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Nonhematopoietic Peroxisome Proliferator-Activated Receptor-? Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.

ABSTRACT: Peroxisome proliferator-activated receptor-? is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-? null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-? in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-? confers a survival advantage.Prospective randomized preclinical study.Laboratory investigation.Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses.Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-? status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara mice that received wild-type versus Ppara marrow or in wild-type mice receiving wild-type versus Ppara marrow. In septic, nontransplanted mice at 24 hours, Ppara mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara mice, but more so in the Ppara mice.Peroxisome proliferator-activated receptor-? expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator-activated receptor-? 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 peroxisome proliferator-activated receptor-?-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.

SUBMITTER: Standage SW

PROVIDER: S-EPMC4940302 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.

Standage Stephen W SW Waworuntu Rachel L RL Delaney Martha A MA Maskal Sara M SM Bennion Brock G BG Duffield Jeremy S JS Parks William C WC Liles W Conrad WC McGuire John K JK

Critical care medicine 20160801 8

<h4>Objectives</h4>Peroxisome proliferator-activated receptor-α is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-α null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-α in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-α confers a su ...[more]

PMID: 26757163

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Project description:The development of cardiac dysfunction caused by microbial infection predicts high mortality in sepsis patients. Specialized pro-resolving mediators (SPMs) mediate resolution of inflammation in many inflammatory diseases, and are differentially expressed in plasma of sepsis patients. Here, we investigated whether the levels of SPMs are altered in the murine septic heart following polymicrobial sepsis-induced cardiac dysfunction. Ten weeks-old male C57BL/6 mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP), which is a clinically relevant sepsis model receiving analgesics, antibiotics, and fluid resuscitation. CLP caused a significant systolic dysfunction assessed by echocardiography. The hearts were subjected to LC-MS/MS based lipid mediator profiling. Many SPMs were significantly reduced in septic hearts, among which RvE1 had a ~93-fold reduction. Treatment of CLP mice with synthetic RvE1 (1 μg/mouse i.v.) at 1 h after CLP increased peritoneal macrophages number, particularly MHC II- macrophages. RvE1 reduced pro-inflammatory gene expression (interleukin-1β, interleukin-6, and CCL2) in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs) in vitro. RvE1 attenuated cardiac dysfunction in septic mice and increased cardiac phosphorylated Akt; decreased cardiac phosphorylated IκB kinase α/β, nuclear translocation of the NF-κB subunit p65, extracellular signal-regulated kinase 1/2, and c-Jun amino-terminal kinases 1/2. Most notably, RvE1 treatment reduced peritoneal bacterial load and promoted phagocytosis activity of BMDMs. In conclusion, cardiac SPMs, particularly RvE1, are substantially reduced in mice with polymicrobial sepsis. Delayed therapeutic administration of RvE1 to mice with polymicrobial sepsis attenuates the cardiac dysfunction through modulating immuno-inflammatory responses. In addition to the above effects, the ability to enhance bacterial clearance makes RvE1 an ideal therapeutic to reduce the sequalae of polymicrobial sepsis.

Dataset Information

Nonhematopoietic Peroxisome Proliferator-Activated Receptor-? Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.

Publications

Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.

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