Background
Aberrant activation of β‐catenin signaling by both WNT‐dependent and WNT‐independent pathways has been demonstrated in asthmatic airways, which is thought to contribute critically in remodeling of the airways. Yet, the exact role of β‐catenin in asthma is very poorly defined. As we have previously reported abnormal expression of β‐catenin in a toluene diisocyanate (TDI)‐induced asthma model, in this study, we evaluated the therapeutic efficacy of two small molecules XAV‐939 and ICG‐001 in TDI‐asthmatic male BALB/c mice, which selectively block β‐catenin‐mediated transcription.
Methods
Male BALB/c mice were sensitized and challenged with TDI to generate a chemically induced asthma model. Inhibitors of β‐catenin, XAV‐939, and ICG‐001 were respectively given to the mice through intraperitoneally injection.
Results
TDI exposure led to a significantly increased activity of β‐catenin, which was then confirmed by a luciferase assay in 16HBE transfected with the TOPFlash reporter plasmid. Treatment with either XAV‐939 or ICG‐001 effectively inhibited activation of β‐catenin and downregulated mRNA expression of β‐catenin‐targeted genes in TDI‐asthmatic mice, paralleled by dramatically attenuated TDI‐induced hyperresponsiveness and inflammation of the airway, alleviated airway goblet cell metaplasia and collagen deposition, decreased Th2 inflammation, as well as lower levels of TGFβ1, VEGF, HMGB1, and IL‐1β.
Conclusion
The results showed that β‐catenin is a principal mediator of TDI‐induced asthma, proposing β‐catenin as a promising therapeutic target in asthma.