Changes in peroxisome proliferator-activated receptor-gamma activity in children with septic shock
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To assess changes in peroxisome proliferator-activated receptor-γ (PPARγ) in peripheral blood mononuclear cells (PBMC) from critically ill children with sepsis. Additionally, to investigate the effects of sepsis on the endogenous activator of PPARγ, 15-deoxy-∆12,14-PGJ2 (15d-PGJ2), and the downstream targets of PPARγ activity, adiponectin and resistin.
Single-center, prospective case–control study in critically ill children with systemic inflammatory response syndrome, sepsis or septic shock.
PPARγ nuclear protein expression was decreased but PPARγ activity was increased in PBMC from children with septic shock compared with controls. PPARγ activity on day 1 was significantly higher in patients with higher pediatric risk of mortality (PRISM) score compared with controls [mean 0.22 optical density (OD) ± standard error of the mean (SEM) 0.03 versus 0.12 OD ± 0.02; p < 0.001]. Patients with resolved sepsis had increased levels of the endogenous PPARγ ligand, 15d-PGJ2, compared with patients with systemic inflammatory response syndrome (SIRS) and septic shock (77.7 ± 21.7 versus 58 ± 16.5 pg/ml; p = 0.03). Plasma high-molecular-weight adiponectin (HMWA) and resistin levels were increased in patients with septic shock on day 1 and were significantly higher in patients with higher PRISM scores. Nonsurvivors from sepsis had higher resistin levels on the first day of hospitalization compared with survivors from septic shock [660 ng/ml, interquartile range (IQR) 585–833 ng/ml versus 143 ng/ml, IQR 66–342 ng/ml; p < 0.05].
Sepsis is associated with altered PPARγ expression and activity in PBMC. Plasma adipokines correlate with risk of mortality scores in sepsis and may be useful biomarkers. Further studies are needed to understand the mechanisms underlying changes in PPARγ in sepsis.
KeywordsSepsis Resistin Adiponectin 15-Deoxy-∆12,14-PGJ2 PPARγ Cytokines
We would like to thank the parents who enrolled their children into this study during an emotionally difficult time. Supported, in part, by grants K12 HD028827 (J.M.K.), T32 ES10957 (J.M.K.), R01 GM067202 (B.Z.), and R01 GM064619 (H.W.) from the NIH, Bethesda, MD, and by the Translational Research Initiative at Cincinnati Children’s Hospital Medical Center (J.M.K.).
- 7.Zingarelli B, Sheehan M, Hake PW, O’Connor M, Denenberg A, Cook JA (2003) Peroxisome proliferator activator receptor-gamma ligands, 15-deoxy-delta(12, 14)-prostaglandin J2 and ciglitazone, reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways. J Immunol 171:6827–6837PubMedGoogle Scholar
- 10.Zhou M, Wu R, Dong W, Simms HH, Wang P (2004) Hepatic peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is downregulated in sepsis. Shock 21:39Google Scholar
- 13.Klotz L, Schmidt M, Giese T, Sastre M, Knolle P, Klockgether T, Heneka MT (2005) Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients. J Immunol 175:4948–4955PubMedGoogle Scholar
- 19.Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE (2004) Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279:12152–12162CrossRefPubMedGoogle Scholar
- 21.Han J, Hajjar DP, Tauras JM, Feng J, Gotto AM Jr, Nicholson AC (2000) Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma. J Biol Chem 275:1241–1246CrossRefPubMedGoogle Scholar
- 29.Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, Manabe I, Utsunomiya K, Nagai R (2004) Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun 314:415–419CrossRefPubMedGoogle Scholar
- 32.Way JM, Gorgun CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR Jr, Willson TM, Kliewer SA, Hotamisligil GS (2001) Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 276:25651–25653CrossRefPubMedGoogle Scholar
- 34.Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y (2001) PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094–2099CrossRefPubMedGoogle Scholar
- 35.Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB, Tanen M, Berg AH, O’Rahilly S, Savage DB, Chatterjee K, Weiss S, Larson PJ, Gottesdiener KM, Gertz BJ, Charron MJ, Scherer PE, Moller DE (2002) Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 143:998–1007CrossRefPubMedGoogle Scholar
- 36.Teoh H, Quan A, Bang KW, Wang G, Lovren F, Vu V, Haitsma JJ, Szmitko PE, Al-Omran M, Wang CH, Gupta M, Peterson MD, Zhang H, Chan L, Freedman J, Sweeney G, Verma S (2008) Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality. Am J Physiol Endocrinol Metab 295:E658–E664CrossRefPubMedGoogle Scholar