RESEARCH ARTICLE Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome Mehrdad Pourfathi 1 | Yi Xin 1 | Michael Rosalino 1 | Maurizio Cereda 1,2 | Stephen Kadlecek 1 | Ian Duncan 1 | Harrilla Profka 1 | Hooman Hamedani 1 | Sarmad Siddiqui 1 | Kai Ruppert 1 | Shampa Chatterjee 3 | Rahim R. Rizi 1 1 Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA 2 Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, USA 3 Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA Correspondence Rahim R. Rizi, Ph.D., Department of Radiology, University of Pennsylvania, 3400 Spruce Street, MRI Learning Center, Philadelphia, PA 19104. Email: rahim.rizi@uphs.upenn.edu Funding information National Heart, Lung, and Blood Institute; NIH, Grant/Award Numbers: R01-HL124986, R01-HL139066 Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was con- ducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmo- nary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopath- ological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactate- to-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia. KEYWORDS animal model study, body, hyperpolarized 13 C, lung, MRS, MRSI Abbreviations used: ANOVA, analysis-of-variance; ARDS, acute respiratory distress syndrome; CT, computed tomography; FiO2, fraction of inspired oxygen; FDG, fluorodeoxyglucose; H&E, hematoxylin and eosin; HCl, hydrochloric acid; HIF, hypoxia-inducible factor; HP, hyperpolarized; ICAM, intracellular adhesion molecule; LDH, lactate dehyrogenase; MPO, myeloperoxidase; MRI, magnetic resonance imaging; PET, positron emission tomography; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; ROS, reactive oxygen species; ZEEP, zero end- expiratory pressure. Received: 24 March 2019 Revised: 15 June 2020 Accepted: 29 June 2020 DOI: 10.1002/nbm.4380 NMR in Biomedicine. 2020;e4380. wileyonlinelibrary.com/journal/nbm © 2020 John Wiley & Sons, Ltd. 1 of 14 https://doi.org/10.1002/nbm.4380