Novel Therapeutic Agents in Pediatric Sepsis: Peroxisome Proliferator Receptor γ (PPAR γ) Agonists

Open Inflamm J. Author manuscript; available in PMC 2012 October 7.

Published in final edited form as:

Open Inflamm J. 2011 October 7; 4(Suppl 1-M14): 120–124.

PMCID: PMC3258510

NIHMSID: NIHMS340948

Novel Therapeutic Agents in Pediatric Sepsis: Peroxisome Proliferator Receptor γ (PPAR γ) Agonists

Jennifer M. Kaplan, M.D., M.S. and Basilia Zingarelli, M.D., Ph.D.

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

The publisher's final edited version of this article is available at Open Inflamm J

Introduction

Sepsis is a clinical entity involving a massive systemic inflammatory response that can lead to multiple organ dysfunction and death. Although antibiotic therapy treats the underlying infection, it does not reverse the cascade of signaling events activating the innate immune system. A major pathophysiologic event is that, upon interaction with invading micro-organisms, the immuno-competent or parenchymal cells of the host produce an overwhelming amount of endogenous pro-inflammatory mediators. This production is regulated at the nuclear level by a rapid activation of transcription factors.

Peroxisome Proliferator-Activated Receptors (PPARs)

PPARs are a large superfamily of nuclear receptors which are ligand-dependent transcription factors that influence cellular responses by altering gene expression. Although PPARs were initially described as important in triglyceride and cholesterol homeostasis these receptors are also important in regulating the inflammatory response [1]. PPARs are found in numerous tissues and immune cells such as lymphocytes, monocytes, macrophages, dendritic cells and granulocytes [2-6]. Three isoforms of the PPAR subfamily have been identified: PPARα, PPARβ or δ, and PPARγ [1, 7].

PPARγ is important in regulating adipocyte proliferation, glucose homeostasis, and inflammation. Upon ligand binding, PPARγ forms a heterodimer with the retinoic acid receptor (RXR). The interaction with the RXR allows the recruitment of a set of cofactors. This complex binds to the PPAR response element (PPRE) in the promoter region of certain target genes to modulate transcription [8-10]. PPARγ can transactivate and transrepress target genes through ligand-dependent and independent mechanisms [11-14].

Modulation of PPARγ activity

Inflammatory conditions affect PPARγ expression and function in many tissues including lung, liver, and adipose tissue [15-17]. PPARγ expression was downregulated on the endothelium of thoracic aortas and in the lung in polymicrobial sepsis in rats [16, 17]. Zhou et al. demonstrated that hepatic PPARγ protein expression was downregulated in the late stages of polymicrobial sepsis but was maintained early in sepsis [18, 19].

PPARγ activity is also altered in human inflammatory conditions. For example, biopsies obtained from the colon of children with Crohn's disease demonstrated a significant reduction of PPARγ mRNA expression compared to control subjects [20]. Culver et al. demonstrated that nuclear PPARγ expression is decreased in alveolar macrophages in patients with the inflammatory disease sarcoidosis [21]. Similarly, patients with multiple sclerosis have a significant reduction in PPARγ protein expression in peripheral blood mononuclear cells (PBMC) [22].

One of the few studies to evaluate PPARγ from patients with sepsis demonstrated an increase in PPARγ expression in T lymphocytes and suggested that PPARγ contributes to T cell apoptosis during sepsis, leading to sepsis-induced lymphopenia [23]. Similar findings on PPARγ were demonstrated by Reddy et al in polymorphonuclear (PMN) cells from patients with sepsis. It was found that PPARγ mRNA expression was significantly increased in PMNs from patients with sepsis compared to the control group. The authors suggest that PPARγ may play a role in the chemotactic response of PMNs in sepsis [24]. Data from our laboratory demonstrate that PBMCs isolated from children with sepsis demonstrate a decrease in nuclear PPARγ protein expression (in press). However despite this decrease, we found that PPARγ activity was increased in patients with septic shock compared to control patients (in press). The PPARγ activity increase in patients with septic shock may be a result of an increase in plasma levels of the endogenous ligand 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂). Together these studies suggest that PPARγ expression and activity is altered in many inflammatory conditions and in many tissues and immunologic cells.

