Role of peroxisome proliferator activator receptor-gamma (PPAR-γ) in lung sepsis


Downloads: 430
Usha Q Patel 1, Grazia V Clemencet 1, Colleen B Latruffe 2, Peter A Reddy 1, Qin Chu 3, Charlene J Heyman, Alice E Griffin1*
Author Affiliations
∗Correspondence author e-mail: Alice.G11@yahoo.com: 1Department of Medicine, University of Pittsburgh School of Medicine, PA, USA. 2Department of Biochemistry, Faculty of Medicine, Johann Wolfgang Goethe-University Frankfurt, Germany. 3Jinling Hospital, Medical School of Nanjing University, China

 

Abstract

PPAR-gamma has been implicated in the pathology of numerous diseases including; obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine). In the present study, to directly determine the role of PPARγ in lung sepsis we used PPARγ-knockout and C57/BL6 mice model. Mice are treated with Lipopolysaccharide LPS (0.5 mg/kg, iv) for 6-hours, the plasma and tissue cytokines TNF-α, IL-1β, IL-6, IL-10, MIP-1 and KC are analyzed by ELISA. The infiltrations of the mononuclear cells in the lung tissue and degree of lung tissue injury are examined using immunofluorescent and histopathology staining respectively. In PPARγ-knockout mice, LPS induced more expression of pro-inflammatory cytokines expression, which was associated with a marked monocyte infiltration, tissue injury and elevated lung activity of myeloperoxidase compared with wild type C57/BL6 mice. Present study, suggests that PPARγ has a critical role in attenuate lung sepsis and further study need to elucidate the clinical value.

Key words: PPARγ; LPS; Proinflammatory cytokines; Lung; Immunofluorescent; PPARγ-knockout mice

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

Article citationReferencesFull-Text/PDFBecome reviewer
The citation data is computed by the following citation measuring services:

