Usefulness of 18F-FPP-RGD2 PET in pathophysiological evaluation of lung fibrosis using a bleomycin-induced rat model

Abstract

Purpose: Integrins α_v are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin α_vβ₃ imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an ¹⁸F-FPP-RGD₂ PET probe in a rat model of bleomycin-induced lung fibrosis.

Methods: Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat). Positron emission tomography (PET)/computerized tomography scans were performed 4 weeks after bleomycin administration using ¹⁸F-FPP-RGD₂. Total distribution volume (V_T) was estimated using one-tissue/two-compartment, two-tissue/three-compartment models, and Logan graphical analysis (Logan plot; t* = 30 min). Plasma-free fractions were estimated from images of the left ventricle. Correlation between Logan V_T and lung pathology was assessed by Spearman's rank correlation.

Results: Histopathological evaluation demonstrated the development of fibrosis in IPF-model group. Integrin α_v protein expression and lung radioactivity were higher in IPF-model group compared with control group. The lung radioactivity of ¹⁸F-FPP-RGD₂ rapidly reached the peak after administration and then gradually decreased, whereas left ventricular radioactivity rapidly disappeared. Logan graphical analysis was found to be suitable for ¹⁸F-FPP-RGD₂ kinetic analysis in the IPF-model lung. Logan V_T values for ¹⁸F-FPP-RGD₂ were significantly higher in IPF rats compared with control rats and strongly correlated with lung fibrosis, pathology, integrin α_v protein expression, and oxygen partial pressure.

Conclusion: Our findings demonstrate that the integrin α_vβ₃ PET probe ¹⁸F-FPP-RGD₂ can detect pathophysiological changes in lungs, including fibrosis accompanying upregulated integrin α_v of IPF-model rats. These findings support the utility of ¹⁸F-FPP-RGD₂ PET imaging for the pathophysiological evaluation of pulmonary fibrosis.

Keywords: Arginine-glycine-aspartic acid (RGD); Fibrosis; Idiopathic pulmonary fibrosis (IPF); Integrin; Oxygen partial pressure (pO2); Positron emission tomography (PET).