Protection by Inhaled Hydrogen Therapy in a Rat Model of Acute Lung Injury can be Tracked in vivo Using Molecular Imaging

Audi, Said H.; Jacobs, Elizabeth R.; Zhang, Xiao; Camara, Amadou K.S.; Zhao, Ming; Medhora, Meetha; Rizzo, Benjamin M.; Clough, Anne V.

doi:10.1097/shk.0000000000000872

Cited by 21 publications

(14 citation statements)

References 33 publications

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“…In addition, increased 99m Tc-HMPAO lung uptake has been reported in patients with lung injury resulting from chemotherapy and radiation injury in the absence of perfusion impairment or roentgenographic abnormalities (25) and in patients with diffuse infiltrative lung disease (13). Also, we and others have reported the potential utility of 99m Tc-HMPAO imaging for detecting and monitoring lung injury in preclinical models involving prolonged exposure to high concentrations of oxygen (hyperoxia) (4,5,10), the sepsis mimic lipopolysaccharide (6), and chemotoxic agents (12). These studies revealed increased lung uptake in subjects with subclinical lung injury, suggesting that 99m Tc-HMPAO imaging may be a means for quantitatively detecting lung injury before detection with conventional clinical tools and for assessing the efficacy of novel therapies (5).…”

Section: Introductionmentioning

confidence: 89%

“…Also, we and others have reported the potential utility of 99m Tc-HMPAO imaging for detecting and monitoring lung injury in preclinical models involving prolonged exposure to high concentrations of oxygen (hyperoxia) (4,5,10), the sepsis mimic lipopolysaccharide (6), and chemotoxic agents (12). These studies revealed increased lung uptake in subjects with subclinical lung injury, suggesting that 99m Tc-HMPAO imaging may be a means for quantitatively detecting lung injury before detection with conventional clinical tools and for assessing the efficacy of novel therapies (5).…”

Section: Introductionmentioning

confidence: 95%

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Pharmacokinetics of ^99mTc-HMPAO in isolated perfused rat lungs

Clough

Barry

Rizzo

et al. 2019

Journal of Applied Physiology

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Lung uptake of technetium-labeled hexamethylpropyleneamine oxime (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 with a range of pump flows and perfusate albumin concentrations and before and after depletion of 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 the 99mTc-HMPAO lung time-activity curve, was inversely related to pump flow. Also, 99mTc-HMPAO lung uptake decreased by ~65% after 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. NEW & NOTEWORTHY We developed an approach for studying the pharmacokinetics of technetium-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) in isolated perfused lungs. A distributed-in-space-and-time computational model was fit to data and used to investigate questions that cannot readily be addressed in vivo. Experimental and modeling results indicate that tissue GSH is the dominant factor in 99mTc-HMPAO retention in lung tissue. This modeling approach can be readily extended to investigate the lung pharmacokinetics of other biomarkers and models of lung injury and treatment thereof.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 95%

Pharmacokinetics of ^99mTc-HMPAO in isolated perfused rat lungs

Clough

Barry

Rizzo

et al. 2019

Journal of Applied Physiology

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“…As previously described [ 19 ], mitochondrial membrane potential (ΔΨ m ) studies were performed at room temperature (23°C) using a Photon Technology International (PTI) QuantaMaster spectrofluorometer (HORIBA Scientific, Edison, New Jersey) that monitored and recorded the R123 fluorescent signal (503/527 nm excitation/emission wavelength) continuously over time. Briefly, a cuvette containing 1 ml of the respiration buffer (pH 7.2), R123 (200 nM), and either pyruvate (10 mM) + malate (5 mM) or succinate (7 mM) as respiratory substrate was placed in the cuvette holder of the spectrofluorometer.…”

Section: Methodsmentioning

confidence: 99%

Integrated computational model of the bioenergetics of isolated lung mitochondria

et al. 2018

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Integrated computational modeling provides a mechanistic and quantitative framework for describing lung mitochondrial bioenergetics. Thus, the objective of this study was to develop and validate a thermodynamically-constrained integrated computational model of the bioenergetics of isolated lung mitochondria. The model incorporates the major biochemical reactions and transport processes in lung mitochondria. A general framework was developed to model those biochemical reactions and transport processes. Intrinsic model parameters such as binding constants were estimated using previously published isolated enzymes and transporters kinetic data. Extrinsic model parameters such as maximal reaction and transport velocities were estimated by fitting the integrated bioenergetics model to published and new tricarboxylic acid cycle and respirometry data measured in isolated rat lung mitochondria. The integrated model was then validated by assessing its ability to predict experimental data not used for the estimation of the extrinsic model parameters. For example, the model was able to predict reasonably well the substrate and temperature dependency of mitochondrial oxygen consumption, kinetics of NADH redox status, and the kinetics of mitochondrial accumulation of the cationic dye rhodamine 123, driven by mitochondrial membrane potential, under different respiratory states. The latter required the coupling of the integrated bioenergetics model to a pharmacokinetic model for the mitochondrial uptake of rhodamine 123 from buffer. The integrated bioenergetics model provides a mechanistic and quantitative framework for 1) integrating experimental data from isolated lung mitochondria under diverse experimental conditions, and 2) assessing the impact of a change in one or more mitochondrial processes on overall lung mitochondrial bioenergetics. In addition, the model provides important insights into the bioenergetics and respiration of lung mitochondria and how they differ from those of mitochondria from other organs. To the best of our knowledge, this model is the first for the bioenergetics of isolated lung mitochondria.

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“…So far, the preventive and therapeutic effects of molecular hydrogen for various lung diseases, such as ALI, chronic obstructive pulmonary disease, asthma, and pulmonary arterial hypertension, have been extensively investigated (Kishimoto et al 2015;Audi et al 2017;Wang et al 2020). China's National Health Commission (7th trial ed NHC: Bejing, 2020) and the Chinese Center for Disease Control and Prevention (6th ed.…”

Section: Introductionmentioning

confidence: 99%

Molecular hydrogen is a potential protective agent in the management of acute lung injury

Zhang

2022

Mol Med

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Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.

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Protection by Inhaled Hydrogen Therapy in a Rat Model of Acute Lung Injury can be Tracked in vivo Using Molecular Imaging

Cited by 21 publications

References 33 publications

Pharmacokinetics of ^99mTc-HMPAO in isolated perfused rat lungs

Pharmacokinetics of ^99mTc-HMPAO in isolated perfused rat lungs

Integrated computational model of the bioenergetics of isolated lung mitochondria

Molecular hydrogen is a potential protective agent in the management of acute lung injury

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Protection by Inhaled Hydrogen Therapy in a Rat Model of Acute Lung Injury can be Tracked in vivo Using Molecular Imaging

Cited by 21 publications

References 33 publications

Pharmacokinetics of 99mTc-HMPAO in isolated perfused rat lungs

Pharmacokinetics of 99mTc-HMPAO in isolated perfused rat lungs

Integrated computational model of the bioenergetics of isolated lung mitochondria

Molecular hydrogen is a potential protective agent in the management of acute lung injury

Contact Info

Product

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Pharmacokinetics of ^99mTc-HMPAO in isolated perfused rat lungs

Pharmacokinetics of ^99mTc-HMPAO in isolated perfused rat lungs