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PPAR Research
Volume 2007, Article ID 71323, 10 pages
http://dx.doi.org/10.1155/2007/71323
Review Article

The Role of PPARs in Lung Fibrosis

1Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
2Lung Biology and Disease Program, University of Rochester, Rochester, NY 14642, USA
3Department of Medicine, University of Rochester, Rochester, NY 14642, USA
4Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA

Received 14 February 2007; Accepted 18 May 2007

Academic Editor: Jesse Roman

Copyright © 2007 Heather F. Lakatos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. V. J. Thannickal, G. B. Toews, E. S. White, J. P. Lynch III, and F. J. Martinez, “Mechanisms of pulmonary fibrosis,” Annual Review of Medicine, vol. 55, pp. 395–417, 2004. View at Publisher · View at Google Scholar
  2. P. J. Sime and K. M. A. O'Reilly, “Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment,” Clinical Immunology, vol. 99, no. 3, pp. 308–319, 2001. View at Publisher · View at Google Scholar
  3. T. Geiser, “Idiopathic pulmonary fibrosis—a disorder of alveolar wound repair?” Swiss Medical Weekly, vol. 133, no. 29-30, pp. 405–411, 2003. View at Google Scholar
  4. N. Fujimura, “Pathology and pathophysiology of pneumoconiosis,” Current Opinion in Pulmonary Medicine, vol. 6, no. 2, pp. 140–144, 2000. View at Publisher · View at Google Scholar
  5. B. T. Mossman and A. Churg, “Mechanisms in the pathogenesis of asbestosis and silicosis,” American Journal of Respiratory and Critical Care Medicine, vol. 157, no. 5, part 1, pp. 1666–1680, 1998. View at Google Scholar
  6. D. A. Zisman, M. P. Keane, J. A. Belperio, R. M. Strieter, and J. P. Lynch III, “Pulmonary fibrosis,” Methods in Molecular Medicine, vol. 117, pp. 3–44, 2005. View at Google Scholar
  7. K. B. Baumgartner, J. M. Samet, D. B. Coultas et al., “Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Collaborating Centers,” American Journal of Epidemiology, vol. 152, no. 4, pp. 307–315, 2000. View at Publisher · View at Google Scholar
  8. K. B. Baumgartner, J. M. Samet, C. A. Stidley, T. V. Colby, and J. A. Waldron, “Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis,” American Journal of Respiratory and Critical Care Medicine, vol. 155, no. 1, pp. 242–248, 1997. View at Google Scholar
  9. E. S. White, M. H. Lazar, and V. J. Thannickal, “Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis,” Journal of Pathology, vol. 201, no. 3, pp. 343–354, 2003. View at Publisher · View at Google Scholar
  10. P. de Vuyst and P. Camus, “The past and present of pneumoconioses,” Current Opinion in Pulmonary Medicine, vol. 6, no. 2, pp. 151–156, 2000. View at Publisher · View at Google Scholar
  11. H. R. Collard, J. H. Ryu, W. W. Douglas et al., “Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis,” Chest, vol. 125, no. 6, pp. 2169–2174, 2004. View at Publisher · View at Google Scholar
  12. J. J. Swigris, W. G. Kuschner, J. L. Kelsey, and M. K. Gould, “Idiopathic pulmonary fibrosis: challenges and opportunities for the clinician and investigator,” Chest, vol. 127, no. 1, pp. 275–283, 2005. View at Publisher · View at Google Scholar
  13. D. S. Kim, H. R. Collard, and T. E. King Jr., “Classification and natural history of the idiopathic interstitial pneumonias,” Proceedings of the American Thoracic Society, vol. 3, no. 4, pp. 285–292, 2006. View at Publisher · View at Google Scholar
  14. S. H. Phan, “The myofibroblast in pulmonary fibrosis,” Chest, vol. 122, 6, pp. 286S–289S, 2002. View at Publisher · View at Google Scholar
  15. R. S. Smith, T. J. Smith, T. M. Blieden, and R. P. Phipps, “Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation,” American Journal of Pathology, vol. 151, no. 2, pp. 317–322, 1997. View at Google Scholar
