Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma
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Le résumé fourni par la source
Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma
- Date Crossref
- 21/11/2018
- Éditeur
- American Association for the Advancement of Science (AAAS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Charles River Laboratories (United Kingdom) pays non établi dans la noticeEntreprise
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Department of Immunology Discovery pays non établi dans la noticeInstitution
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Department of Translational Immunology pays non établi dans la noticeInstitution
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Department of Biochemical Pharmacology pays non établi dans la noticeInstitution
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Department of Biology pays non établi dans la noticeInstitution
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Department of Safety Assessment Pathology pays non établi dans la noticeInstitution
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Department of Drug Metabolism and Pharmacokinetics pays non établi dans la noticeInstitution
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Department of Chemistry pays non établi dans la noticeInstitution
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Department of Discovery Chemistry pays non établi dans la noticeInstitution
Charles River Laboratories (United Kingdom), Department of Immunology Discovery et Department of Translational Immunology, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.