Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis

Nives Zimmermann, Nina E. King, Johanne Laporte, Ming Yang, Anil Mishra, Sam M. Pope, Emily E. Muntel, David P. Witte, Anthony A. Pegg, Paul S. Foster, Qutayba Hamid, Marc E. Rothenberg*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    451 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1863-1874
    Number of pages12
    JournalJournal of Clinical Investigation
    Volume111
    Issue number12
    DOIs
    Publication statusPublished - Jun 2003

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