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Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival
Charles E. McCall, … , Peter W. Stacpoole, Vidula Vachharajani
Charles E. McCall, … , Peter W. Stacpoole, Vidula Vachharajani
Published August 9, 2018
Citation Information: JCI Insight. 2018;3(15):e99292. https://doi.org/10.1172/jci.insight.99292.
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Research Article Immunology Infectious disease

Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival

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Abstract

Limited understanding of the mechanisms responsible for life-threatening organ and immune failure hampers scientists’ ability to design sepsis treatments. Pyruvate dehydrogenase kinase 1 (PDK1) is persistently expressed in immune-tolerant monocytes of septic mice and humans and deactivates mitochondrial pyruvate dehydrogenase complex (PDC), the gate-keeping enzyme for glucose oxidation. Here, we show that targeting PDK with its prototypic inhibitor dichloroacetate (DCA) reactivates PDC; increases mitochondrial oxidative bioenergetics in isolated hepatocytes and splenocytes; promotes vascular, immune, and organ homeostasis; accelerates bacterial clearance; and increases survival. These results indicate that the PDC/PDK axis is a druggable mitochondrial target for promoting immunometabolic and organ homeostasis during sepsis.

Authors

Charles E. McCall, Manal Zabalawi, Tiefu Liu, Ayana Martin, David L. Long, Nancy L. Buechler, Rob J. W. Arts, Mihai Netea, Barbara K. Yoza, Peter W. Stacpoole, Vidula Vachharajani

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Figure 9

Dichloroacetate (DCA) improves survival and accelerates bacterial clearance in septic mice.

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Dichloroacetate (DCA) improves survival and accelerates bacterial cleara...
(A) To assess the effect of DCA on survival, we treated mice 24 hours after cecal ligation and puncture (CLP) with a single i.p. dose of 25 mg/kg of DCA (CLP+ DCA) vs. a vehicle control (CLP+ vehicle) and followed 14-day survival. Kaplan-Maier survival curve shows that DCA (CLP+ DCA) significantly improved 14-day survival vs. vehicle treatment (CLP+ vehicle) in the absence of antibiotics. n = 20 in each of 2 cohorts. n = 20 mice/cohort; Log-rank (Mantel-Cox) test. **P < 0.01. (B) To determine the effect of infection in the absence of antibiotics, we assessed bacterial clearance from the peritoneal cavity, using colony count methodology. Animals were treated with vehicle or DCA as a single dose of 25 mg/kg i.p. 24 hours after CLP sepsis induction, and samples were obtained 6 hours after vehicle or DCA treatment. DCA significantly reduced the microbial colony counts in the peritoneum. SHAM, n = 4; CLP, n = 7; CLP+ DCA, n = 7,. Sidak’s multiple comparisons test. Note: Since the axis is logarithmic, only values greater than zero can be plotted. For this graph, 2 values were zero or negative, so they are not visible on the graph.

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