title: Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma.
abstract: BACKGROUND
  Arginase overexpression contributes to airways hyperresponsiveness (AHR) in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR.
  
  
  METHODS
  To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA) and challenged with nebulized PBS (OVA/PBS) or OVA (OVA/OVA) for three consecutive days (sub-acute model) or 12 weeks (chronic model), which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O₃), or HEPA-filtered air (FA), for 4 hours. After the CAP+O₃ exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S-boronoethyl-L-cysteine; BEC) or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent®. Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization.
  
  
  RESULTS
  Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O₃-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O₃-induced increase in AHR in both models.
  
  
  CONCLUSIONS
  This study demonstrates that arginase is upregulated following environmental exposures in murine models of asthma, and contributes to the pollution-induced exacerbation of airways responsiveness. Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog.
authors.affiliation: Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: North
authors.forename: Hajera
authors.initials: H
authors.lastname: Amatullah
authors.forename: Nivedita
authors.initials: N
authors.lastname: Khanna
authors.forename: Bruce
authors.initials: B
authors.lastname: Urch
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
authors.forename: Frances
authors.initials: F
authors.lastname: Silverman
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Scott
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001249:Asthma / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D018384:Oxidative Stress / Q000187:drug effects; D010126:Ozone / Q000633:toxicity*; D052638:Particulate Matter / Q000633:toxicity*; D015854:Up-Regulation
chemical_list: C425062:(2-boronoethyl)-cysteine; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D052638:Particulate Matter; D010126:Ozone; D010047:Ovalbumin; C544448:Arg1 protein, mouse; D001119:Arginase