  16. M. B. Vaughan, E. W. Howard, and J. J. Tomasek, “Transforming growth factor-β1 promotes the morphological and functional differentiation of the myofibroblast,” Experimental Cell Research, vol. 257, no. 1, pp. 180–189, 2000. View at Publisher · View at Google Scholar
  17. G. Gabbiani, “The myofibroblast in wound healing and fibrocontractive diseases,” Journal of Pathology, vol. 200, no. 4, pp. 500–503, 2003. View at Publisher · View at Google Scholar
  18. S. H. Phan, K. Zhang, H. Y. Zhang, and M. Gharaee-Kermani, “The myofibroblast as an inflammatory cell in pulmonary fibrosis,” Current Topics in Pathology, vol. 93, pp. 173–182, 1999. View at Google Scholar
  19. M. Selman, T. E. King Jr., and A. Pardo, “Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy,” Annals of Internal Medicine, vol. 134, no. 2, pp. 136–151, 2001. View at Google Scholar
  20. J. Gauldie, M. Kolb, and P. J. Sime, “A new direction in the pathogenesis of idiopathic pulmonary fibrosis?” Respiratory Research, vol. 3, p. 1, 2001. View at Publisher · View at Google Scholar
  21. U. Bartram and C. P. Speer, “The role of transforming growth factor β in lung development and disease,” Chest, vol. 125, no. 2, pp. 754–765, 2004. View at Publisher · View at Google Scholar
  22. M. Kelly, M. Kolb, P. Bonniaud, and J. Gauldie, “Re-evaluation of fibrogenic cytokines in lung fibrosis,” Current Pharmaceutical Design, vol. 9, no. 1, pp. 39–49, 2003. View at Publisher · View at Google Scholar
  23. H.-Y. Zhang and S. H. Phan, “Inhibition of myofibroblast apoptosis by transforming growth factor β1,” American Journal of Respiratory Cell and Molecular Biology, vol. 21, no. 6, pp. 658–665, 1999. View at Google Scholar
  24. P. J. Sime, Z. Xing, F. L. Graham, K. G. Csaky, and J. Gauldie, “Adenovector-mediated gene transfer of active transforming growth factor- β1 induces prolonged severe fibrosis in rat lung,” Journal of Clinical Investigation, vol. 100, no. 4, pp. 768–776, 1997. View at Google Scholar
  25. C. Blanquart, O. Barbier, J. C. Fruchart, B. Staels, and C. Glineur, “Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation,” Journal of Steroid Biochemistry and Molecular Biology, vol. 85, no. 2–5, pp. 267–273, 2003. View at Publisher · View at Google Scholar
  26. I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990. View at Publisher · View at Google Scholar
  27. O. Braissant, F. Foufelle, C. Scotto, M. Dauça, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996. View at Publisher · View at Google Scholar
  28. M. Ricote, J. Huang, L. Fajas et al., “Expression of the peroxisome proliferator-activated receptor ? (PPAR?) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 13, pp. 7614–7619, 1998. View at Publisher · View at Google Scholar
  29. S. G. Harris, J. Padilla, L. Koumas, D. Ray, and R. P. Phipps, “Prostaglandins as modulators of immunity,” Trends in Immunology, vol. 23, no. 3, pp. 144–150, 2002. View at Publisher · View at Google Scholar
  30. J. Padilla, E. Leung, and R. P. Phipps, “Human B lymphocytes and B lymphomas express PPAR-γ and are killed by PPAR-γ agonists,” Clinical Immunology, vol. 103, no. 1, pp. 22–33, 2002. View at Publisher · View at Google Scholar
  31. F. Akbiyik, D. M. Ray, K. F. Gettings, N. Blumberg, C. W. Francis, and R. P. Phipps, “Human bone marrow megakaryocytes and platelets express PPARγ, and PPARγ agonists blunt platelet release of CD40 ligand and thromboxanes,” Blood, vol. 104, no. 5, pp. 1361–1368, 2004. View at Publisher · View at Google Scholar
  32. D. M. Simon, M. C. Arikan, S. Srisuma et al., “Epithelial cell PPAR? is an endogenous regulator of normal lung maturation and maintenance,” Proceedings of the American Thoracic Society, vol. 3, no. 6, pp. 510–511, 2006. View at Publisher · View at Google Scholar