Changes in PPARγ function may also be reflected in alterations in PPARγ target proteins, such as the plasma adipokines, adiponectin and resistin, which have a PPARγ response element in their promoter regions [25-27]. In a recent clinical study, we have observed that plasma levels of resistin and high molecular weight adiponectin (HMWA), the form of adiponectin with metabolic properties, were increased in children with septic shock on the first day of hospitalization compared with control subjects (in press). Similar to PPARγ activity levels, HMWA and resistin levels were higher in patients with higher PRISM scores. Furthermore, day one resistin levels were higher in patients who did not survive from septic shock compared to survivors from septic shock (in press). These findings suggest that the adipokines, HMWA and resistin, may be used clinically to reflect changes in PPARγ activity and may represent valid biomarkers to predict outcome in patients with sepsis.

The molecular mechanisms, which alter PPARγ in sepsis remain unknown. Post-translational modifications, including phosphorylation, can regulate the function of PPARγ [28]. The AF-1 domain of PPARγ contains a consensus mitogen-activated protein kinase (MAPK) site and phosphorylation at serine residue 82 (or 112 for PPARγ2) leads to inhibition of PPARγ transactivation [29, 30]. Furthermore, this phosphorylated-induced repression is due to conformational changes that lead to altered affinity for ligands and cofactors [29, 30]. Another potential mechanism affecting PPARγ involves changes in co-activator and/or co-repressor activity. Cardiac and adipose PGC-1α expression is decreased after lipopolysaccharide (LPS) administration and this correlates with a decrease in PPARγ target gene activation [31, 32]. The transcription factor FoxO1 can also directly transrepresses PPARγ through direct protein-protein interactions to inhibit PPARγ gene expression [33, 34]. The mechanisms responsible for the changes in PPARγ in sepsis are unknown and are the focus of current investigations.

The PPARγ ligands and inflammation

The insulin-sensitizing drugs, thiazolidinediones (TZDs), and the cyclopentenone prostaglandin, 15d-PGJ₂, are specific PPARγ agonists [9, 10, 35]. Thiazolidinediones are Food and Drug Administration (FDA) approved insulin-sensitizing drugs for the treatment of type 2 diabetes mellitus. However, preclinical experimental in vitro and in vivo studies have demonstrated that pharmacological activation of PPARγ provides potent anti-inflammatory effects, which may be independent from their metabolic properties. In 1998, Ricote et al. and Jiang et al. independently made the initial observation that PPARγ is involved in the regulation of the inflammatory response in monocytes/macrophages and raised the possibility that synthetic PPARγ ligands may be of therapeutic value in inflammatory diseases [3, 36]. TZDs include rosiglitazone, pioglitazone, troglitazone, and ciglitazone [37, 38]. There is recent controversy regarding long-term treatment of type II diabetic patients with rosiglitazone and an associated increase in cardiovascular events [39]. Thiazolidinediones remain effective at reducing inflammatory mediators in non-diabetic patients with carotid artery stenosis, metabolic syndrome, and polycystic ovary syndrome [40-42].

The endogenous ligand, 15d-PGJ₂, is produced from arachidonic acid via cyclo-oxygenases (COX). COX-1 is constitutively expressed but COX-2 is induced after LPS stimulation through activation of nuclear factor-κB (NF-κB) [43, 44]. 15d-PGJ₂ can also repress the expression of inflammatory genes in activated macrophages including tumor necrosis factor-α (TNFα) and COX-2 [3]. Data from our laboratory and others demonstrate that, although 15d-PGJ₂ is a PPARγ ligand, its anti-inflammatory effects on NF-κB activation occurs through PPARγ-dependent and independent mechanisms [45-48]. One mechanism by which 15d-PGJ₂ has effects is through binding of the electrophilic carbon in the cyclopentenone ring to cellular proteins, modifying signaling pathways [49]. This mechanism may account for the direct repression of NF-κB by 15d-PGJ₂ [50]. Non-steroidal anti-inflammatory drugs, which inhibit cyclo-oxygenase (COX)-1 and COX-2, such as ibuprofen, indomethacin, flufenamic acid and fenoprofen, also bind to PPARγ and activate PPARγ-dependent transcription, but at much higher concentrations compared to other PPARγ ligands [51].

Clinically, 15d-PGJ₂ production may predict PPARγ activation in vivo. 15d-PGJ₂ can be measured in urine, synovial fluid and plasma [52, 53]. Urinary 15d-PGJ₂ has been detected in healthy volunteers in the range of 6 to 7 pg/mg creatinine [52]. Our experimental animal data demonstrates that plasma levels of 15d-PGJ₂ are decreased in sepsis and correlate with a similar decrease in PPARγ activity [54]. In humans, 15d-PGJ₂ levels also correlate with PPARγ activity. Children with resolved sepsis had elevated 15d-PGJ₂ levels compared to patients with the systemic inflammatory response syndrome (SIRS) and septic shock (in press). It is not surprising that 15d-PGJ₂ is activated during the inflammatory response from sepsis. 15d-PGJ₂ is produced from arachidonic acid via cyclo-oxygenases (COX), enzymes known to be induced after LPS stimulation [43]. Therefore, 15d-PGJ₂ levels may be increased in sepsis as a compensatory mechanism and contribute to an increase in PPARγ activity.

