Severe sepsis occurs in over 750,000 patients each year in the United States and is the leading cause of morbidity and mortality in critical care units. Activation of pro-inflammatory cells by bacterial products leads to a release of inflammatory mediators that induces the systemic inflammatory response of sepsis. The production of these mediators is regulated at the transcriptional level by enhancer elements nuclear factor kappaB(NF-kappaB) and activator protein-1 (AP-1) through interactions with specific kinases. In preliminary in vitro and in vivo studies we have obtained evidence that the systemic inflammatory response of sepsis may be counter-regulated by the nuclear reporter peroxisome proliferator activated receptor-gamma (PPARgamma). Pretreatment of macrophages with the specific PPARgamma ligands 15deoxy-delta12,14-PGJ2 (15d-PGJ2) or the thiazolidinedione troglitazone inhibits pro-inflammatory mediators induced by bacterial lipopolysaccharide (LPS) and heat killed Staphylococcus aureus (HK S. aureus). Consistent with this finding, we have found that PPARgamma ligands improve survival, reduce hemodynamic alterations, cytokine production and neutrophil infiltration in lung, colon and liver in rats subjected to septic shock induced by cecal ligation and puncture. Our central hypothesis is that the nuclear receptor PPARgamma is a critical anti-inflammatory pathway and that PPARgamma activation is beneficial in septic shock. Three interrelated specific aims will test this hypothesis. (1) We will evaluate the therapeutic efficacy of PPARgamma ligands on cardiovascular derangement and organ failure during polymicrobial sepsis in vivo. The effects of 15d-PGJ2, thiazolidinediones and nonthiazolidinedione PPARgamma ligands on septic sequelae will be examined in vivo in rats subjected to cecal ligation and puncture. (2) We will identify the molecular mechanisms of the actions of PPARgamma ligands in polymicrobial sepsis in vivo. The effect of PPARgamma ligands on nuclear activation of NF-kappaB and AP-1 and their regulatory kinases will be examined. (3) We will determine the role of cyclopentencne prostaglandins and PPARgamma in regulating cell signaling and inflammatory mediator production in macrophages/monocytes challenged in vitro with LPS and HK S. aureus. This approach will employ pharmacologic antagonists of PPARgamma and genetic manipulations with PPARgamma dominant/negative constructs and PPARgamma deficient macrophages from Cre-lox mice. The combination of in vivo and in vitro approaches will provide a strong test of the hypothesis that activation of PPARgamma is beneficial in sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067202-02
Application #
6749541
Study Section
Special Emphasis Panel (ZRG1-SSS-W (47))
Program Officer
Somers, Scott D
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$274,794
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Ayalon, Itay; Shen, Hui; Williamson, Lauren et al. (2018) Sepsis Induces Adipose Tissue Browning in Nonobese Mice But Not in Obese Mice. Shock 50:557-564
Kim, Paul; Piraino, Giovanna; O'Connor, Michael et al. (2018) Metformin Exerts Beneficial Effects in Hemorrhagic Shock in An AMPK?1-Independent Manner. Shock 49:277-287
Zingarelli, Basilia; Coopersmith, Craig M; Drechsler, Susanne et al. (2018) Part I: Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) for Study Design And Humane Modeling Endpoints. Shock :
Inata, Yu; Piraino, Giovanna; Hake, Paul W et al. (2018) Age-dependent cardiac function during experimental sepsis: effect of pharmacological activation of AMP-activated protein kinase by AICAR. Am J Physiol Heart Circ Physiol 315:H826-H837
Inata, Yu; Kikuchi, Satoshi; Samraj, Ravi S et al. (2018) Autophagy and mitochondrial biogenesis impairment contribute to age-dependent liver injury in experimental sepsis: dysregulation of AMP-activated protein kinase pathway. FASEB J 32:728-741
Matsiukevich, Dzmitry; Piraino, Giovanna; Klingbeil, Lindsey R et al. (2017) The AMPK Activator Aicar Ameliorates Age-Dependent Myocardial Injury in Murine Hemorrhagic Shock. Shock 47:70-78
Klingbeil, Lindsey R; Kim, Paul; Piraino, Giovanna et al. (2017) Age-Dependent Changes in AMPK Metabolic Pathways in the Lung in a Mouse Model of Hemorrhagic Shock. Am J Respir Cell Mol Biol 56:585-596
Matsiukevich, Dzmitry; Piraino, Giovanna; Lahni, Patrick et al. (2017) Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock. Biochim Biophys Acta Mol Basis Dis 1863:2680-2691
Kaplan, Jennifer M; Nowell, Marchele; Lahni, Patrick et al. (2016) Obesity enhances sepsis-induced liver inflammation and injury in mice. Obesity (Silver Spring) 24:1480-8
Atkinson, Sarah J; Nolan, Meghan; Klingbeil, Lindsey et al. (2016) Intestine-Derived Matrix Metalloproteinase-8 Is a Critical Mediator of Polymicrobial Peritonitis. Crit Care Med 44:e200-6

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