  33. D. M. Simon, M. C. Arikan, S. Srisuma et al., “Epithelial cell PPAR? contributes to normal lung maturation,” The FASEB Journal, vol. 20, no. 9, pp. 1507–1509, 2006. View at Publisher · View at Google Scholar
  34. E. Marian, S. Baraldo, A. Visentin et al., “Up-regulated membrane and nuclear leukotriene B4 receptors in COPD,” Chest, vol. 129, no. 6, pp. 1523–1530, 2006. View at Publisher · View at Google Scholar
  35. D. A. Culver, B. P. Barna, B. Raychaudhuri et al., “Peroxisome proliferator-activated receptor ? activity is deficient in alveolar macrophages in pulmonary sarcoidosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 30, no. 1, pp. 1–5, 2004. View at Publisher · View at Google Scholar
  36. T. L. Bonfield, C. F. Farver, B. P. Barna et al., “Peroxisome proliferator-activated receptor-? is deficient in alveolar macrophages from patients with alveolar proteinosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 29, no. 6, pp. 677–682, 2003. View at Publisher · View at Google Scholar
  37. G. Rizzo and S. Fiorucci, “PPARs and other nuclear receptors in inflammation,” Current Opinion in Pharmacology, vol. 6, no. 4, pp. 421–427, 2006. View at Publisher · View at Google Scholar
  38. T. Sher, H.-F. Yi, O. W. McBride, and F. J. Gonzalez, “cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor,” Biochemistry, vol. 32, no. 21, pp. 5598–5604, 1993. View at Publisher · View at Google Scholar
  39. S. Cuzzocrea, “Peroxisome proliferator-activated receptors and acute lung injury,” Current Opinion in Pharmacology, vol. 6, no. 3, pp. 263–270, 2006. View at Publisher · View at Google Scholar
  40. T. Toyama, H. Nakamura, Y. Harano et al., “PPARa ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats,” Biochemical and Biophysical Research Communications, vol. 324, no. 2, pp. 697–704, 2004. View at Publisher · View at Google Scholar
  41. G. Svegliati-Baroni, C. Candelaresi, S. Saccomanno et al., “A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-a and n-3 polyunsaturated fatty acid treatment on liver injury,” American Journal of Pathology, vol. 169, no. 3, pp. 846–860, 2006. View at Publisher · View at Google Scholar
  42. E. Ip, G. Farrell, P. Hall, G. Robertson, and I. Leclercq, “Administration of the potent PPARα agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice,” Hepatology, vol. 39, no. 5, pp. 1286–1296, 2004. View at Publisher · View at Google Scholar
  43. T. Ogata, T. Miyauchi, S. Sakai, Y. Irukayama-Tomobe, K. Goto, and I. Yamaguchi, “Stimulation of peroxisome-proliferator-activated receptor α (PPARα) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts,” Clinical Science, vol. 103, 48, pp. 284S–288S, 2002. View at Google Scholar
  44. M. Iglarz, R. M. Touyz, E. C. Viel et al., “Peroxisome proliferator-activated receptor-a and receptor-? activators prevent cardiac fibrosis in mineralocorticoid-dependent hypertension,” Hypertension, vol. 42, no. 4, pp. 737–743, 2003. View at Publisher · View at Google Scholar
  45. A. C. Calkin, S. Giunti, K. A. Jandeleit-Dahm, T. J. Allen, M. E. Cooper, and M. C. Thomas, “PPAR-α and -γ agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse,” Nephrology Dialysis Transplantation, vol. 21, no. 9, pp. 2399–2405, 2006. View at Publisher · View at Google Scholar
  46. V. Reynders, S. Loitsch, C. Steinhauer, T. Wagner, D. Steinhilber, and J. Bargon, “Peroxisome proliferator-activated receptor α (PPARα) down-regulation in cystic fibrosis lymphocytes,” Respiratory Research, vol. 7, p. 104, 2006. View at Publisher · View at Google Scholar
