Date of Award
Master of Science (MS)
The single-photon emission tomography (SPECT) imaging biomarker technetium-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) exists in two forms, the oxidized, cell-permeable form and the reduced, cell-impermeable form. Recent studies revealed that the lung uptake of 99mTc-HMPAO increases early in rat models of human acute lung injury. Lung uptake of 99mTc-HMPAO is the net result of multiple cellular and vascular processes, many of which can vary with acute illness. Thus, when a change in the lung uptake of 99mTc-HMPAO is detected, it is unclear how much of this change is due to alteration in the activity of the targeted cellular process versus alteration of some other process(es). The objective was to investigate the pharmacokinetics of 99mTc-HMPAO uptake in isolated perfused rat lungs and identify the dominant vascular and tissue processes involved in that uptake. Rats were anesthetized, and the lungs were excised and connected to an isolated perfused lung ventilation-perfusion system. 99mTc-HMPAO (1.5 mCi) was injected into the pulmonary arterial cannula, and a time-sequence of images was acquired. Imaging was repeated using a range of pump flow rates, perfusate protein concentrations, and before and after lung treatment with the glutathione-depleting agent diethyl maleate (DEM). A pharmacokinetic (PBPK) model for the pulmonary disposition of 99mTc-HMPAO was developed and used for quantitative interpretation of the 99mTc-HMPAO lung time-activity curves. DEM decreased 99mTc-HMPAO lung uptake, consistent with a dominant role of lung GSH content in 99mTc-HMPAO uptake. The PBPK model was used to assess the sensitivity of 99mTc-HMPAO lung uptake to changes in flow rate, plasma protein concentration, capillary perfusion kinematics, lung 99mTc-HMPAO input function, and microvascular permeability. The approach we developed allows for evaluation of the dominant factors that determine 99mTc-HMPAO lung uptake, separation of the contributions of pulmonary processes from systemic processes, and application of this knowledge to in vivo studies. The approach can be extended to other biomarkers. These results may be important for clinical application of 99mTc-HMPAO as a means for early detection of acute lung injury and for assessing the efficacy of novel therapies.