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Investigating the Impact of Hypoxia on Lung Metabolism using Hyperpolarized Carbon-13 MRSI1Radiology, University of Pennsylvania, Philadelphia, PA, United States, 2Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United States
Synopsis
Systemic hypoxemia is a clinical hallmark of many lung pathologies, yet its impact on lung metabolism is not well understood. In this hyperpolarized carbon-13 MRI study, we seek to demonstrate the impact of both moderate and severe systemic hypoxemia on lung pyruvate metabolism using an imaging approach.
Introduction
Systemic hypoxemia is a clinical hallmark of lung injury as well as several lung pathologies which result from impaired gas exchange (1). Hypoxia is a prominent feature of inflammatory pathology, in which neutrophils’ increased metabolic demands reduce the availability of metabolic substrates to the native cells (2, 3). Hypoxia leads to an increase in both anaerobic metabolism and overall lactate levels in the blood and muscle tissue (4, 5); however, several studies suggest that overall lung metabolism tolerates moderate reductions in oxygen availability and continues to produce normal lactate levels (6-9). In this hyperpolarized (HP) 13C MRI study, we seek to demonstrate the impact of both moderate and severe systemic hypoxemia on lung pyruvate metabolism using an imaging approach.Materials and Methods
HP [1-13C]pyruvate MRI was performed using a horizontal-bore 4.7T small animal imaging system (Varian Inc.) as previously described (10).An arterial line was placed in the tail artery for arterial blood gas (ABG) analysis. Twenty-one Sprague-Dawley rats were ventilated with the following parameters: VT=8 ml/kg, FiO2=1.0, PEEP=3 cmH2O, frequency=52 min-1. After baseline ABG and HP-MRI, seven control rats received continued ventilation with the same parameters. Moderate hypoxia was induced in seven rats (hyp90) by reducing the FiO2 to ~0.15 until a stable SpO2≈ 90% was achieved. Severe hypoxia was induced in the remaining seven rats (hyp75) by reducing the FiO2 to ~0.1 until a stable SpO2≈ 75% was achieved. At least three follow-up HP-MRI scans were performed at 60, 150 and 240 minutes after start of hypoxemia, followed by final ABG analysis.Results and Discussion
The pyruvate signal did not change significantly over time in any of the groups and was at its most intense in the major vasculature close to the heart. We observed a significant, time-dependent increase in the pulmonary lactate-to-pyruvate ratio in the severely hypoxic rats beginning 1 hour after the start of hypoxia (Figures 1 and 2). The ratio increased slightly in the moderately hypoxic rats compared to the control groups, but this increase did not reach the level of significance. Similarly, arterial blood lactate levels increased in both hypoxic groups relative to controls, but this increase was only significant in the severely hypoxic rats (Figure 4). Our findings are consistent with earlier studies suggesting that overall lung metabolism produces normal levels of lactate even in the presence of moderate reductions in oxygen availability. In contrast, severe hypoxemia results in a metabolic shift from oxidative phosphorylation to glycolysis in the lungs, leading to increased lactate production.Conlusion
We used hyperpolarized [1-13C] pyruvate MRI to assess the effect of hypoxia on pulmonary lactate production. Our results indicate that severe hypoxia results in increased pulmonary lactate-to-pyruvate ratio measured by HP-MRI, while moderate hypoxia does not. Assessing lactate production using an imaging approach enables the evaluation of severely hypoxic regions of the lung that may otherwise be masked by the preponderance of well-aerated regions. Furthermore, this study suggests that previously observed increased anaerobic metabolism in moderately hypoxic and injured lungs (10,11) is predominantly due to the increased metabolic demands of inflamed rather than hypoxic tissue.Acknowledgements
This work has been supported by R01-HL139066.References
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