Cited by (CrossRef)
Google Scholar

  1. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546–1554. [PubMed]
  2. Hacham M, White RM, Argov S, Segal S, Apte RN. Interleukin-6 and interleukin-10 are expressed in organs of normal young and old mice. EUR Cytokine Netw 2004;15: 37–46. [PubMed]
  3. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA. Nature 2008; 456 (7220): 350–356. [PubMed]
  4. Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev 2006; 58(4): 726–41. [PubMed] [Full-Text]
  5. Berger J, Patel HV, Woods J, Hayes NS, Parent SA, Clemas J, Leibowitz MD, Elbrecht A, Rachubinski RA, Capone JP, Moller DE. A PPARgamma mutant serves as a dominant negative inhibitor of PPAR signaling and is localized in the nucleus. Mol. Cell. Endocrinol 2000; 162(1–2): 57. [PubMed]
  6. Abraham E,  Matthay MA, Dinarello CA, Vincent JL., Cohen J, Opal SM, Glauser M, Parsons P, Fisher CJ, Repine Jr JE. . Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation. Crit. Care Med 2000; 28:232. [CrossRefMedline]
  7. Rocchi S, Auwerx J. 1999. Peroxisome proliferator-activated receptor-γ: a versatile metabolic regulator. Ann. Med 1999; 31:342. [Medline]
  8. Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flanigan A, Murthy S, Lazar MA, Wu GD. A novel therapy for colitis utilizing PPARγ ligands to inhibit the epithelial inflammatory response. J. Clin. Invest 1999; 104:383. [pubMed]
  9. Hill MR, Young MD, McCurdy CM, Gimble JM. Decreased expression of murine PPARγ in adipose tissue during endotoxemia. Endocrinology 1997; 138:3073. [Abstract/FREE Full Text]
  10. Atanasov AG1, Blunder M, Fakhrudin N, Liu X, Noha SM, Malainer C, Kramer MP, Cocic A, Kunert O, Schinkovitz A, Heiss EH, Schuster D, Dirsch VM, Bauer R.Polyacetylenes from Notopterygium incisum-new selective partial agonists of peroxisome proliferator-activated receptor-gamma. PLoS ONE 2013; 8 (4): e61755. [PubMed] [Full-Text]
  11. Masamune A, Satoh K, Sakai Y, Yoshida M, Satoh A, Shimosegawa T. Ligands of peroxisome proliferator-activated receptor-gamma induce apoptosis in AR42J cells. Pancreas. 2002; 24(2):130-8. [PubMed]
  12. Nathan C. Points of control in inflammation. Nature 2000; 420:846. [CrossRefMedline]
  13. Castrillo, A., M. Mojena, S. Hortelano, L. Bosca. Peroxisome proliferator-activated receptor-γ-independent inhibition of macrophage activation by the non-thiazolidinedione agonist L-796,449: comparison with the effects of 13. 15-deoxy-Δ12,14-prostaglandin J2. J. Biol. Chem 2001; 276:34082. [Abstract/FREE Full Text]
  14. Thieringer R, Fenyk-Melody JE, Le Grand CB, Shelton BA, Detmers PA, Somers EP, Carbin LD, Moller E, Wright SD, Berger J. Activation of peroxisome proliferator-activated receptor γ does not inhibit IL-6 or TNF-α responses of macrophages to lipopolysaccharide in vitro or in vivo. J. Immunol 2000; 164:1046. [Abstract/FREE Full Text]
  15. Delerive P, Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, Duriez P , Staels B. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ. Res 1999; 85:394. [Abstract/FREE Full Text]
  16. Peters K, Unger RE, Kirkpatrick CJ. Molecular basis of endothelial dysfunction in sepsis. Cardiovasc. Res 2003; 60: 49–57. [Abstract/FREE Full Text]
  17. Milam JE, Keshamouni VG, Phan SH, Hu B, Gangireddy SR, Hogaboam CM, Standiford TJ, Thannickal V J, Reddy RC. PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol 2008; 294: L891–L901. [Abstract/FREE Full Text]
  18. Honda K, Marquillies P, Capron M, Dombrowicz D. Peroxisome proliferator-activated receptor-γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model. J Allergy Clin Immunol 2004; 113: 882–888. [OpenUrlCrossRefMedlineWeb of Science]
  19. Huang JT,Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase. Nature 1999; 400: 378–382. [OpenUrlCrossRefMedline]
  20. Miyahara T,Schrum L, Rippe R, Xiong S, Yee HF Jr, Motomura K, Anania FA, Willson TM, Tsukamoto H. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 2000; 275: 35715–35722. [OpenUrlAbstract/FREE Full Text]
  21. Poleni PE, Bianchi A, Etienne S, Koufany M, Sebillaud S, Netter P, Terlain B, Jouzeau JY. Agonists of peroxisome proliferator-activated receptors (PPAR) α, β/δ or γ reduce transforming growth factor (TGF)-β-induced proteoglycan production in chondrocytes. Osteoarthritis Cartilage 2007; 15: 493–505. [OpenUrlCrossRefMedlineWeb of Science]
