Positron emission tomographic (PET) imaging of silicosis in a rabbit model using an F-fluorinated proline amino acid analog tracer.
Wallace-WE; Gupta-NC; Hubbs-AF; Mazza-SM; Bishop-HA; Keane-MJ; Battelli-LA; Ma-JYC; Schleiff-P
Med Lav 2002 Oct; 93(Suppl):S66
The sensitivity of positron emission tomography using a proline amino acid analog was tested for detection of pulmonary response in early silicosis in an animal model subject to an acute instillation exposure to quartz dust. Cis-4-18F fluoro-L- proline (FP) was synthesized as a positron-emitting 18F-labeled analog of the amino acid proline. Proline and glycine are used extensively in procollagen synthesis by pulmonary fibroblasts in active silicosis. Proline is taken up by the fibroblasts to provide both the proline and hydroxyproline residues of procollagen, which is then secreted into the extracellular space for maturation into collagen scar tissue in fibrosis. 18F is covalently bound in the FP proline analog. 18F has an 110 minute half-life and decays by positron emission, finally resulting in emission of two 0.511 MeV gamma rays which provide a means to map the location of the tracer. Most clinical PET imaging uses an analog of sugar, fluorodeoxyglucose (FDG), to map areas of generally heightened metabolism, e.g., tumors. Instead, fluoroproline was tested here for above-background uptake associated with heightened metabolism specific to silicosis. Rabbits were instilled with respirable quartz dust in saline, or with saline alone for controls, and subsequently at 1, 2, 4, or 5 months animals were injected with 1mCi of FP and imaged in a clinical PET system. Animals were killed two days later and their lung tissue subjected to histopathology examination for fibrosis distribution and severity. PET images were graded for features by consensus of three readers blinded to the identity of silica- or saline-challenged animals imaged in sets of three, with at least one control and one test animal in each set. Histopathology scores were statistically correlated with PET image scores. Innate PET resolution, the small animal size relative to the clinical imager, animal respiration, and the presence of an azygous lung lobe in some animals limited localization of the PET imaged features to about a centimeter. JH proline autoradiography studies are addressing the question of the specificity of location of heightened proline uptake, i.e., to pulmonary interstitial sites of fibroblast collagen synthesis activity or to pulmonary alveolar surface locations of neutrophil-associated inflammatory response. Resolution of questions of specificity of the uptake to collagen synthesis activity will clarify the feasibility of PET imaging for detection of active stages of fibrosis and for possible application for early disease detection and prevention or for evaluation of the active status of fibrosis for guiding medical management of advanced disease. Toxicological evaluations of FP will determine if FP is safe for use or if 11C-proline is needed for possible further testing and development of the method.
Silicates; Silicosis; Silica-dusts; Pulmonary-disorders; Pulmonary-function; Pulmonary-system-disorders; Animal-studies; Laboratory-animals; Quartz-dust; Amino-acids; Fibrosis
Abstract; Conference/Symposia Proceedings
Research Tools and Approaches: Exposure Assessment Methods
La Medicina del Lavoro. 3rd International Symposium on Silica, Silicosis, Cancer and Other Diseases, S. Margherita Ligure, 21-25 October 2002