Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a ravaging condition of progressive lung scarring and destruction. Anti-inflammatory therapies including corticosteroids have limited efficacy in this ultimately fatal disorder. An important unmet need is to identify new agents that interact with key molecular pathways involved in the pathogenesis of pulmonary fibrosis to prevent progression or reverse fibrosis in these patients. Because aberrant activation of the Wnt/beta-catenin signaling cascade occurs in lungs of patients with IPF, we have targeted this pathway for intervention in pulmonary fibrosis using ICG-001, a small molecule that specifically inhibits T-cell factor/beta-catenin transcription in a cyclic AMP response-element binding protein binding protein (CBP)-dependent fashion. ICG-001 selectively blocks the beta-catenin/CBP interaction without interfering with the beta-catenin/p300 interaction. We report here that ICG-001 (5 mg/kg per day) significantly inhibits beta-catenin signaling and attenuates bleomycin-induced lung fibrosis in mice, while concurrently preserving the epithelium. Administration of ICG-001 concurrent with bleomycin prevents fibrosis, and late administration is able to reverse established fibrosis and significantly improve survival. Because no effective treatment for IPF exists, selective inhibition of Wnt/beta-catenin-dependent transcription suggests a potential unique therapeutic approach for pulmonary fibrosis.
Henderson
William R
WR
Center for Allergy and Inflammation and Department of Medicine, University of Washington, Seattle, WA 98109, USA. joangb@u.washington.edu
Chi
Emil Y
EY
Ye
Xin
X
Nguyen
Cu
C
Tien
Ying-tzang
YT
Zhou
Beiyun
B
Borok
Zea
Z
Knight
Darryl A
DA
Kahn
Michael
M
D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D050882:CREB-Binding Protein / Q000378:metabolism*; D051379:Mice; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D051153:Wnt Proteins; D051176:beta Catenin; D001761:Bleomycin; D050882:CREB-Binding Protein