  47. S. Cuzzocrea, E. Mazzon, R. Di Paola et al., “The role of the peroxisome proliferator-activated receptor-a (PPAR-a) in the regulation of acute inflammation,” Journal of Leukocyte Biology, vol. 79, no. 5, pp. 999–1010, 2006. View at Publisher · View at Google Scholar
  48. T. H. Thatcher, P. J. Sime, and R. K. Barth, “Sensitivity to bleomycin-induced lung injury is not moderated by an antigen-limited T-cell repertoire,” Experimental Lung Research, vol. 31, no. 7, pp. 685–700, 2005. View at Publisher · View at Google Scholar
  49. D. H. Bowden, “Unraveling pulmonary fibrosis: the bleomycin model,” Laboratory Investigation, vol. 50, no. 5, pp. 487–488, 1984. View at Google Scholar
  50. T. Genovese, E. Mazzon, R. Di Paola et al., “Role of endogenous and exogenous ligands for the peroxisome proliferator-activated receptor a in the development of bleomycin-induced lung injury,” Shock, vol. 24, no. 6, pp. 547–555, 2006. View at Publisher · View at Google Scholar
  51. E. Dyrøy, A. Yndestad, T. Ueland et al., “Antiinflammatory effects of tetradecylthioacetic acid involve both peroxisome proliferator-activated receptor a-dependent and -independent pathways,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 7, pp. 1364–1369, 2005. View at Publisher · View at Google Scholar
  52. J. M. Lehmann, J. M. Lenhard, B. B. Oliver, G. M. Ringold, and S. A. Kliewer, “Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs,” Journal of Biological Chemistry, vol. 272, no. 6, pp. 3406–3410, 1997. View at Publisher · View at Google Scholar
  53. L. Michalik, B. Desvergne, N. S. Tan et al., “Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)a and PPARß mutant mice,” Journal of Cell Biology, vol. 154, no. 4, pp. 799–814, 2001. View at Publisher · View at Google Scholar
  54. N. S. Tan, L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome proliferator-activated receptor-β as a target for wound healing drugs,” Expert Opinion on Therapeutic Targets, vol. 8, no. 1, pp. 39–48, 2004. View at Publisher · View at Google Scholar
  55. F. Y. Ali, K. Egan, G. A. FitzGerald et al., “Role of prostacyclin versus peroxisome proliferator-activated receptor ß receptors in prostacyclin sensing by lung fibroblasts,” American Journal of Respiratory Cell and Molecular Biology, vol. 34, no. 2, pp. 242–246, 2006. View at Publisher · View at Google Scholar
  56. K. Matsusue, J. M. Peters, and F. J. Gonzalez, “PPARβ/δ potentiates PPARγ-stimulated adipocyte differentiation,” The FASEB Journal, vol. 18, no. 12, pp. 1477–1479, 2004. View at Publisher · View at Google Scholar
  57. T. H.-W. Huang, V. Razmovski-Naumovski, B. P. Kota, D. S.-H. Lin, and B. D. Roufogalis, “The pathophysiological function of peroxisome proliferator-activated receptor-γ in lung-related diseases,” Respiratory Research, vol. 6, p. 102, 2005. View at Publisher · View at Google Scholar
  58. B. M. Forman, P. Tontonoz, J. Chen, R. P. Brun, B. M. Spiegelman, and R. M. Evans, “15-deoxy-Δ12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ,” Cell, vol. 83, no. 5, pp. 803–812, 1995. View at Publisher · View at Google Scholar
  59. S. A. Kliewer, J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann, “A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation,” Cell, vol. 83, no. 5, pp. 813–819, 1995. View at Publisher · View at Google Scholar
  60. T. M. McIntyre, A. V. Pontsler, A. R. Silva et al., “Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPAR? agonist,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 1, pp. 131–136, 2003. View at Publisher · View at Google Scholar
  61. F. J. Schopfer, Y. Lin, P. R. S. Baker et al., “Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor ? ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2340–2345, 2005. View at Publisher · View at Google Scholar
