[R406 -- Inhibition of Syk Prevents Mast Cell Activation and Airway Hyperresponsiveness]
>>Am J Respir Crit Care Med. 2005 Sep 28
Inhibition of Spleen Tyrosine Kinase Prevents Mast Cell Activation and Airway Hyperresponsiveness.
Matsubara S, Li G, Takeda K, Loader JE, Pine P, Masuda E, Miyahara N, Miyahara S, Lucas JJ, Dakhama A, Gelfand EW.
Department of Pediatrics, Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO, United States.
Rationale: Spleen tyrosine kinase (Syk) is important for Fc and B cell receptor-mediated-signaling. Objective: To determine the activity of a specific Syk kinase inhibitor (R406) on mast cell activation in vitro and on the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in vivo. Methods: Airway responsiveness and inflammation was induced following 10 days of allergen (ovalbumin, OVA) exposure exclusively via the airways and in the absence of adjuvant. This approach was previously established to be IgE-, FcepsilonRI- and mast cell-dependent. Alternatively, mice were passively sensitized with OVA-specific IgE, followed by limited airway challenge. In vitro, the inhibitor was added to cultures of IgE-sensitized bone marrow-derived mast cells (BMMC) prior to crosslinking with allergen. Results: The inhibitor prevented OVA-induced degranulation of (IgE) passively sensitized murine bone marrow-derived mast cells (BMMCs) and inhibited the production of IL-13, TNF-alpha, IL-2 and IL-6 in these sensitized BMMCs. When administered in vivo, R406 inhibited AHR which developed in BALB/c mice exposed to aerosolized 1% OVA for 10 consecutive days (20 min/day), as well as pulmonary eosinophilia and goblet cell hyperplasia. A similar inhibition of AHR was demonstrated in mice passively sensitized with OVA-specific IgE and exposed to limited airway challenge. Conclusion: This study delineates a functional role for Syk in the development of mast cell and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk kinase may be a target in the treatment of allergic asthma.<<
You'll likely recall that National Jewish also ran some of the human trials.
Cheers, Tuck |
