FGF/FGFR1,2 targeting can attenuate lung parenchymal and vascular remodeling: an opportunity for drug repurposing against chronic lung disease and post COVID‐19 sequelae

Abstract Purpose The fibroblast growth factor and its receptors (FGF/FGFR-1,2) are expressed in lung mesenchyme and vasculature in chronic lung diseases (DPLD). They form complexes with ECM, vessels and fine-tune epithelial/endothelial cell proliferation and regeneration. Therefore they may prove to be important therapeutic targets for chronic lung diseases. We assessed the FGF/FGFR-1,2 expression in the bleomycin model of lung fibrosis. We evaluated the effect of Sildenafil, Bosentan monotherapy and combination therapy in modulating the FGF/FGFR-1,2 expression in the lung and thereby attenuating parenchymal and vascular remodeling. Materials and methods Male Wistar rats were divided into five groups: Group I (Saline), Group II (Bleomycin), Group III (Bleomycin + Sildenafil), Group IV (Bleomycin + Bosentan), Group V (Bleomycin + Sildenafil + Bosentan). Animals were euthanized on day 7, 14 & 28 in each group. Lung- bFGF, FGFR1-2 mRNA and protein levels were assessed in all groups. Results Bleomycin induced parenchymal and vascular remodeling from day 7 to 28, associated with upregulation of bFGF, & FGFR1 mRNA (Day 7 onwards), FGFR2 mRNA (day 14 onwards), and upregulation of their protein expression by the AECs, BECs, endothelial cells, perivascular inflammatory cells and fibroblasts. Sildenafil and Bosentan monotherapy significantly attenuated lung parenchymal & vascular remodeling with reduction in bFGF & FGFR-1,2 levels in AEC, BECs and perivascular cells. Conclusion Progressive Lung parenchymal/vascular remodeling and fibrosis is associated with increased bFGF-FGFR-1,2 expression suggesting their utility as biomarkers of progressive fibrosis. We demonstrate the efficacy of repurposing Sildenafil and bosentan, drugs used for treating vascular changes of pulmonary artery hypertension, in attenuating lung parenchymal remodeling in DPLD.