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

Abstract

We read with great interest the paper by PORTER et al. [1] published in the October 2021 issue of the European Respiratory Journal. The authors' aim was to explore the potential benefit of the hypoxia tracer [ 18 F]fluoromisonidazole ([ 18 F]F-MISO) in idiopathic pulmonary fibrosis (IPF). Given the lack of non-invasive imaging tools for the diagnosis and/or the follow-up of patients with IPF, this study appears to be an essential first step towards the personalised management of IPF patients through imaging biomarkers for early/active fibrosis. In vivo molecular imaging, in particular positron emission tomography (PET), has become a crucial tool in preclinical research, clinical trials and medical practice, especially in the field of oncology. In lung fibrosis, recent advances have been made with the aim of developing molecular imaging tools in preclinical models, a necessary step toward clinical certification [2]. Among tracers validated at the preclinical level, imaging probes targeting collagen ( 68 Ga-CBP8 [3]), integrins ([ 18 F]FB-A20FMDV2 [4]) and glucose metabolism ([ 18 F]FDG [5]) have been successfully evaluated in clinical trials and may ultimately improve IPF management.While chronic hypoxia of the lung is a significant clinical feature in patients with IPF, the study by PORTER et al. [1] is the first to explore the potential role of the hypoxia tracer [ 18 F]F-MISO in these patients. 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. In our opinion, the main issue resides in the use of lung areas with a "normal" appearance as controls for fibrotic areas. When they used this control, PORTER et al. [1] assumed that the regions of IPF lungs that appear to be normal are de facto not hypoxic. We believe that this assumption may be incorrect since we demonstrated in our preclinical results that there was also an increase in [ 18 F]F-MISO lung uptake in areas that seemed "normal" on computed tomography (figure 1). These data are in line with other studies demonstrating that hypoxia inducible transcription factor (HIF)-1α and CA-IX are upregulated, not only in areas of active fibrosis, but also within areas of IPF lungs that appear histologically normal [8]. These findings suggest that the activation of hypoxia signalling is an early event that drives the remodelling of areas in the IPF lung that are not yet fibrotic, thus promoting disease progression. As an alternative, considering that hypoxic volumes are more localised in lung cance...

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“…Beyond senescence, hypoxia is a major hallmark of IPF, where scar tissue deposition hampers gas exchange. Hypoxia also gains attention as a predictive marker of the disease [ 40 , 41 , 42 ]. As a consequence, hypoxia leads to an increase in oxidative stress, dysfunction of mitochondria, and an unfolded protein response [ 43 , 44 ].…”

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“…68 Ga-CBP8 has a high affinity for COL1A1 in a mouse lung injury model of radiation lung injury and has good pharmacological and pharmacokinetic characteristics, with high target uptake and low retention in background tissues and organs. 8 Ga-CBP8 has high specificity and a high target background ratio for pulmonary fibrosis in diseased animals, and it can be used to effectively detect pulmonary fibrosis and its response to therapy [91][92][93].…”