Research ArticlePulmonary fibrosis

Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models

See allHide authors and affiliations

Science Translational Medicine  28 Oct 2020:
Vol. 12, Issue 567, eaay3724
DOI: 10.1126/scitranslmed.aay3724

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Mitigating collagen production

Idiopathic pulmonary fibrosis (IPF) is characterized by deposition of collagen in the lung parenchyma by activated myofibroblasts, cell type exclusively expressing fibroblast activation protein (FAP). Now, Hettiarachchi et al. took advantage of this property and developed a low–molecular weight FAP agonist that could be used to deliver therapeutics to fibrotic tissue. A FAP-targeted phosphatidylinositol 3-kinase (PI3K) inhibitor was shown to reduce collagen production in human IPF lung fibroblasts and had therapeutic effects in a mouse model of IPF. The results suggest that FAP-targeting therapeutics could be effective for treating IPF.

Abstract

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.

View Full Text

Stay Connected to Science Translational Medicine