Objective
Peroxisome-proliferator activated receptor alpha (PPARα) is significantly downregulated in circulating leukocytes from children with sepsis. PPARα null (Ppara−/−) mice have greater mortality than wild type (WT) mice when subjected to sepsis by cecal ligation and puncture (CLP). We sought to characterize the role of PPARα in sepsis and to identify the mechanism whereby PPARα confers a survival advantage.
Design
Prospective randomized pre-clinical study.
Setting
Laboratory investigation.
Subjects
Male C57Bl/6J and Ppara−/− mice (B6.129S4-Pparatm1Gonz/J), aged 12–16 weeks.
Interventions
Bone marrow chimeric mice were generated and subjected to CLP. Survival was measured for seven days. Separate groups of non-transplanted mice underwent CLP and were euthanized 24 hours later for plasma and tissue analyses.
Measurements and Main Results
Ppara−/− mice had dramatically reduced survival compared to WT mice irrespective of the PPARα status of the bone marrow they received (3% vs. 63%, p < 0.0001). No difference in survival was observed between Ppara−/− mice that received WT vs. Ppara−/− marrow or in WT mice receiving WT vs. Ppara−/− marrow. In septic, non-transplanted mice at 24 hours, Ppara−/− mice had elevated cardiac troponin levels compared to WT mice. Cardiac histologic injury scores were greater in Ppara−/− vs. WT mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly downregulated in both WT and Ppara−/− mice, but more so in the Ppara−/− mice.
Conclusions
PPARα expression in non-hematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic PPARα expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara−/− mice. These results suggest that altered PPARα-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.
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