title: Beneficial effects of arginase inhibition and inhaled L-arginine administration on airway histology in a murine model of chronic asthma.
abstract: BACKGROUND
  Increased arginase activity in the airways induces reduced bioavailability of L-arginine and cause deficiency of bronchodilatating and anti-inflammatory nitric oxide (NO). Therefore, arginine and arginase inhibitors may have therapeutic potential in the treatment of asthma. Using a murine model of asthma, we aimed to investigate the effects of inhaled L-arginine and arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA) and co-treatment on airway histology of asthmatic lung tissue.
  
  
  METHODS
  Forty-two BALB/c mice were divided into six groups: I (control), II (placebo), III, IV, V and VI. All mice except for control group were sensitised by an intraperitoneal injection of ovalbumin with alum adjuvant and then challenged with an aerosol of ovalbumin on three days of the week for eight weeks beginning from the 21st day of the study. Lung histology and bronchoalveolar lavage cell (BAL) counts were evaluated after treatment with inhaled L-arginine, nor-NOHA, l-arginine-nor-NOHA combination, budesonide and placebo. Interleukin(IL)-4 and IL-5 levels are determined in lung homogenates with ELISA.
  
  
  RESULTS
  L-Arginine group was similar to budesonide group in lowering all histological parameters. Results of groups treated with nor-NOHA were also similar to budesonide group except for epithelial thickness. The number of eosinophils in BAL decreased significantly in groups receiving study drugs. Decrease was only noted in IL-4 levels in group receiving nor-NOHA.
  
  
  CONCLUSIONS
  We demonstrated that inhaled l-arginine administration alleviated all histological parameters similar to budesonide and treatment with arginase inhibitor improved not all but some of the pathological changes in chronic asthma. Combination therapy had no additive effect on either treatment.
authors.affiliation: Department of Pediatric Allergy, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: zeynep.ayyildiz@deu.edu.tr.
authors.forename: Z
authors.initials: Z
authors.lastname: Arıkan-Ayyıldız
authors.affiliation: Department of Experimental Animal Laboratory, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: meral.karaman@deu.edu.tr.
authors.forename: M
authors.initials: M
authors.lastname: Karaman
authors.affiliation: Department of Pediatric Allergy, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: tuba.tuncel@deu.edu.tr.
authors.forename: T
authors.initials: T
authors.lastname: Tuncel
authors.affiliation: Department of Physiology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: muge.kiray@deu.edu.tr.
authors.forename: M
authors.initials: M
authors.lastname: Kiray
authors.affiliation: Department of Histology and Embriology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: alper.bagriyanik@deu.edu.tr.
authors.forename: A
authors.initials: A
authors.lastname: Bağrıyanık
authors.affiliation: Department of Experimental Animal Laboratory, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: osman.yilmaz@deu.edu.tr.
authors.forename: O
authors.initials: O
authors.lastname: Yilmaz
authors.affiliation: Department of Pediatric Allergy, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: nevin.uzuner@deu.edu.tr.
authors.forename: N
authors.initials: N
authors.lastname: Uzuner
authors.affiliation: Department of Pediatric Allergy, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey. Electronic address: ozkan.karaman@deu.edu.tr.
authors.forename: O
authors.initials: O
authors.lastname: Karaman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001119:Arginase / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001249:Asthma / Q000201:enzymology / Q000473:pathology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D018927:Anti-Asthmatic Agents; C404735:N(omega)-hydroxynorarginine; D001120:Arginine; D001119:Arginase
keywords: Arginase inhibition; Asthma; Murine model; l-Arginine; nor-NOHA