, Bernard M. and Levine, Jay F. and Gerig, Thomas M.}, year={1991}, month={Sep}, pages={259–262} }