  62. J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995. View at Publisher · View at Google Scholar
  63. A. E. Place, N. Suh, C. R. Williams et al., “The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo,” Clinical Cancer Research, vol. 9, no. 7, pp. 2798–2806, 2003. View at Google Scholar
  64. M. G. Belvisi, D. J. Hele, and M. A. Birrell, “Peroxisome proliferator-activated receptor γ agonists as therapy for chronic airway inflammation,” European Journal of Pharmacology, vol. 533, no. 1–3, pp. 101–109, 2006. View at Publisher · View at Google Scholar
  65. D. Liu, B. X. Zeng, S. H. Zhang, and S. L. Yao, “Rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ, reduces pulmonary inflammatory response in a rat model of endotoxemia,” Inflammation Research, vol. 54, no. 11, pp. 464–470, 2005. View at Publisher · View at Google Scholar
  66. K.-I. Inoue, H. Takano, R. Yanagisawa et al., “Effect of 15-deoxy-?12,14-prostaglandin J2 on acute lung injury induced by lipopolysaccharide in mice,” European Journal of Pharmacology, vol. 481, no. 2-3, pp. 261–269, 2003. View at Publisher · View at Google Scholar
  67. J. E. Ward, D. J. Fernandes, C. C. Taylor, J. V. Bonacci, L. Quan, and A. G. Stewart, “The PPARγ ligand, rosiglitazone, reduces airways hyperresponsiveness in a murine model of allergen-induced inflammation,” Pulmonary Pharmacology and Therapeutics, vol. 19, no. 1, pp. 39–46, 2006. View at Publisher · View at Google Scholar
  68. K. Honda, P. Marquillies, M. Capron, and D. Dombrowicz, “Peroxisome proliferator-activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model,” Journal of Allergy and Clinical Immunology, vol. 113, no. 5, pp. 882–888, 2004. View at Publisher · View at Google Scholar
  69. C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998. View at Publisher · View at Google Scholar
  70. A. C. C. Wang, X. Dai, B. Luu, and D. J. Conrad, “Peroxisome proliferator-activated receptor-γ regulates airway epithelial cell activation,” American Journal of Respiratory Cell and Molecular Biology, vol. 24, no. 6, pp. 688–693, 2001. View at Google Scholar
  71. S. E. Feldon, C. W. O'Loughlin, D. M. Ray, S. Landskroner-Eiger, K. E. Seweryniak, and R. P. Phipps, “Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes,” American Journal of Pathology, vol. 169, no. 4, pp. 1183–1193, 2006. View at Publisher · View at Google Scholar
  72. I. A. Leclercq, C. Sempoux, P. Stärkel, and Y. Horsmans, “Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats,” Gut, vol. 55, no. 7, pp. 1020–1029, 2006. View at Publisher · View at Google Scholar
  73. K. Kawaguchi, I. Sakaida, M. Tsuchiya, K. Omori, T. Takami, and K. Okita, “Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet,” Biochemical and Biophysical Research Communications, vol. 315, no. 1, pp. 187–195, 2004. View at Publisher · View at Google Scholar
  74. H. Uto, C. Nakanishi, A. Ido et al., “The peroxisome proliferator-activated receptor-? agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, L-amino acid-defined diet,” Hepatology Research, vol. 32, no. 4, pp. 235–242, 2005. View at Publisher · View at Google Scholar
  75. R. E. Buckingham, “Thiazolidinediones: pleiotropic drugs with potent anti-inflammatory properties for tissue protection,” Hepatology Research, vol. 33, no. 2, pp. 167–170, 2005. View at Publisher · View at Google Scholar
  76. M. C. Lansang, C. Coletti, S. Ahmed, M. S. Gordon, and N. K. Hollenberg, “Effects of the PPAR-γ agonist rosiglitazone on renal haemodynamics and the renin-angiotensin system in diabetes,” Journal of the Renin-Angiotensin-Aldosterone System, vol. 7, no. 3, pp. 175–180, 2006. View at Google Scholar