PPARγ ligands and Sepsis

Several studies have demonstrated that activation of PPARγ by specific ligands significantly improves survival in clinically relevant models of septic shock [16, 17, 55]. The beneficial effect of PPARγ activation is likely to be secondary to inhibition of the production of several inflammatory mediators. Data from our laboratory demonstrate that treatment with 15d-PGJ₂ and ciglitazone improves hypotension and vascular injury and reduces neutrophil infiltration in the lung, colon and liver following polymicrobial sepsis [16]. Furthermore, this reduction in inflammation leads to significantly improved survival. PPARγ ligands provide beneficial effects through modulating the NF-κB and AP-1 signal transduction pathways. Additionally in a model of endotoxic shock post-treatment with 15d-PGJ₂ improved survival and reduced adhesion molecule expression and neutrophil infiltration through a reduction in NF-κB activation [17].

These potent anti-inflammatory actions of PPARγ ligands have been also demonstrated during the cellular innate immune response to bacterial stimuli. For example, 15d-PGJ₂ and the thiazolidinedione troglitazone suppressed thromboxane 2 (TxB₂) and NO production in a dose dependent manner in rat peritoneal macrophages stimulated with heat-killed Staphylococcus aureus or Escherichia coli [56]. Ciglitazone-treated C57Bl/6 mice inoculated with Streptococcus pneumoniae had fewer bacteria, reduced pro-inflammatory cytokine expression in the lung, and increased survival compared with vehicle-treated mice [57]. This effect however was not secondary to an increase in alveolar macrophage phagocytosis of bacteria.

Other PPARγ activators have been described. Recently, the yellow in phyto-chemical pigment of curry, curcurmin has been demonstrated to exhibit anti-inflammatory properties in a rat model of sepsis by up-regulation of PPARγ expression [19]. Experimental in vitro studies in kidney proximal tubular cells have also shown that c-peptide, the 31 amino acid peptide of pro-insulin, induces a concentration-dependent transcriptional activation of PPARγ [58]. Interestingly, when adiminstered in vivo to mice subjected to endotoxic shock, c-peptide demonstrated beneficial effects in improving survival and reducing the systemic inflammatory response. This therapeutic effect was associated with activation of PPARγ [59].

Conclusion

The PPARγ pathway is clearly altered in inflammatory conditions including sepsis. Experimental in vitro and in vivo studies demonstrate the benefits of using PPARγ agonists on decreasing the inflammatory response in sepsis. These agents improve outcomes in animal studies. The effects of sepsis on the PPARγ pathway in clinical sepsis demonstrate that the changes in PPARγ changes may be dependent on cell type studied. Furthermore it has been determined whether PPARγ agonists will have an impact clinically in patients with sepsis.

Acknowledgments

Supported in part by grants K12 HD028827 (JK), R01 GM067202 (BZ) and R01 AG027990 (BZ).

References

1. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–50. [PubMed]

2. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, et al. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol. 2000;164:1364–71. [PubMed]

3. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82. [PubMed]

4. Appel S, Mirakaj V, Bringmann A, et al. PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood. 2005;106:3888–94. [PubMed]

5. Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation. 2000;101:235–8. [PubMed]

6. Jackson SM, Parhami F, Xi XP, et al. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vasc Biol. 1999;19:2094–104. [PubMed]

7. Kliewer SA, Forman BM, Blumberg B, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994;91:7355–9. [PubMed]

8. Nolte RT, Wisely GB, Westin S, et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998;395:137–43. [PubMed]

9. Palmer CN, Hsu MH, Griffin HJ, Johnson EF. Novel sequence determinants in peroxisome proliferator signaling. J Biol Chem. 1995;270:16114–21. [PubMed]

10. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992;358:771–4. [PubMed]

11. Dowell P, Ishmael JE, Avram D, et al. p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha. J Biol Chem. 1997;272:33435–43. [PubMed]

12. Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol. 2006;6:44–55. [PubMed]

