title: Lung arginase expression and activity is increased in cystic fibrosis mouse models.
abstract: The activity of arginase is increased in airway secretions of patients with cystic fibrosis (CF). Downstream products of arginase activity may contribute to CF lung disease. We hypothesized that pulmonary arginase expression and activity would be increased in mouse models of CF and disproportionally increased in CF mice with Pseudomonas aeruginosa pneumonia. Expression of arginase isoforms in lung tissue was quantified with reverse transcriptase-PCR in naive cystic fibrosis transmembrane conductance regulator (Cftr)-deficient mice and β-epithelial sodium channel-overexpressing [β-ENaC-transgenic (Tg)] mice. An isolated lung stable isotope perfusion model was used to measure arginase activity in Cftr-deficient mice before and after intratracheal instillation of Pseudomonas aeruginosa. The expression of arginase-2 in lung was increased in adult Cftr-deficient animals and in newborn β-ENaC-Tg. Arginase-1 lung expression was normal in Cftr-deficient and in newborn β-ENaC-Tg mice, but was increased in β-ENaC-Tg mice at age 1, 3, and 6 wk. Arginase activity was significantly higher in lung (5.0 ± 0.7 vs. 3.2 ± 0.3 nmol·(-1)·h(-1), P = 0.016) and airways (204.6 ± 49.8 vs. 79.3 ± 17.2 nmol·(-1)·h(-1), P = 0.045) of naive Cftr-deficient mice compared with sex-matched wild-type littermate controls. Infection with Pseudomonas aeruginosa resulted in a far greater increase in lung arginase activity in Cftr-deficient mice (10-fold) than in wild-type controls (6-fold) (P = 0.01). This is the first ex vivo characterization of arginase expression and activity in CF mouse lung and airways. Our data show that pulmonary arginase expression and activity is increased in CF mice, especially with Pseudomonas aeruginosa infections.
authors.affiliation: Program in Physiology & Experimental Medicine, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Critical Care Medicine, Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Thomas
authors.initials: T
authors.lastname: Jaecklin
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center, Member of the German Center for Lung Research, University of Heidelberg, Heidelberg, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Duerr
authors.affiliation: Program in Physiology & Experimental Medicine, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Hailu
authors.initials: H
authors.lastname: Huang
authors.affiliation: Program in Physiology & Experimental Medicine, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Mahroukh
authors.initials: M
authors.lastname: Rafii
authors.affiliation: Program in Molecular Structure & Function, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Christine E
authors.initials: CE
authors.lastname: Bear
authors.affiliation: Program in Physiology & Experimental Medicine, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Felix
authors.initials: F
authors.lastname: Ratjen
authors.affiliation: Program in Physiology & Experimental Medicine, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Paul
authors.initials: P
authors.lastname: Pencharz
authors.affiliation: Program in Physiology & Experimental Medicine, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Critical Care Medicine, Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kavanagh
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center, Member of the German Center for Lung Research, University of Heidelberg, Heidelberg, Germany; Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Heidelberg, Germany; and.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.affiliation: Program in Physiology & Experimental Medicine, The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, and University of Toronto, Toronto, Ontario, Canada hartmut.grasemann@sickkids.ca.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000378:metabolism*; D008171:Lung Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011014:Pneumonia / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000378:metabolism; D011550:Pseudomonas aeruginosa
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D001119:Arginase
keywords: arginase activity; cystic fibrosis; nitric oxide; stable isotopes