• 四川大學(xué)華西醫(yī)院膽道外科(四川成都 610041);

目的總結(jié)過氧化物酶體增殖物激活受體γ(PPARγ)激動(dòng)劑抗轉(zhuǎn)化生長(zhǎng)因子-β(TGF-β)促器官纖維化作用的研究進(jìn)展。方法復(fù)習(xí)有關(guān)PPARγ激動(dòng)劑抗TGF-β促器官纖維化作用的文獻(xiàn)并進(jìn)行綜述。結(jié)果TGF-β是一種主要的促纖維化細(xì)胞因子，能促進(jìn)多種器官的纖維化進(jìn)程，而PPARγ激動(dòng)劑則可以有效地阻斷TGF-β的信號(hào)傳導(dǎo)，從而發(fā)揮抗器官纖維化的作用。結(jié)論研究PPARγ激動(dòng)劑主要通過阻斷TGF-β信號(hào)傳導(dǎo)來實(shí)現(xiàn)抗器官纖維化的機(jī)理，有助于PPARγ激動(dòng)劑在臨床上的推廣運(yùn)用，為治療器官纖維化疾病提供一種新途徑。

引用本文： 鄧毅磊,程南生. 過氧化物酶體增殖物激活受體γ激動(dòng)劑抗轉(zhuǎn)化生長(zhǎng)因子-β促器官纖維化作用的研究進(jìn)展. 中國(guó)普外基礎(chǔ)與臨床雜志, 2011, 18(3): 348-352. doi: 復(fù)制

1. Blobe GC, Schiemann WP, Lodish HF. Mechanisms of disease: Role of transforming growth factor β in human disease [J]. New Engl J Med, 2000, 342(18): 13501358.
2. Verrecchia F, Mauviel A. Transforming growth factorβ signaling through the Smad pathway: role in extracellular matrix gene expression and regulation [J]. J Invest Dermatol, 2002, 118(2): 211215.
3. Verrecchia F, Mauviel A. Transforming growth factorβ and fibrosis [J]. World J Gastroenterol, 2007, 13(22): 30563062.
4. Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGFβ as major players and therapeutic targets [J]. J Cell Mol Med, 2006, 10(1): 7699.
5. Gressner AM, Weiskirchen R, Breitkopf K, et al. Roles of TGFβ in hepatic fibrosis [J]. Front Biosci, 2002, 7: d793d807.
6. MeindlBeinker NM, Dooley S. Transforming growth factorβ and hepatocyte transdifferentiation in liver fibrogenesis [J]. J Gastroenterol Hepatol, 2008, 23 Suppl 1: S122S127.
7. De Bleser PJ, Niki T, Rogiers V, et al. Transforming growth factorβ gene expression in normal and fibrotic rat liver [J]. J Hepatol, 1997, 26(4): 886893.
8. Yasuda H, Imai E, Shiota A, et al. Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats [J]. Hepatology, 1996, 24(3): 636642.
9. Zhao C, Chen W, Yang L, et al. PPARγ agonists prevent TGFβ1/Smad3signaling in human hepatic stellate cells [J]. Biochem Biophys Res Commun, 2006, 350(2): 385391.
10. Abreu JG, Ketpura NI, Reversade B, et al. Connectivetissue growth factor (CTGF) modulates cell signalling by BMP and TGFβ [J]. Nat Cell Biol, 2002, 4(8): 599604.
11. Sun K, Wang Q, Huang XH. PPAR gamma inhibits growth of rat hepatic stellate cells and TGF betainduced connective tissue growth factor expression [J]. Acta Pharmacol Sin, 2006, 27(6): 715723.
12. Fonseca C, Abraham D, Black CM. Lung fibrosis [J]. Springer Semin Immunopathol, 1999, 21(4): 453474.
13. Khalil N, Greenberg AH. The role of TGFbeta in pulmonary fibrosis [J]. Ciba Found Symp, 1991, 157: 194207.
14. Wen FQ, Kohyama T, Skld CM, et al. Glucocorticoids modulate TGFβ production by human fetal lung fibroblasts [J]. Inflammation, 2003, 27(1): 919.
15. Sime PJ, Xing Z, Graham FL, et al. Adenovectormediated gene transfer of active transforming growth factorbeta1 induces prolonged severe fibrosis in rat lung [J]. J Clin Invest, 1997, 100(4): 768776.
16. Yao HW, Xie QM, Chen JQ, et al. TGFβ1 induces alveolar epithelial to mesenchymal transition in vitro [J]. Life Sci, 2004, 76(1): 2937.