  22. Ray DM, Akbiyik F, Bernstein SH, Phipps RP. CD40 engagement prevents peroxisome proliferator-activated receptor-γ agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-κB-dependent mechanism. J Immunol 2005; 174: 4060–4069. [OpenUrlAbstract/FREE Full Text]
  23. Saika S, Yamanaka O, Okada Y, Miyamoto T, Kitano A, Flanders KC, Ohnishi Y, Nakajima Y, Kao WW, Ikeda K. Effect of overexpression of PPARγ on the healing process of corneal alkali burn in mice. Am J Physiol Cell Physiol 2007; 293: C75–C86. [OpenUrlAbstract/FREE Full Text]
  24. Shiau CW, Yang CC, Kulp SK, Chen KF, Chen CS, Huang JW, Chen CS. Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARγ. Cancer Res 2005; 65: 1561–1569. [OpenUrlAbstract/FREE Full Text]
  25. Zhao C, Chen W, Yang L, Chen L, Stimpson SA, Diehl AM. PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells. Biochem Biophys Res Commun 2006; 350: 385–391. [OpenUrlCrossRefMedlineWeb of Science]
  26. Altiok S, Xu M, Spiegelman BM. PPARγ induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev 1997; 11: 1987–1998. [OpenUrlAbstract/FREE Full Text]
  27. Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Phipps RP, Sime PJ. PPARγ agonists inhibit TGF-β induced pulmonary myofibroblast differentiation and ollagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2005; 288: L1146–L1153. [Abstract/FREE Full Text]
  28. Fu M, Zhang J, Lin Y, Zhu X, Zhao L, Ahmad M, Ehrengruber MU, Chen YE . Early stimulation and late inhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) gene expression by transforming growth factor beta in human aortic smooth muscle cells: role of early growth-response factor-1 (Egr-1), activator protein 1 (AP1) and Smads. Biochem J 2003; 370: 1019–1025. [CrossRefMedlineWeb of Science]
  29. Honda K, Marquillies P, Capron M, Dombrowicz D. Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model. J Allergy Clin Immunol 2004; 113: 882–888.[CrossRefMedlineWeb of Science]
  30. Milam JE, Keshamouni VG, Phan SH, Hu B, Gangireddy SR, Hogaboam CM, Standiford TJ, Thannickal VJ, Reddy RC. PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008; 294: L891–L901. [Abstract/FREE Full Text]
  31. Simon DM, Mariani TJ. Role of PPARs and retinoid x receptors in the regulation of lung maturation and development (Abstract). PPAR Res 2007; 91240.[Medline]
  32. Chinetti G, Fruchart JC, and Staels B. Peroxisome proliferator-activated receptors and inflammation: from basic science to clinical applications. Int J Obes Relat Metab Disord 2003; 27 Suppl 3: S41–45. [PubMed]
  33. Jiang C, Ting AT, and Seed B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82-86.  [CrossRefMedlineWeb of Science]
  34. Lemberger T, Desvergne B, and Wahli W. Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 1996; 12: 335-363. [CrossRefMedlineWeb of Science]
  35. Nagy L, Tontonoz P, Alvarez JG, Chen H, and Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 1998; 93: 229-240. [CrossRefMedlineWeb of Science]
  36. Schoonjans K, Staels B, and Auwerx J. The peroxisome proliferator-activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996; 1302: 93-109.  [Medline]
  37. Thieringer R, Fenyk-Melody JE, Le Grand CB, Shelton BA, Detmers PA, Somers EP, Carbin L, Moller DE, Wright SD, and Berger J. Activation of peroxisome proliferator-activated receptor γ does not inhibit IL-6 or TNF-α responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol 2000; 164: 1046-1054. [Abstract/FREE Full Text]
  38. Wu Z, Bucher NL, and Farmer SR. Induction of peroxisome proliferator-activated receptor γ during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPβ, C/EBPδ, and glucocorticoids. Mol Cell Biol 1996; 16: 4128-4136. [Abstract/FREE Full Text]

3. Purchase this article at rate $33.00

For any technique error please contact us 

Who Can Become a Reviewer?
Any expert in the article's research field can become a reviewer with American Journal of Biomedicine. Editors might ask you to look at a specific aspect of an article,...

Find out more

Review Article
DOI: http://dx.doi.org/10.18081/2333-5106/014-04/228-246
American Journal of BioMedicine 2014, Volume 2, Issue 4, pages 228-246
Received 21 May 2014; accepted September 11, 2014, Published October 22, 2014

How to cite this article
Patel UQ, Clemencet GV, Latruffe CB, Reddy PA, et al. Role of peroxisome proliferator activator receptor-gamma (PPAR-γ) in lung sepsis. American Journal of BioMedicine 2014;2(4):227-246.

Case report outline
1. Abstract
2. Keywords
3. Introduction
4. Methods
5. Results
6. Discussion
7. References

Article metric