Abstract
Background: Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-β is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of 18F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD.Methods: The pulmonary expression of folate receptor-β was analyzed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the 18F-based folate radiotracer 18F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies.Results: Folate receptor-β expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodeling. A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it also correlated with disease extent. In the mouse model of BLM-induced ILD, pulmonary accumulation of 18F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-β positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated vs. control animals (0.31 ± 0.06% % injected activity/lung; p < 0.01).Conclusion: Our preclinical proof-of-concept study demonstrated the potential of 18F-AzaFol as a novel imaging tool for the visualization of macrophage-driven fibrotic lung diseases.
Highlights
In the US, 45% of deaths can be attributed to fibrotic disorders including pulmonary fibrosis [1], for which a global rise in mortality is observed [2]
A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it correlated with disease extent
To assess the presence of folate receptor-β (FR-β)-positive macrophages in human interstitial lung disease (ILD), we performed IHC for FR-β on lung explants derived from patients with idiopathic pulmonary fibrosis (IPF) (n = 39) and Connective tissue diseaseassociated interstitial lung disease (CTD-ILD) (n = 14), who underwent lung transplantation
Summary
In the US, 45% of deaths can be attributed to fibrotic disorders including pulmonary fibrosis [1], for which a global rise in mortality is observed [2]. This large and heterogeneous group of parenchymal lung disorders, termed interstitial lung disease (ILD) shares the common feature of pulmonary fibrosis resulting in impaired respiratory function and often failure. The most prevalent forms of ILD are idiopathic pulmonary fibrosis (IPF) and ILD associated with connective tissue diseases (CTDILD). We aimed to pre-clinically evaluate the potential of 18F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD
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