[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach

Abstract

Purpose Idiopathic 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. Methods Eight-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. Results We 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.

Measurement of hypoxia in the lung in idiopathic pulmonary fibrosis: a matter of control

“…However, the results of this study were disappointingly far from our expectations considering that high levels of hypoxia biomarkers have been found in IPF patients, suggesting a hypoxic microenvironment in the IPF lung [6]. In addition, our group previously suggested that [ 18 F]F-MISO imaging could be a promising tool for early detection and monitoring in a preclinical model of lung fibrosis [7]. Although we are aware that our preclinical results may not be entirely relevant for human IPF, we believe that the study from PORTER et al[1] may suffer from flaws that could explain, at least in part, their underwhelming results.…”

Pivotal role of micro-CT technology in setting up an optimized lung fibrosis mouse model for drug screening

“…micro-CT and PET/CT) might be helpful within the drug discovery process, in order to increase the reliability of preclinical data and facilitate drug candidates’ translation into the clinic. Even though PET/CT can’t be used for primary screening due to its cost and complexity, this imaging technique could be extremely useful to better profiling the most promising anti-fibrotic drugs before clinical applications, as it enables to investigate the capacity of a drug to modulate the expression of relevant disease biomarkers by using specific probes [ 26 ].…”

The lungs were on fire: a pilot study of 18F-FDG PET/CT in idiopathic-inflammatory-myopathy-related interstitial lung disease

“…Elevated 18 F-FDG uptake could therefore serve as a marker for focal and global inflammatory activation and elevated metabolism in bilateral lungs. In addition, two antifibrotic drugs, namely, nintedanib and pirfenidone, were found to significantly decrease pulmonary FDG uptake in bleomycin-treated mice, indicating the value of PET/CT scans in evaluating the response to antifibrotic medications [31,32].…”

“…Compared with conventional HRCT, PET/CT scans seemed to be more intuitive for predicting RP-ILD. In IPF patients, PET/CT scans have been widely studied and found to be valuable for the evaluation of disease activity and therapy efficacy as well as the prediction of disease progression and survival [31,33,34]. In patients with lung cancer, elevated pulmonary FDG uptake is associated with acute exacerbation of ILD after chemotherapy or surgery [35][36][37].…”