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Expression of peroxisome proliferator-activated receptor (PPAR)-${\alpha}$ and PPAR-${\gamma}$ in the lung tissue of obese mice and the effect of rosiglitazone on proinflammatory cytokine expressions in the lung tissue

  • Ryu, Seung Lok (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Shim, Jae Won (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Kim, Duk Soo (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Jung, Hye Lim (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Park, Moon Soo (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Park, Soo-Hee (Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Lee, Jinmi (Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Lee, Won-Young (Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine) ;
  • Shim, Jung Yeon (Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine)
  • 투고 : 2012.08.29
  • 심사 : 2012.10.24
  • 발행 : 2013.04.15

초록

Purpose: We investigated the mRNA levels of peroxisome proliferator-activated receptor (PPAR)-${\alpha}$, PPAR-${\gamma}$, adipokines, and cytokines in the lung tissue of lean and obese mice with and without ovalbumin (OVA) challenge, and the effect of rosiglitazone, a PPAR-${\gamma}$ agonist. Methods: We developed 6 mice models: OVA-challenged lean mice with and without rosiglitazone; obese mice with and without rosiglitazone; and OVA-challenged obese mice with and without rosiglitazone. We performed real-time polymerase chain reaction for leptin, leptin receptor, adiponectin, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-${\alpha}$, transforming growth factor (TGF)-${\beta}$, PPAR-${\alpha}$ and PPAR-${\gamma}$ from the lung tissue and determined the cell counts and cytokine levels in the bronchoalveolar lavage fluid. Results: Mice with OVA challenge showed airway hyperresponsiveness. The lung mRNA levels of PPAR${\alpha}$ and PPAR-${\gamma}$ increased significantly in obese mice with OVA challenge compared to that in other types of mice and decreased after rosiglitazone administeration. Leptin and leptin receptor expression increased in obese mice with and without OVA challenge and decreased following rosiglitazone treatment. Adiponectin mRNA level increased in lean mice with OVA challenge. Lung VEGF, TNF-${\alpha}$, and TGF-${\beta}$ mRNA levels increased in obese mice with and without OVA challenge compared to that in the control mice. However, rosiglitazone reduced only TGF-${\beta}$ expression in obese mice, and even augmented VEGF expression in all types of mice. Rosiglitazone treatment did not reduce airway responsiveness, but increased neutrophils and macrophages in the bronchoalveolar lavage fluid. Conclusion: PPAR-${\alpha}$ and PPAR-${\gamma}$ expressions were upregulated in the lung tissue of OVA-challenged obese mice however, rosiglitazone treatment did not downregulate airway inflammation in these mice.

