Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models
| Autor: | Ehab A. Ayaub, Estela Puchulu-Campanella, Philip S. Low, Ivan O. Rosas, Spencer D. Lindeman, Yen Hsing Li, Jyoti Roy, Suraj U. Hettiarachchi, Fenghua Zhang, Cheryl Nickerson-Nutter, Xiaoliang Liang, Konstantin Tsoyi, Madduri Srinivasarao |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences Hydroxyproline chemistry.chemical_compound Idiopathic pulmonary fibrosis 0302 clinical medicine Fibroblast activation protein alpha Fibrosis Pulmonary fibrosis Animals Medicine Lung PI3K/AKT/mTOR pathway business.industry TOR Serine-Threonine Kinases General Medicine Fibroblasts Models Theoretical respiratory system medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Cancer research business Myofibroblast |
| Zdroj: | Science Translational Medicine. 12 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aay3724 |
| Popis: | Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an average life expectancy of 3 to 5 years. IPF is characterized by progressive stiffening of the lung parenchyma due to excessive deposition of collagen, leading to gradual failure of gas exchange. Although two therapeutic agents have been approved from the FDA for IPF, they only slow disease progression with little impact on outcome. To develop a more effective therapy, we have exploited the fact that collagen-producing myofibroblasts express a membrane-spanning protein, fibroblast activation protein (FAP), that exhibits limited if any expression on other cell types. Because collagen-producing myofibroblasts are only found in fibrotic tissues, solid tumors, and healing wounds, FAP constitutes an excellent marker for targeted delivery of drugs to tissues undergoing pathologic fibrosis. We demonstrate here that a low-molecular weight FAP ligand can be used to deliver imaging and therapeutic agents selectively to FAP-expressing cells. Because induction of collagen synthesis is associated with phosphatidylinositol 3-kinase (PI3K) activation, we designed a FAP-targeted PI3K inhibitor that selectively targets FAP-expressing human IPF lung fibroblasts and potently inhibited collagen synthesis. Moreover, we showed that administration of the inhibitor in a mouse model of IPF inhibited PI3K activation in fibrotic lungs, suppressed production of hydroxyproline (major building block of collagen), reduced collagen deposition, and increased mouse survival. Collectively, these studies suggest that a FAP-targeted PI3K inhibitor might be promising for treating IPF. |
| Databáze: | OpenAIRE |
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