Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma
| Autor: | John Liu, Stephanie Addo, Gauri Deshmukh, Wyne P. Lee, Mark Zak, Ivan Peng, Hart S. Dengler, Julia Lloyd, Simon Charles Goodacre, Nicholas Charles Ray, Eric Suto, Pawan Bir Kohli, Savita Ubhayakar, Cristine M. Quiason-Huynh, Xiumin Wu, Cornelia H. Rinderknecht, Sheerin K. Shahidi-Latham, Youngsu Kwon, Marya Liimatta, Janet Jackman, Gary Cain, Jane R. Kenny, Gary Salmon, Brent S. McKenzie, Mike Briggs, Adam R. Johnson, Kathy Barrett, Nico Ghilardi |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Ovalbumin Guinea Pigs Inflammation Dexamethasone Guinea pig 03 medical and health sciences 0302 clinical medicine Administration Inhalation medicine Animals Lung Protein Kinase Inhibitors Asthma biology Janus kinase 1 business.industry General Medicine Janus Kinase 1 respiratory system Allergens medicine.disease respiratory tract diseases Eosinophils Disease Models Animal 030104 developmental biology medicine.anatomical_structure Treatment Outcome 030220 oncology & carcinogenesis Immunology biology.protein STAT protein medicine.symptom Signal transduction business Signal Transduction |
| Zdroj: | Science translational medicine. 10(468) |
| ISSN: | 1946-6242 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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