Wednesday, May 14, 2025
5/14/2025
Theraputic targeting of pulmonary endothelial cells to inhibit pathological lung remodeling - Summary Existing anti-fibrotic treatments for pulmonary fibrosis have not significantly improved survival. There is a critical need for new therapeutic approaches. Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood, even though lung fibrogenesis is associated with vascular remodeling, increased vessel permeability, hypoxia, partial loss of capillaries, focal increase in pathological angiogenesis and development of pulmonary hypertension. Our long- term goal is to develop clinically relevant approaches to correct EC dysfunctions, prevent loss of microvasculature, and slow down progression of lung fibrosis. Our preliminary data identify FOXF1 as a key transcription factor in pulmonary endothelial cell functions, down-regulation of which is indispensable for transition of normal lung EC into fibrosis-associated EC. We also demonstrate that FOXF1 transcriptionally activates R-Ras, a G protein from Ras family of GTPases, which is shown to be important for lumenization of newly formed microvessels and maintenance of EC barrier function in mouse models of muscle ischemia and cancers. Our central hypothesis is that lung EC-specific nanoparticle delivery of FOXF1 or R-Ras or transplantation of FOXF1+cKIT+ endothelial progenitor cells (EPCs) will improve lung microvascular integrity and inhibit the progression of pulmonary fibrosis. To test the hypothesis, we propose two specific aims: (1) to determine whether restoring microvascular integrity via nanoparticle gene therapy will inhibit lung fibrogenesis, (2) to define whether transplantation of FOXF1+cKIT+ EPCs will restore microvascular integrity and inhibit lung fibrosis. Altogether, nanoparticle gene therapy or cell transplantation with FOXF1+cKIT+ EPCs have translational potential in IPF and other pulmonary diseases associated with fibrosis.
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