Non-invasive quantification of acute macrophagic lung inflammation with [11C](R)-PK11195 using a three-tissue compartment kinetic model in experimental acute respiratory distress syndrome

Abstract

Purpose: Imaging of acute lung inflammation is pivotal to evaluate innovative ventilation strategies. We aimed to develop and validate a three-tissue compartment kinetic model (3TCM) of [¹¹C](R)-PK11195 lung uptake in experimental acute respiratory distress syndrome (ARDS) to help quantify macrophagic inflammation, while accounting for the impact of its non-specific and irreversible uptake in lung tissues.

Material and methods: We analyzed the data of 38 positron emission tomography (PET) studies performed in 21 swine with or without experimental ARDS, receiving general anesthesia and mechanical ventilation. Model input function was a plasma, metabolite-corrected, image-derived input function measured in the main pulmonary artery. Regional lung analysis consisted in applying both the 3TCM and the two-tissue compartment model (2TCM); in each region, the best model was selected using a selection algorithm with a goodness-of-fit criterion. Regional best model binding potentials (BP_ND) were compared to lung macrophage presence, semi-quantified in pathology.

Results: The 3TCM was preferred in 142 lung regions (62%, 95% confidence interval: 56 to 69%). BP_ND determined by the 2TCM was significantly higher than the value computed with the 3TCM (overall median with interquartile range: 0.81 [0.44-1.33] vs. 0.60 [0.34-0.94], p < 0.02). Regional macrophage score was significantly associated with the best model BP_ND (p = 0.03). Regional BP_ND was significantly increased in the hyperinflated lung compartment, compared to the normally aerated one (median with interquartile range: 0.8 [0.6-1.7] vs. 0.6 [0.3-0.8], p = 0.03).

Conclusion: To assess the intensity and spatial distribution of acute macrophagic lung inflammation in the context of experimental ARDS with mechanical ventilation, PET quantification of [¹¹C](R)-PK11195 lung uptake was significantly improved in most lung regions using the 3TCM. This new methodology offers the opportunity to non-invasively evaluate innovative ventilatory strategies aiming at controlling acute lung inflammation.

Keywords: Acute respiratory distress syndrome; Inflammation; Positron emission tomography; Tissue compartment kinetic model; Ventilator-induced lung injury; [11C](R)-PK11195.