title: Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice.
abstract: Asthma is a chronic inflammatory disease of the small airways, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. Recent studies suggest a role for arginase in asthma pathogenesis, possibly because arginine is the substrate for both arginase and NO synthase and because NO modulates bronchial tone and inflammation. Our objective was to investigate the importance of increased pulmonary arginase 1 expression on methacholine-induced AHR and lung inflammation in a mouse model of allergic asthma. Arginase 1 expression in the lung was ablated by crossing Arg1(fl/fl) with Tie2Cre(tg/-) mice. Mice were sensitized and then challenged with ovalbumin. Lung function was measured with the Flexivent. Adaptive changes in gene expression, chemokine and cytokine secretion, and lung histology were quantified with quantitative PCR, ELISA, and immunohistochemistry. Arg1 deficiency did not affect the allergic response in lungs and large-airway resistance, but it improved peripheral lung function (tissue elastance and resistance) and attenuated adaptive increases in mRNA expression of arginine-catabolizing enzymes Arg2 and Nos2, arginine transporters Slc7a1 and Slc7a7, chemokines Ccl2 and Ccl11, cytokines Tnfa and Ifng, mucus-associated epithelial markers Clca3 and Muc5ac, and lung content of IL-13 and CCL11. However, expression of Il4, Il5, Il10, and Il13 mRNA; lung content of IL-4, IL-5, IL-10, TNF-α, and IFN-γ protein; and lung pathology were not affected. Correlation analysis showed that Arg1 ablation disturbed the coordinated pulmonary response to ovalbumin challenges, suggesting arginine (metabolite) dependence of this response. Arg1 ablation in the lung improved peripheral lung function and affected arginine metabolism but had little effect on airway inflammation.
authors.affiliation: Department of Anatomy & Embryology and NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, The Netherlands.
authors.forename: Roy H E
authors.initials: RH
authors.lastname: Cloots
authors.forename: Selvakumari
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Chiel C
authors.initials: CC
authors.lastname: de Theije
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.forename: Els
authors.initials: E
authors.lastname: Terwindt
authors.forename: Paul
authors.initials: P
authors.lastname: van Dijk
authors.forename: Theodorus B M
authors.initials: TB
authors.lastname: Hakvoort
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.forename: S Eleonore
authors.initials: SE
authors.lastname: Köhler
mesh_terms: D000403:Airway Resistance / Q000502:physiology; D000818:Animals; D001119:Arginase / Q000502:physiology*; D001249:Asthma / Q000503:physiopathology*; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016085:Bronchoconstrictor Agents / Q000633:toxicity; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006967:Hypersensitivity / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D008168:Lung / Q000166:cytology / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D010047:Ovalbumin / Q000502:physiology; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016085:Bronchoconstrictor Agents; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D016210:Methacholine Chloride; D010047:Ovalbumin; D001119:Arginase
keywords: airway hyperresponsiveness; arginine; inflammation