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Biomedical subjects

Hazel A Jones

Publications and source records attributed to Hazel A Jones.

7 recordsLinked to original sources
PubMed2005

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

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.

Animals↗
PubMed2005

Inflammation imaging.

Acute and chronic lung diseases are almost invariably associated with some degree of inflammation. Cells that evolved as an effective mechanism to counter infection and heal lung tissue may, in some circumstances, themselves be partially responsible for the pathogenesis of chronic lung disease that leads to irreversible lung damage and loss of lung function. Although standard measurements of lung function can document the progression of disease, the contributions of the numerous interacting elements to the process are difficult to measure in life. The use of molecular imaging techniques allows the different components of the inflammatory response to be monitored in situ in humans. In particular, positron emission tomography of selected markers targeted to specific cells and biochemical pathways can provide accurate measurements of disease activity, enabling a better understanding of inflammatory processes at all stages of disease. The practicability of sequential measurements allows one to monitor the natural history of different lung diseases. More importantly, imaging provides a unique tool for quantification of the modulation of discrete and specific aspects of inflammatory lung disease by targeted interventions. This should facilitate the development of new treatment strategies with better specificity for key elements of each disease.

Cell Adhesion Molecules↗
PubMed2004

Use of 18FDG-pet to discriminate between infection and rejection in lung transplant recipients.

18F-fluorodeoxyglucose (18FDG) uptake measured by positron emission tomography (PET) allows assessment of neutrophil activity in vivo and is increased in patients with airway inflammation or infection. Because infection but not rejection elicits a highly neutrophilic response, we assessed the ability of this non-invasive technique to differentiate these two events in lung transplant recipients. 18FDG-PET was measured in 15 patients classified by clinical, radiologic, and pathologic criteria. 18FDG-PET signal was increased with proven infection but not when no infection was identified (mean [standard error of mean]: 8.00 [1.81] and 3.16 [0.61], respectively [P = 0.021]. Rejection alone did not increase the signal. These data confirm that neutrophil activation is not a feature of acute rejection and indicate that a high 18FDG-PET signal is indicative of infection but not rejection in lung transplant recipients. This non-invasive and repeatable test could reduce the number of transbronchial biopsies required during episodes of breathlessness after lung transplantation.

Diagnosis, Differential↗
PubMed2004

In vivo measurement of circulating leucocyte activation in patients following cardiopulmonary bypass.

We have developed a simple technique to measure in vivo activation of circulating leucocytes and assessed it in 6 patients undergoing cardiopulmonary bypass (CPB). Arterial, mixed venous, and jugular bulb blood samples were taken following i.v. [18F]FDG, before and after CPB. [18F]FDG uptake in leucocytes was measured by phosphor imaging of spun blood-filled capillary tubes. Leucocyte radioactivity was quantified ([(leucocytes-plasma)/plasma radioactivity] and normalised to leucocyte counts. [18F]FDG uptake (mean+/-SEM)) before CPB was undetectable, being -0.014+/-0.007, -0.011+/-0.003, -0.012+/-0.006, -0.010+/-0.005, whereas increased uptake was demonstrated following CPB, 0.006+/-0.006, 0.009+/-0.005, 0.021+/-0.005, 0.034+/-0.006, at 20, 40, 60, and 80 min, respectively. There was no significant difference in activation between sampling sites before or after CPB. This method gives a sensitive index of activation of circulating leucocytes in whole blood, enabling investigation of activation of circulating white cells without the influence of sample handling or the requirement for time-consuming cell separation procedures.

Adult↗
PubMed2002

Kinetics of lung macrophages monitored in vivo following particulate challenge in rabbits.

The ligand PK11195 binds specifically in macrophages. We have assessed the use of positron emission tomography (PET) of [(11)C]R-PK11195 to monitor macrophage disposition following particulate challenge to the lung. Repeated PET scanning was performed over 4 weeks following iv [(11)C]R-PK11195 in rabbits treated with 5-microm particles of either amorphous (aSiO(2)) or microcrystalline (xSiO(2)) silica instilled into right upper pulmonary lobes. aSiO(2) resulted in increased macrophages, few neutrophils, and no fibrosis, while xSiO(2) increased macrophages and neutrophils and caused fibrosis. After both stimuli, (11)C localized to the challenged area and correlated with macrophage numbers. Radioactive counts in challenged/control lung regions peaked at 4 days for aSiO(2) (2.88, n = 2) and 6 days for xSiO(2) (4.62, n = 2). The signal remained elevated throughout the study (aSiO(2), 2.33 +/- 0.77 SD, n = 14; xSiO(2), 3.99 +/- 1.29 SD, n = 9), as did macrophage accumulation. (11)C also localized to regions consistent with macrophage traffic through lymph ducts 6 days after aSiO(2) challenge, but not until 4 weeks after xSiO(2). Specific binding of R-PK11195 in macrophages was demonstrated by microautoradiography in lavage fluid from an inflamed rabbit knee-joint model. These data suggest that PET scanning after [(11)C]PK11195 provides a new noninvasive approach for the study of macrophage kinetics in the lung.

Animals↗
PubMed2002

Dissociation between respiratory burst activity and deoxyglucose uptake in human neutrophil granulocytes: implications for interpretation of (18)F-FDG PET images.

UNLABELLED: Neutrophil granulocytes play a key role in the pathogenesis of a wide variety of pulmonary diseases. In many such conditions, the injury observed reflects the activation status rather than the total number of inflammatory cells present. The metabolic activity of neutrophils can now be assessed noninvasively using PET to measure the regional uptake of (18)F-FDG after intravenous injection. METHODS: To understand the mechanism responsible for the increased (18)F-FDG signal, we have measured the uptake of tritiated deoxyglucose (DG) in neutrophils isolated from human peripheral blood and sought to determine which aspects of neutrophil function correlate with an increase in DG uptake. RESULTS: Our results show that formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated respiratory burst activity and (3)H-DG uptake are temporally dissociated, that neutrophil-priming agents such as tumor necrosis factor-alpha (TNFalpha) cause an identical increase in (3)H-DG uptake compared with fMLP without affecting respiratory burst activity, and that fMLP stimulation of TNFalpha-primed cells causes major upregulation of superoxide anion generation (O(2)(-)) yet no incremental increase in (3)H-DG uptake. Furthermore, direct activation of reduced nicotinamide adenine dinucleotide phosphate oxidase activity with the ester phorbol 12-myristate 13-acetate resulted in a concentration-dependent loss of cell-associated (3)H-DG, and preincubation of neutrophils with the phosphoinositide 3-kinase inhibitor wortmannin, which abolished both agonist-stimulated superoxide anion generation and degranulation, had no effect on TNFalpha- or fMLP-stimulated (3)H-DG uptake. In contrast, the fMLP-stimulated change in neutrophil shape was not influenced by priming or wortmannin, and of the functional responses examined, this appeared to correlate most closely with (3)H-DG uptake. CONCLUSION: DG uptake occurs in both primed and activated neutrophils. It does not correlate with respiratory burst or secretory activity but may reflect the polarization and migrational status of these cells. These data have important implications for the analysis of (18)F-FDG signals in vivo.

Deoxyglucose↗