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Published on: August 25, 2020
Blockade of β-catenin signaling attenuates toluene diisocyanate-induced experimental asthma
1Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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.
Insights
Beta-catenin signaling plays a key role in toluene diisocyanate (TDI)-induced asthma. Inhibiting beta-catenin with XAV-939 or ICG-001 effectively reduced asthma symptoms and airway inflammation in mice.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Aberrant beta-catenin signaling is implicated in airway remodeling in asthma.
- The precise role of beta-catenin in asthma pathogenesis remains unclear.
- Previous studies indicated abnormal beta-catenin expression in a toluene diisocyanate (TDI)-induced asthma model.
Purpose of the Study:
- To evaluate the therapeutic efficacy of XAV-939 and ICG-001, small molecules that inhibit beta-catenin-mediated transcription.
- To investigate the role of beta-catenin in a TDI-induced asthma model.
Main Methods:
- A TDI-induced asthma model was established in male BALB/c mice.
- Mice were treated intraperitoneally with beta-catenin inhibitors XAV-939 or ICG-001.
- Luciferase assays confirmed beta-catenin activity.
Main Results:
- TDI exposure significantly increased beta-catenin activity.
- XAV-939 and ICG-001 treatment inhibited beta-catenin activation and downregulated target genes.
- Treatments attenuated airway hyperresponsiveness, inflammation, goblet cell metaplasia, and collagen deposition.
- Th2 inflammation, TGFβ1, VEGF, HMGB1, and IL-1β levels were reduced.
Conclusions:
- Beta-catenin is a key mediator in TDI-induced asthma.
- Targeting beta-catenin represents a promising therapeutic strategy for asthma.
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