title: Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis.
abstract: Asthma is on the rise despite intense, ongoing research underscoring the need for new scientific inquiry. In an effort to provide unbiased insight into disease pathogenesis, we took an approach involving expression profiling of lung tissue from mice with experimental asthma. Employing asthma models induced by different allergens and protocols, we identified 6.5% of the tested genome whose expression was altered in an asthmatic lung. Notably, two phenotypically similar models of experimental asthma were shown to have distinct transcript profiles. Genes related to metabolism of basic amino acids, specifically the cationic amino acid transporter 2, arginase I, and arginase II, were particularly prominent among the asthma signature genes. In situ hybridization demonstrated marked staining of arginase I, predominantly in submucosal inflammatory lesions. Arginase activity was increased in allergen-challenged lungs, as demonstrated by increased enzyme activity, and increased levels of putrescine, a downstream product. Lung arginase activity and mRNA expression were strongly induced by IL-4 and IL-13, and were differentially dependent on signal transducer and activator of transcription 6. Analysis of patients with asthma supported the importance of this pathway in human disease. Based on the ability of arginase to regulate generation of NO, polyamines, and collagen, these results provide a basis for pharmacologically targeting arginine metabolism in allergic disorders.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Nives
authors.initials: N
authors.lastname: Zimmermann
authors.forename: Nina E
authors.initials: NE
authors.lastname: King
authors.forename: Johanne
authors.initials: J
authors.lastname: Laporte
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Anil
authors.initials: A
authors.lastname: Mishra
authors.forename: Sam M
authors.initials: SM
authors.lastname: Pope
authors.forename: Emily E
authors.initials: EE
authors.lastname: Muntel
authors.forename: David P
authors.initials: DP
authors.lastname: Witte
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Pegg
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics* / Q000502:physiology*; D001120:Arginine / Q000378:metabolism; D001249:Asthma / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008168:Lung / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics
chemical_list: D016207:Cytokines; D005819:Genetic Markers; D007527:Isoenzymes; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D009569:Nitric Oxide; D001120:Arginine; D001119:Arginase