17. Burgess HA, Daugherty LE, Thatcher TH, et al. PPARγ agonists inhibit TGFβ induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis [J]. Am J Physiol Lung Cell Mol Physiol, 2005, 288(6): L1146L1153.
18. Milam JE, Keshamouni VG, Phan SH, et al. PPARγ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycininduced pulmonary fibrosis [J]. Am J Physiol Lung Cell Mol Physiol, 2008, 294(5): L891L901.
19. Tan X, Dagher H, Hutton CA, et al. Effects of PPARγ ligands on TGFβ1induced epithelialmesenchymal transition in alveolar epithelial cells [J]. Respir Res, 2010, 11: 2133.
20. Eddy AA. Molecular basis of renal fibrosis [J]. Pediatr Nephrol, 2000, 15(34): 290301.
21. Tamaki K, Okuda S. Role of TGFβ in the progression of renal fibrosis [J]. Contrib Nephrol, 2003, 139: 4465.
22. Wang W, Koka V, Lan HY. Transforming growth factorβ and Smad signalling in kidney diseases [J]. Nephrology (Carlton), 2005, 10(1): 4856.
23. Yang CW, Hsueh S, Wu MS, et al. Glomerular transforming growth factorβ1 mRNA as a marker of glomerulosclerosisapplication in renal biopsies [J]. Nephron, 1997, 77(3): 290297.
24. Imai E, Isaka Y, Akagi Y, et al. New therapeutic strategies of molecular intervention in glomerulonephritis [J]. Nephrology, 1997, 3 Suppl 2: S755S757.
25. Moon JA, Kim HT, Cho IS, et al. IN1130, a novel transforming growth factorβ type Ⅰ receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy [J]. Kidney Int, 2006, 70(7): 12341243.
26. Guo B, Koya D, Isono M, et al. Peroxisome proliferatoractivated receptorγ ligands inhibit TGFβ1induced fibronectin expression in glomerular mesangial cells [J]. Diabetes, 2004, 53(1): 200208.
27. Wang W, Liu F, Chen N. Peroxisome proliferatoractivated receptorγ (PPARγ) agonists attenuate the profibrotic response induced by TGFβ1 in renal interstitial fibroblasts [J]. Mediators Inflamm, 2007, 2007: 62641.
28. Kawai T, Masaki T, Doi S, et al. PPARγ agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGFβ [J]. Lab Invest, 2009, 89(1): 4758.
29. Bettinger DA, Yager DR, Diegelmann RF, et al. The effect of TGFβ on keloid fibroblast proliferation and collagen synthesis [J]. Plast Reconstr Surg, 1996, 98(5): 827833.
30. Hsu M, Peled ZM, Chin GS, et al. Ontogeny of expression of transforming growth factorbeta 1 (TGFβ1), TGFβ3, and TGFβ receptors Ⅰ and Ⅱ in fetal rat fibroblasts and skin [J]. Plast Reconstr Surg, 2001, 107(7): 17871794.
31. Wang R, Ghahary A, Shen Q, et al. Hypertrophic scar tissues and fibroblasts produce more transforming growth factorβ1 mRNA and protein than normal skin and cells [J]. Wound Repair Regen, 2000, 8(2): 128137.
32. Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factorβ receptors Ⅰ and Ⅱ and activation of Smad 3 in keloid fibroblasts [J]. Plast Reconstr Surg, 2001, 108(2): 423429.
33. Ghosh AK, Bhattacharyya S, Lakos G, et al. Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferatoractivated receptor γ [J]. Arthritis Rheum, 2004, 50(4): 13051318.
34. Zhang GY, Yi CG, Li X, et al. Troglitazone suppresses transforming growth factorβ1induced collagen type Ⅰ expression in keloid fibroblasts [J]. Br J Dermatol, 2009, 160(4): 762770.
35. Zhang GY, Cheng T, Zheng MH, et al. Peroxisome proliferatoractivated receptorγ (PPARγ) agonist inhibits transforming growth factorbeta1 and matrix production in human dermal fibroblasts [J]. J Plast Reconstr Aesthet Surg, 2010, 63(7): 12091216.
36. Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling [J]. Pharmacol Ther, 2009, 123(2): 255278.
37. Laviades C, Varo N, Díez J. Transforming growth factor β in hypertensives with cardiorenal damage [J]. Hypertension, 2000, 36(4): 517522.
38. Lim H, Zhu YZ. Role of transforming growth factorβ in the progression of heart failure [J]. Cell Mol Life Sci, 2006, 63(22): 25842596.
