Abstract
PurposeIdiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG.MethodsEight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23.ResultsWe demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy.Conclusion[18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung, inducing significant morbidity through worsening dyspnoea and overall lung function decline
The current study evaluates the value of hypoxia in vivo PET imaging with [18F]FMISO to monitor disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis in comparison with computed tomography (CT) and [18F]FDG PET imaging
In light of the lack of tracers to monitor lung fibrosis, our study proposes to evaluate the impact of [18F]FDG PET and [18F]FMISO PET on lung fibrosis monitoring in a preclinical model
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung, inducing significant morbidity through worsening dyspnoea and overall lung function decline. The cause of IPF remains elusive and treatment options are limited with only two approved drugs, nintedanib and pirfenidone, which demonstrate efficacy to slow down fibrosis progression but are unable to reverse or even stop the disease [1]. While it is possible to validate the diagnosis of IPF with typical high-resolution computed tomography (HRCT) in the presence of a usual interstitial pneumonia (UIP) pattern, most patients may require lung biopsy, which is associated with a high morbidity and mortality [2]. Early diagnosis is crucial in IPF since longer time to diagnosis is related to poorer outcome and increased mortality [3]. Imaging biomarkers for early/active fibrosis are needed to promote early diagnosis, which could dramatically shorten current treatment delays
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