Positron emission tomography in the quantification of cellular and biochemical responses to intrapulmonary...

Inhaled mineral dusts and fibres can cause chronic pulmonary inflammation, often leading to permanent scarring with loss of function, but the mechanisms involved remain obscure. There are currently no good methods for monitoring inflammatory processes in situ. Positron emission tomography (PET) of suitable intravenously injected radiolabelled markers provides non-invasive and repeatable methods of quantifying biochemical and cellular responses. We have developed animal models of fibrotic and non-fibrotic pulmonary response to particulate instillation and characterised these by histology. Different components of the inflammatory response have been investigated by PET: (1) [(18)F]-labelled fluoro-deoxyglucose, a positron emitting glucose analogue, accumulates in cells in proportion to their glucose uptake; ex vivo microautoradiography indicates that neutrophils are the cells responsible for an increased signal during pulmonary inflammation; a persistently high uptake is associated with lung scarring. (2) The radioligand [(11)C]-R-PK11195 binds to benzodiazepine-like receptors abundant in macrophages; following particulate instillation, the [(11)C]-R-PK11195 PET signal tracks with lung macrophage accumulation and also localises to regions consistent with macrophage clearance; poor macrophage clearance is associated with fibrosis. (3) [(18)F]-fluoroproline is likely a substrate for extracellular matrix production, especially proline-rich collagen; during active scarring, the rate of lung uptake of fluoroproline is elevated. Localisation of radioactivity in the lung has been validated ex vivo by microautoradiography of tritium analogues of each of the positron emitting tracers. The use of PET to monitor different inflammatory processes by repeated scanning of the same animal or individual is helping to identify key events in the fibrotic process.