Spleen tyrosine kinase inhibition attenuates airway hyperresponsiveness and pollution-induced enhanced airway response in a chronic mouse model of asthma - 30/01/13
, Chung-Wai Chow, MD, PhD a, d, f, ⁎ 
Corresponding author: Chung-Wai Chow, MD, PhD, University Health Network/University of Toronto, 101 College St, TMDT 2-406, Toronto, Ontario M5G 1L7, Canada.Abstract |
Background |
Asthma is a chronic inflammatory disease characterized by airways hyperresponsiveness (AHR), reversible airflow obstruction, airway remodeling, and episodic exacerbations caused by air pollutants, such as particulate matter (PM; PM <2.5 μm in diameter [PM2.5]) and ozone (O3). Spleen tyrosine kinase (Syk), an immunoregulatory kinase, has been implicated in the pathogenesis of asthma.
Objective |
We sought to evaluate the effect of Syk inhibition on AHR in a chronic mouse model of allergic airways inflammation and pollutant exposure.
Methods |
We used a 12-week chronic ovalbumin (OVA) sensitization and challenge mouse model of airways inflammation followed by exposure to PM2.5 plus O3. Respiratory mechanics and methacholine (MCh) responsiveness were assessed by using the flexiVent system. The Syk inhibitor NVP-QAB-205 was nebulized intratracheally by using a treatment-based protocol 15 minutes before assessment of MCh responsiveness.
Results |
Syk expression increased significantly in the airway epithelia of OVA-sensitized and OVA-challenged (OVA/OVA) mice compared with OVA-sensitized but PBS-challenged (OVA/PBS) control mice. OVA/OVA mice exhibited AHR to MCh, which was attenuated by a single administration of NVP-QAB-205 (0.3 and 3 mg/kg). PM2.5 plus O3 significantly augmented AHR to MCh in the OVA/OVA mice, which was abrogated by NVP-QAB-205. Total inflammatory cell counts were significantly higher in the bronchoalveolar lavage fluid from OVA/OVA than OVA/PBS mice and were unaffected by PM2.5 plus O3 or NVP-QAB-205.
Conclusion |
NVP-QAB-205 reduced AHR and the enhanced response to PM2.5 plus O3 to normal levels in an established model of chronic allergic airways inflammation, suggesting that Syk inhibitors have promise as a therapy for asthma.
Le texte complet de cet article est disponible en PDF.Key words : Airways hyperresponsiveness, Syk, asthma, pollution, mouse
Abbreviations used : AHR, ASO, BAL, CC-10, DMSO, FA, KC, LCM, MCh, NF-κB, O3, OVA, OVA/OVA, OVA/PBS, PAS, PI3, PM, PM2.5, Rrs, Syk, VEGF
Plan
| Supported by the GlaxoSmithKline Collaborative and Innovative Research Fund, an Ontario Graduate Scholarship in Science and Technology (to P.C.P.), and a Canada Graduate Scholarship–Doctoral Award (to M.L.N.). |
|
| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 2
P. 512 - février 2013 Retour au numéro
Article précédent
- A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma
- Megan M. Price, Carole A. Oskeritzian, Yves T. Falanga, Kuzhuvelil B. Harikumar, Jeremy C. Allegood, Sergio E. Alvarez, Daniel Conrad, John J. Ryan, Sheldon Milstien, Sarah Spiegel
- Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates TH2 differentiation and allergic airway disease
- Purvi Mehrotra, Andrew Hollenbeck, Jonathan P. Riley, Fang Li, Ravi J. Patel, Nahid Akhtar, Shreevrat Goenka
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?