Blockade of β-catenin signaling attenuates toluene diisocyanate-induced experimental asthma.
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.


CONCLUSIONS
The results showed that β-catenin is a principal mediator of TDI-induced asthma, proposing β-catenin as a promising therapeutic target in asthma.
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
L
L
Yao
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
H
H
Zhao
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
H
H
Tang
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
J
J
Xiong
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
W
W
Zhao
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
L
L
Liu
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
H
H
Dong
School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China.
F
F
Zou
Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
S
S
Cai
D056151:Airway Remodeling / Q000235:genetics / Q000276:immunology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014051:Toluene 2,4-Diisocyanate / Q000009:adverse effects*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006575:Heterocyclic Compounds, 3-Ring; C492448:ICG 001; D011744:Pyrimidinones; C544261:XAV939; D051176:beta Catenin; D014051:Toluene 2,4-Diisocyanate; D007073:Immunoglobulin E
airway inflammation; airway remodeling; asthma; toluene diisocyanate; β-catenin