Increased hyperpolarized [1-13 C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13 C-labelled bicarbonate.
NMR in Biomedicine. 2018-01-30; 31(4): e3892
DOI: 10.1002/nbm.3892
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Wright AJ(1), Husson ZMA(2), Hu DE(1), Callejo G(2), Brindle KM(1)(3), Smith ESJ(2).
Author information:
(1)Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
(2)Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, UK.
(3)Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK.
Arthritic conditions are a major source of chronic pain. Furthering our understanding of disease mechanisms creates the opportunity to develop more targeted therapeutics. In rheumatoid arthritis (RA), measurements of pH in human synovial fluid suggest that acidosis occurs, but that this is highly variable between individuals. Here we sought to determine if tissue acidosis occurs in a widely used rodent arthritis model: complete Freund’s adjuvant (CFA)-induced inflammation. CFA robustly evoked paw and ankle swelling, concomitant with worsening clinical scores over time. We used magnetic resonance spectroscopic imaging of hyperpolarized [1-13 C]pyruvate metabolism to demonstrate that CFA induces an increase in the lactate-to-pyruvate ratio. This increase is indicative of enhanced glycolysis and an increased lactate concentration, as has been observed in the synovial fluid from RA patients, and which was correlated with acidosis. We also measured the 13 CO2 /H13 CO3- ratio, in animals injected with hyperpolarized H13 CO3- , to estimate extracellular tissue pH and showed that despite the apparent increase in glycolytic activity in CFA-induced inflammation there was no accompanying decrease in extracellular pH. The pH was 7.23 ± 0.06 in control paws and 7.32 ± 0.09 in inflamed paws. These results could explain why mice lacking acid-sensing ion channel subunits 1, 2 and 3 do not display any changes in mechanical or thermal hyperalgesia in CFA-induced inflammation.
© 2018 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.