키워드

참고문헌

  1. Calixto MC, Lintomen L, Schenka A, Saad MJ, Zanesco A, Antunes E. Obesity enhances eosinophilic inflammation in a murine model of allergic asthma. Br J Pharmacol 2010;159:617-25. https://doi.org/10.1111/j.1476-5381.2009.00560.x
  2. Kocalis HE, Turney MK, Printz RL, Laryea GN, Muglia LJ, Davies SS, et al. Neuron-specific deletion of peroxisome proliferatoractivated receptor delta ($PPAR{\delta}$) in mice leads to increased susceptibility to diet-induced obesity. PLoS One 2012;7:e42981. https://doi.org/10.1371/journal.pone.0042981
  3. Holguin F, Rojas M, Hart CM. The peroxisome proliferator activated receptor gamma (PPARgamma) ligand rosiglitazone modulates bronchoalveolar lavage levels of leptin, adiponectin, and inflammatory cytokines in lean and obese mice. Lung 2007;185:367-72. https://doi.org/10.1007/s00408-007-9035-9
  4. Belvisi MG, Mitchell JA. Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease. Br J Pharmacol 2009;158:994-1003. https://doi.org/10.1111/j.1476-5381.2009.00373.x
  5. Belvisi MG, Hele DJ. Peroxisome proliferator-activated receptors as novel targets in lung disease. Chest 2008;134:152-7. https://doi.org/10.1378/chest.08-0019
  6. Denning GM, Stoll LL. Peroxisome proliferator-activated receptors: potential therapeutic targets in lung disease? Pediatr Pulmonol 2006;41:23-34. https://doi.org/10.1002/ppul.20338
  7. 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;113:882-8. https://doi.org/10.1016/j.jaci.2004.02.036
  8. Zhao AZ, Shinohara MM, Huang D, Shimizu M, Eldar-Finkelman H, Krebs EG, et al. Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J Biol Chem 2000;275:11348-54. https://doi.org/10.1074/jbc.275.15.11348
  9. Huang TH, Razmovski-Naumovski V, Kota BP, Lin DS, Roufogalis BD. The pathophysiological function of peroxisome proliferatoractivated receptor-gamma in lung-related diseases. Respir Res 2005;6:102. https://doi.org/10.1186/1465-9921-6-102
  10. Benayoun L, Letuve S, Druilhe A, Boczkowski J, Dombret MC, Mechighel P, et al. Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am J Respir Crit Care Med 2001;164(8 Pt 1):1487-94. https://doi.org/10.1164/ajrccm.164.8.2101070
  11. Hwang SJ, Kim JH, Shim JW, Kim DS, Jung HL, Park MS, et al. Peroxisome proliferator-activated receptor-gamma expression in the lung tissue of obese rats. Yonsei Med J 2011;52:495-501. https://doi.org/10.3349/ymj.2011.52.3.495
  12. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315-23. https://doi.org/10.1164/rccm.200906-0896OC
  13. Hashimoto Y, Nakahara K. Improvement of asthma after administration of pioglitazone. Diabetes Care 2002;25:401. https://doi.org/10.2337/diacare.25.2.401
  14. Spears M, Donnelly I, Jolly L, Brannigan M, Ito K, McSharry C, et al. Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma. Clin Pharmacol Ther 2009; 86:49-53. https://doi.org/10.1038/clpt.2009.41
  15. Lee KS, Park SJ, Kim SR, Min KH, Jin SM, Lee HK, et al. Modulation of airway remodeling and airway inflammation by peroxisome proliferator- activated receptor gamma in a murine model of toluene diisocyanate-induced asthma. J Immunol 2006;177:5248-57. https://doi.org/10.4049/jimmunol.177.8.5248
  16. Kobayashi M, Thomassen MJ, Rambasek T, Bonfield TL, Raychaudhuri B, Malur A, et al. An inverse relationship between peroxisome proliferator-activated receptor gamma and allergic airway inflammation in an allergen challenge model. Ann Allergy Asthma Immunol 2005;95:468-73. https://doi.org/10.1016/S1081-1206(10)61173-8
  17. Musri MM, Parrizas M. Epigenetic regulation of adipogenesis. Curr Opin Clin Nutr Metab Care 2012;15:342-9. https://doi.org/10.1097/MCO.0b013e3283546fba
  18. Rhee SD, Sung YY, Jung WH, Cheon HG. Leptin inhibits rosiglitazone- induced adipogenesis in murine primary adipocytes. Mol Cell Endocrinol 2008;294:61-9. https://doi.org/10.1016/j.mce.2008.08.018
  19. Nair P, Radford K, Fanat A, Janssen LJ, Peters-Golden M, Cox PG. The effects of leptin on airway smooth muscle responses. Am J Respir Cell Mol Biol 2008;39:475-81. https://doi.org/10.1165/rcmb.2007-0091OC
  20. Shin JH, Kim JH, Lee WY, Shim JY. The expression of adiponectin receptors and the effects of adiponectin and leptin on airway smooth muscle cells. Yonsei Med J 2008;49:804-10. https://doi.org/10.3349/ymj.2008.49.5.804
  21. Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K. Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 2003;14:561-6. https://doi.org/10.1097/00041433-200312000-00003
  22. Johnston RA, Theman TA, Shore SA. Augmented responses to ozone in obese carboxypeptidase E-deficient mice. Am J Physiol Regul Integr Comp Physiol 2006;290:R126-33. https://doi.org/10.1152/ajpregu.00306.2005
  23. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 2003;112:1785-8. https://doi.org/10.1172/JCI20514
  24. Rhee CK, Lee SY, Kang JY, Kim SJ, Kwon SS, Kim YK, et al. Effect of peroxisome proliferator-activated receptor-gamma on airway smooth muscle thickening in a murine model of chronic asthma. Int Arch Allergy Immunol 2009;148:289-96. https://doi.org/10.1159/000170382
  25. Yang B, Lin P, Carrick KM, McNulty JA, Clifton LG, Winegar DA, et al. PPARgamma agonists diminish serum VEGF elevation in dietinduced insulin resistant SD rats and ZDF rats. Biochem Biophys Res Commun 2005;334:176-82. https://doi.org/10.1016/j.bbrc.2005.06.078
  26. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998;101:1354-61. https://doi.org/10.1172/JCI1235

피인용 문헌

  1. Adiponectin and Asthma: Knowns, Unknowns and Controversies vol.22, pp.16, 2013, https://doi.org/10.3390/ijms22168971