LAUSR

Lung uptake of technetium-labeled hexamethylpropyleneamineoxime (HMPAO) increases in rat models of human acute lung injury, consistent with increases in lung tissue glutathione (GSH). Since 99mTc-HMPAO uptake is the net result of multiple cellular and vascular processes, the objective was to develop an approach to investigate the pharmacokinetics of 99mTc-HMPAO uptake in isolated perfused rat lungs. Lungs of anesthetized rats were excised and connected to a ventilation-perfusion system. 99mTc-HMPAO (56 MBq) was injected into the pulmonary arterial cannula, a time-sequence of images was acquired, and lung time-activity curves were constructed. Imaging was repeated using a range of pump flows, perfusate albumin concentrations, and before and after depleting GSH with diethyl maleate (DEM). A pharmacokinetic model of 99mTc-HMPAO pulmonary disposition was developed and used for quantitative interpretation of the time-activity curves.Experimental results reveal that 99mTc-HMPAO lung uptake, defined as the steady-state value of 99mTc-HMPAO lung time-activity curve, was inversely related to pump flow. Also 99mTc-HMPAO lung uptake decreased by ~65% following addition of DEM to the perfusate. Increased perfusate albumin concentration also resulted in decreased 99mTc-HMPAO lung uptake. Model simulations under in vivo flow conditions indicate that lung tissue GSH is the dominant factor in 99mTc-HMPAO retention in lung tissue. The approach allows for evaluation of the dominant factors that determine imaging biomarker uptake, separation of the contributions of pulmonary versus systemic processes, and application of this knowledge to in vivo studies.