13. Pascual G, Fong AL, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–63. [PMC free article] [PubMed]

14. Ghisletti S, Huang W, Ogawa S, et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell. 2007;25:57–70. [PMC free article] [PubMed]

15. Hill MR, Young MD, McCurdy CM, Gimble JM. Decreased expression of murine PPARgamma in adipose tissue during endotoxemia. Endocrinology. 1997;138:3073–6. [PubMed]

16. Zingarelli B, Sheehan M, Hake PW, et al. 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. 2003;171:6827–37. [PubMed]

17. Kaplan JM, Cook JA, Hake PW, et al. 15-deoxy-delta12,14-prostaglandin J2 (15D-PGJ2), a peroxisome proliferator activated receptor gamma ligand, reduces tissue leukosequestration and mortality in endotoxic shock. SHOCK. 2005;24:59–65. [PubMed]

18. Zhou M, Wu R, Dong W, Simms HH, Wang P. Hepatic peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is downregulated in sepsis. SHOCK. 2004;21:39.

19. Siddiqui AM, Cui X, Wu R, et al. The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma. Crit Care Med. 2006;34:1874–82. [PubMed]

20. Han X, Osuntokun B, Benight N, et al. Signal transducer and activator of transcription 5b promotes mucosal tolerance in pediatric Crohn's disease and murine colitis. Am J Pathol. 2006;169:1999–2013. [PubMed]

21. Culver DA, Barna BP, Raychaudhuri B, et al. Peroxisome proliferator-activated receptor gamma activity is deficient in alveolar macrophages in pulmonary sarcoidosis. Am J Respir Cell Mol Biol. 2004;30:1–5. [PubMed]

22. Klotz L, Schmidt M, Giese T, et al. 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. 2005;175:4948–55. [PubMed]

23. Soller M, Tautenhahn A, Brune B, et al. Peroxisome proliferator-activated receptor gamma contributes to T lymphocyte apoptosis during sepsis. J Leukoc Biol. 2006;79:235–43. [PubMed]

24. Reddy RC, Narala VR, Keshamouni VG, et al. Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-{gamma} Blood. 2008;112:4250–8. [PubMed]

25. Patel L, Buckels AC, Kinghorn IJ, et al. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun. 2003;300:472–6. [PubMed]

26. Yang B, Brown KK, Chen L, et al. Serum adiponectin as a biomarker for in vivo PPARgamma activation and PPARgamma agonist-induced efficacy on insulin sensitization/lipid lowering in rats. BMC Pharmacol. 2004;4:23. [PMC free article] [PubMed]

27. Iwaki M, Matsuda M, Maeda N, et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes. 2003;52:1655–63. [PubMed]

28. Han J, Hajjar DP, Tauras JM, et al. 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. 2000;275:1241–6. [PubMed]

29. Camp HS, Tafuri SR. Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. J Biol Chem. 1997;272:10811–6. [PubMed]

30. Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK. Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem. 1997;272:5128–32. [PubMed]

31. Lu B, Moser AH, Shigenaga JK, Feingold KR, Grunfeld C. Type II nuclear hormone receptors, coactivator, and target gene repression in adipose tissue in the acute-phase response. J Lipid Res. 2006;47:2179–90. [PubMed]

32. Feingold K, Kim MS, Shigenaga J, Moser A, Grunfeld C. Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab. 2004;286:E201–7. [PubMed]

33. Fan W, Imamura T, Sonoda N, et al. FOXO1 Transrepresses Peroxisome Proliferator-activated Receptor {gamma} Transactivation, Coordinating an Insulin-induced Feed-forward Response in Adipocytes. J Biol Chem. 2009;284:12188–97. [PubMed]

34. Kim JJ, Li P, Huntley J, et al. FoxO1 haploinsufficiency protects against high fat diet-induced insulin resistance with enhanced PPAR{gamma} activation in adipose tissue. Diabetes. 2009 [PMC free article] [PubMed]

35. Kliewer SA, Lenhard JM, Willson TM, et al. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995;83:813–9. [PubMed]

36. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82–6. [PubMed]

37. Willson TM, Lehmann JM, Kliewer SA. Discovery of ligands for the nuclear peroxisome proliferator-activated receptors. Ann N Y Acad Sci. 1996;804:276–83. [PubMed]

38. Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) J Biol Chem. 1995;270:12953–6. [PubMed]

39. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71. [PubMed]

40. Samaha FF, Szapary PO, Iqbal N, et al. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol. 2006;26:624–30. [PubMed]