  77. T. Genovese, S. Cuzzocrea, R. Di Paola et al., “Effect of rosiglitazone and 15-deoxy-?12,14-prostaglandin J2 on bleomycin-induced lung injury,” European Respiratory Journal, vol. 25, no. 2, pp. 225–234, 2005. View at Publisher · View at Google Scholar
  78. Y. Barak, M. C. Nelson, E. S. Ong et al., “PPAR? is required for placental, cardiac, and adipose tissue development,” Molecular Cell, vol. 4, no. 4, pp. 585–595, 1999. View at Publisher · View at Google Scholar
  79. H. A. Burgess, L. E. Daugherty, T. H. Thatcher et al., “PPAR? agonists inhibit TGF-ß induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis,” American Journal of Physiology, vol. 288, no. 6, pp. L1146–L1153, 2005. View at Publisher · View at Google Scholar
  80. T. Miyahara, L. Schrum, R. Rippe et al., “Peroxisome proliferator-activated receptors and hepatic stellate cell activation,” Journal of Biological Chemistry, vol. 275, no. 46, pp. 35715–35722, 2000. View at Publisher · View at Google Scholar
  81. M. L. Hautekeete and A. Geerts, “The hepatic stellate (Ito) cell: its role in human liver disease,” Virchows Archiv, vol. 430, no. 3, pp. 195–207, 1997. View at Publisher · View at Google Scholar
  82. D. M. Bissell, “Connective tissue metabolism and hepatic fibrosis: an overview,” Seminars in Liver Disease, vol. 10, no. 1, pp. iii–iv, 1990. View at Google Scholar
  83. F. Marra, E. Efsen, R. G. Romanelli et al., “Ligands of peroxisome proliferator-activated receptor ? modulate profibrogenic and proinflammatory actions in hepatic stellate cells,” Gastroenterology, vol. 119, no. 2, pp. 466–478, 2000. View at Publisher · View at Google Scholar
  84. Y. Li, X. Wen, B. C. Spataro, K. Hu, C. Dai, and Y. Liu, “Hepatocyte growth factor is a downstream effector that mediates the antifibrotic action of peroxisome proliferator-activated receptor-γ agonists,” Journal of the American Society of Nephrology, vol. 17, no. 1, pp. 54–65, 2006. View at Publisher · View at Google Scholar
  85. A. Masamune, K. Satoh, Y. Sakai, M. Yoshida, A. Satoh, and T. Shimosegawa, “Ligands of peroxisome proliferator-activated receptor-γ induce apoptosis in AR42J cells,” Pancreas, vol. 24, no. 2, pp. 130–138, 2002. View at Publisher · View at Google Scholar
  86. S. Zafiriou, S. R. Stanners, S. Saad, T. S. Polhill, P. Poronnik, and C. A. Pollock, “Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts,” Journal of the American Society of Nephrology, vol. 16, no. 3, pp. 638–645, 2005. View at Publisher · View at Google Scholar
  87. U. Panchapakesan, S. Sumual, C. A. Pollock, and X. Chen, “PPARγ agonists exert antifibrotic effects in renal tubular cells exposed to high glucose,” American Journal of Physiology, vol. 289, no. 5, pp. F1153–F1158, 2005. View at Publisher · View at Google Scholar
  88. C. Zhao, W. Chen, L. Yang, L. Chen, S. A. Stimpson, and A. M. Diehl, “PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells,” Biochemical and Biophysical Research Communications, vol. 350, no. 2, pp. 385–391, 2006. View at Publisher · View at Google Scholar
  89. S. J. Lee, E. K. Yang, and S. G. Kim, “Peroxisome proliferator-activated receptor-γ and retinoic acid X receptor α represses the TGFβ1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation,” Molecular Pharmacology, vol. 70, no. 1, pp. 415–425, 2006. View at Publisher · View at Google Scholar
  90. R. E. Teresi, C.-W. Shaiu, C.-S. Chen, V. K. Chatterjee, K. A. Waite, and C. Eng, “Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone,” International Journal of Cancer, vol. 118, no. 10, pp. 2390–2398, 2006. View at Publisher · View at Google Scholar
  91. E. S. White, R. G. Atrasz, B. Hu et al., “Negative regulation of myofibroblast differentiation by PTEN (phosphatase and tensin homolog deleted on chromosome 10),” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 1, pp. 112–121, 2006. View at Publisher · View at Google Scholar
