A104-15 Hif1a-related Glycolysis Quantified by 18Ffdg-pet: A Polit Analysis in an ARDS Sheep Model

Abstract Introduction Hypoxia-inducible factor (HIF)1A is a crucial factor for cellular adaptation to hypoxia. In acute respiratory distress syndrome (ARDS), HIF1A is stabilized by hypoxia or nonhypoxic mechanism like cyclic mechanical stretch. Such stabilization has been reported in mice to attenuate lung inflammation via enhancement of glycolysis. 18FFDG-PET allows for noninvasive assessment of in vivo glycolysis including glucose transport and metabolism. However, it is unclear whether HIF1A promotes glycolysis in the heterogeneously expanded large size injured lungs and that can be quantified by 18FFDG-PET imaging. We therefore hypothesize that, in large animal ARDS lungs, HIF1A induces local glycolysis in both hypoxic atelectatic and nonhypoxic aerated regions, which correlates with 18FFDG-quantified local in vivo pulmonary cellular metabolic activity. Methods Twelve female sheep (18.2 ± 2.3 kg) underwent general anesthesia, unilateral lung atelectasis using a left bronchial blocker and lateral thoracotomy while the right lung was mechanically ventilated for 8 hours in the absence (n = 6) or presence (n = 6) of systemic lipopolysaccharide (LPS). 18FFDG-PET scans were performed at the end of experiment and computed tomography (CT)-guided samples were harvested from the hypoxic atelectatic and nonhypoxic aerated lung regions. HIF1A-related glycolysis was analyzed in both lung regions and correlated with 18FFDG dynamic parameters including tissue-normalized uptake rate, an in vivo measure of cellular metabolic activity, and cellular phosphorylation rate. Results Lung regions of interest were confirmed by CT showing the hypoxic atelectatic lung with gas fraction0.1 and the nonhypoxic aerated lung with gas fraction consistent with normal aeration. With LPS exposure, HIF1A-related glycolysis was enhanced as evidenced by significantly increased gene expression of HIF1A and its targeted glycolysis relevant genes including HK2, HK1, LDH and PKM in both atelectatic and aerated lung regions. PET-quantified glycolysis was also increased in both lung regions, characterized by substantial increases in tissue-normalized 18FFDG uptake rate and cellular phosphorylation rate. HIF1A gene expression was significantly correlated with tissue-normalized 18FFDG uptake rate (Figure A) and cellular phosphorylation rate (Figure B). In addition, HIF1A-targeted glycolysis enzyme HK2 (Figure C) and relevant signaling factor PFKFB3 (Figure D) were further correlated with tissue-normalized 18FFDG uptake rate. Conclusion In heterogeneously expanded large size lungs, there is a functional link between HIF1A-related glycolysis signaling and 18FFDG-PET-quantified in vivo pulmonary cellular metabolic activity during ARDS. These findings support HIF1A as an adaptive molecule mediating cellular metabolism in ARDS and demonstrate the applicability of an imaging technique translatable to humans to assess in vivo relevant HIF1A-related processes. This abstract is funded by: NIH-NHLBI Grant R01 HL121228