41. Majuri A, Santaniemi M, Rautio K, et al. Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study. Eur J Endocrinol. 2007;156:263–9. [PubMed]

42. Meisner F, Walcher D, Gizard F, et al. Effect of Rosiglitazone Treatment on Plaque Inflammation and Collagen Content in Nondiabetic Patients: Data From a Randomized Placebo-Controlled Trial. Arterioscler Thromb Vasc Biol. 2006;26:845–50. [PubMed]

43. Shibata T, Kondo M, Osawa T, et al. 15-deoxy-delta 12,14-prostaglandin J2. A prostaglandin D2 metabolite generated during inflammatory processes. J Biol Chem. 2002;277:10459–66. [PubMed]

44. Inoue H, Tanabe T. Transcriptional role of the nuclear factor kappa B site in the induction by lipopolysaccharide and suppression by dexamethasone of cyclooxygenase-2 in U937 cells. Biochem Biophys Res Commun. 1998;244:143–8. [PubMed]

45. Straus DS, Pascual G, Li M, et al. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci U S A. 2000;97:4844–9. [PubMed]

46. Giri S, Rattan R, Singh AK, Singh I. The 15-deoxy-delta12,14-prostaglandin J2 inhibits the inflammatory response in primary rat astrocytes via down-regulating multiple steps in phosphatidylinositol 3-kinase-Akt-NF-kappaB-p300 pathway independent of peroxisome proliferator-activated receptor gamma. J Immunol. 2004;173:5196–208. [PubMed]

47. Yang XY, Wang LH, Chen T, et al. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J Biol Chem. 2000;275:4541–4. [PubMed]

48. Kaplan J, Cook JA, O'Connor M, Zingarelli B. Peroxisome proliferator-activated receptor gamma is required for the inhibitory effect of ciglitazone but not 15-deoxy-Delta 12,14-prostaglandin J2 on the NFkappaB pathway in human endothelial cells. Shock. 2007;28:722–6. [PubMed]

49. Atsmon J, Sweetman BJ, Baertschi SW, Harris TM, Roberts LJ., 2nd Formation of thiol conjugates of 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 and delta 12(E)-prostaglandin D2. Biochemistry. 1990;29:3760–5. [PubMed]

50. Inoue H, Tanabe T, Umesono K. Feedback control of cyclooxygenase-2 expression through PPARgamma. J Biol Chem. 2000;275:28028–32. [PubMed]

51. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997;272:3406–10. [PubMed]

52. Bell-Parikh LC, Ide T, Lawson JA, et al. Biosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPARgamma. J Clin Invest. 2003;112:945–55. [PMC free article] [PubMed]

53. Shan ZZ, Masuko-Hongo K, Dai SM, et al. A potential role of 15-deoxy-delta(12,14)-prostaglandin J2 for induction of human articular chondrocyte apoptosis in arthritis. J Biol Chem. 2004;279:37939–50. [PubMed]

54. Kaplan JM, Hake PW, Denenberg A, Zingarelli B. Downregulation of Peroxisome Proliferator-Activated Receptor-Gamma in Polymorphonuclear Cells During Polymicrobial Sepsis. Crit Care Med. 2006;33:A132.

55. Collin M, Patel NS, Dugo L, Thiemermann C. Role of peroxisome proliferator-activated receptor-gamma in the protection afforded by 15-deoxydelta12,14 prostaglandin J2 against the multiple organ failure caused by endotoxin. Crit Care Med. 2004;32:826–31. [PubMed]

56. Guyton K, Zingarelli B, Ashton S, et al. Peroxisome proliferator-activated receptor-gamma agonists modulate macrophage activation by gram-negative and gram-positive bacterial stimuli. Shock. 2003;20:56–62. [PubMed]

57. Stegenga ME, Florquin S, de Vos AF, van der Poll T. The thiazolidinedione ciglitazone reduces bacterial outgrowth and early inflammation during Streptococcus pneumoniae pneumonia in mice. Crit Care Med. 2009;37:614–8. [PubMed]

58. Al-Rasheed NM, Chana RS, Baines RJ, Willars GB, Brunskill NJ. Ligand-independent activation of peroxisome proliferator-activated receptor-gamma by insulin and C-peptide in kidney proximal tubular cells: dependent on phosphatidylinositol 3-kinase activity. J Biol Chem. 2004;279:49747–54. [PubMed]

59. Vish MG, Mangeshkar P, Piraino G, et al. Proinsulin c-peptide exerts beneficial effects in endotoxic shock in mice. Crit Care Med. 2007;35:1348–55. [PubMed]