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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.

Published version
Peer-reviewed

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Authors

Husson, Zoé MA 
Hu, De-En 
Callejo, Gerard 

Abstract

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.

Description

Keywords

MRI, acidosis, arthritis, inflammation, lactate, pain, Acidosis, Animals, Bicarbonates, Carbon Dioxide, Carbon Isotopes, Disease Models, Animal, Female, Freund's Adjuvant, Hydrogen-Ion Concentration, Inflammation, Joints, Lactic Acid, Mice, Inbred C57BL

Journal Title

NMR Biomed

Conference Name

Journal ISSN

0952-3480
1099-1492

Volume Title

31

Publisher

Wiley
Sponsorship
ARTHRITIS RESEARCH UK (20930)
Cancer Research UK (CB4100)
Cancer Research UK (C14303/A17197)
Cancer Research UK (17242)
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