  92. E. S. White, V. J. Thannickal, S. L. Carskadon et al., “Integrin a4ß1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10,” American Journal of Respiratory and Critical Care Medicine, vol. 168, no. 4, pp. 436–442, 2003. View at Publisher · View at Google Scholar
  93. Y. Zuo, L. Qiang, and S. R. Farmer, “Activation of CCAAT/enhancer-binding protein (C/EBP) α expression by C/EBPβ during adipogenesis requires a peroxisome proliferator-activated receptor-γ-associated repression of HDAC1 at the C/ebpα gene promoter,” Journal of Biological Chemistry, vol. 281, no. 12, pp. 7960–7967, 2006. View at Publisher · View at Google Scholar
  94. S. S. Chung, H. H. Choi, Y. M. Cho, H. K. Lee, and K. S. Park, “Sp1 mediates repression of the resistin gene by PPARγ agonists in 3T3-L1 adipocytes,” Biochemical and Biophysical Research Communications, vol. 348, no. 1, pp. 253–258, 2006. View at Publisher · View at Google Scholar
  95. J. Atsmon, B. J. Sweetman, S. W. Baertschi, T. M. Harris, and L. J. Roberts II, “Formation of thiol conjugates of 9-deoxy-Δ9,Δ12(E)-prostaglandin D2 and Δ12(E)-prostaglandin D2,” Biochemistry, vol. 29, no. 15, pp. 3760–3765, 1990. View at Publisher · View at Google Scholar
  96. T. Shibata, T. Yamada, T. Ishii et al., “Thioredoxin as a molecular target of cyclopentenone prostaglandins,” Journal of Biological Chemistry, vol. 278, no. 28, pp. 26046–26054, 2003. View at Publisher · View at Google Scholar
  97. K. Shimizu, K. Shiratori, M. Kobayashi, and H. Kawamata, “Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARγ- independent mechanism,” Pancreas, vol. 29, no. 1, pp. 67–74, 2004. View at Publisher · View at Google Scholar
  98. H.-J. Kim, J.-Y. Kim, Z. Meng et al., “15-deoxy-?12,14-prostaglandin J2 inhibits transcriptional activity of estrogen receptor-a via covalent modification of DNA-binding domain,” Cancer Research, vol. 67, no. 6, pp. 2595–2602, 2007. View at Publisher · View at Google Scholar
  99. I. Issemann, R. A. Prince, J. D. Tugwood, and S. Green, “The peroxisome proliferator-activated receptor: retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs,” Journal of Molecular Endocrinology, vol. 11, no. 1, pp. 37–47, 1993. View at Google Scholar
  100. H. S. Ahuja, A. Szanto, L. Nagy, and P. J. A. Davies, “The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death,” Journal of Biological Regulators and Homeostatic Agents, vol. 17, no. 1, pp. 29–45, 2003. View at Google Scholar
  101. P. Germain, P. Chambon, G. Eichele et al., “International union of pharmacology. LXIII. Retinoid X receptors,” Pharmacological Reviews, vol. 58, no. 4, pp. 760–772, 2006. View at Publisher · View at Google Scholar
  102. K. Hellemans, P. Verbuyst, E. Quartier et al., “Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids,” Hepatology, vol. 39, no. 1, pp. 97–108, 2004. View at Publisher · View at Google Scholar
  103. M. Ohata, M. Lin, M. Satre, and H. Tsukamoto, “Diminished retinoic acid signaling in hepatic stellate cells in cholestatic liver fibrosis,” American Journal of Physiology, vol. 272, no. 3, part 1, pp. G589–G596, 1997. View at Google Scholar
  104. X. Wen, Y. Li, K. Hu, C. Dai, and Y. Liu, “Hepatocyte growth factor receptor signaling mediates the anti-fibrotic action of 9-cis-retinoic acid in glomerular mesangial cells,” American Journal of Pathology, vol. 167, no. 4, pp. 947–957, 2005. View at Google Scholar
  105. G. Chinetti, J.-C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors and inflammation: from basic science to clinical applications,” International Journal of Obesity and Related Metabolic Disorders, vol. 27, 3, pp. S41–S45, 2003. View at Publisher · View at Google Scholar