39. Lijnen P, Petrov V, Fagard R. Transforming growth factorβ1mediated collagen gel contraction by cardiac fibroblasts [J]. J Renin Angiotensin Aldosterone Syst, 2003, 4(2): 113118.
40. Brooks WW, Conrad CH. Myocardial fibrosis in transforming growth factor β1 heterozygous mice [J]. J Mol Cell Cardiol, 2000, 32(2): 187195.
41. Rosenkranz S. TGFβ1 and angiotensin networking in cardiac remodeling [J]. Cardiovasc Res, 2004, 63(3): 423432.
42. Kawano H, Do YS, Kawano Y, et al. Angiotensin Ⅱ has multiple profibrotic effects in human cardiac fibroblasts [J]. Circulation, 2000, 101(10): 11301137.
43. Wenzel S, Taimor G, Piper HM, et al. Redoxsensitive intermediates mediate angiotensin Ⅱinduced p38 MAP kinase activation, AP1 binding activity, and TGFβ expression in adult ventricular cardiomyocytes [J]. FASEB J, 2001, 15(12): 22912293.
44. Chen K, Chen J, Li D, et al. Angiotensin Ⅱ regulation of collagen type Ⅰ expression in cardiac fibroblasts: modulation by PPARγ ligand pioglitazone [J]. Hypertension, 2004, 44(5): 655661.
45. Zhao SM, Shen LH, Li HW, et al. Downregulation of the expression of angiotensin Ⅱ type 1 receptor in neonatal rat cardiac fibroblast by activation of PPARγ signal pathway [J]. Chin J Physiol, 2008, 51(6): 357362.
46. Hao GH, Niu XL, Gao DF, et al. Agonists at PPARγ suppress angiotensin Ⅱinduced production of plasminogen activator inhibitor1 and extracellular matrix in rat cardiac fibroblasts [J]. Br J Pharmacol, 2008, 153(7): 14091419.
47. Shiomi T, Tsutsui H, Hayashidani S, et al. Pioglitazone, a peroxisome proliferatoractivated receptorγ agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction [J]. Circulation, 2002, 106(24): 31263132.
48. van Westerloo DJ, Florquin S, de Boer AM, et al. Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice [J]. Am J Pathol, 2005, 166(3): 721728.
49. Peng Y, Liu H, Liu F, et al. Troglitazone inhibits synthesis of transforming growth factorβ1 and reduces matrix production in human peritoneal mesothelial cells [J]. Nephrology (Carlton), 2006, 11(6): 516523.
50. Fu M, Zhang J, Zhu X, et al. Peroxisome proliferatoractivated receptor γ inhibits transforming growth factor βinduced connective tissue growth factor expression in human aortic smooth muscle cells by interfering with Smad3 [J]. J Biol Chem, 2001, 276(49): 4588845894.
51. Honda K, Marquillies P, Capron M, et al. Peroxisome proliferatoractivated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model [J]. J Allergy Clin Immunol, 2004, 113(5): 882888.
  1. 1. Blobe GC, Schiemann WP, Lodish HF. Mechanisms of disease: Role of transforming growth factor β in human disease [J]. New Engl J Med, 2000, 342(18): 13501358.
  2. 2. Verrecchia F, Mauviel A. Transforming growth factorβ signaling through the Smad pathway: role in extracellular matrix gene expression and regulation [J]. J Invest Dermatol, 2002, 118(2): 211215.
  3. 3. Verrecchia F, Mauviel A. Transforming growth factorβ and fibrosis [J]. World J Gastroenterol, 2007, 13(22): 30563062.
  4. 4. Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGFβ as major players and therapeutic targets [J]. J Cell Mol Med, 2006, 10(1): 7699.
  5. 5. Gressner AM, Weiskirchen R, Breitkopf K, et al. Roles of TGFβ in hepatic fibrosis [J]. Front Biosci, 2002, 7: d793d807.
  6. 6. MeindlBeinker NM, Dooley S. Transforming growth factorβ and hepatocyte transdifferentiation in liver fibrogenesis [J]. J Gastroenterol Hepatol, 2008, 23 Suppl 1: S122S127.
  7. 7. De Bleser PJ, Niki T, Rogiers V, et al. Transforming growth factorβ gene expression in normal and fibrotic rat liver [J]. J Hepatol, 1997, 26(4): 886893.
  8. 8. Yasuda H, Imai E, Shiota A, et al. Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats [J]. Hepatology, 1996, 24(3): 636642.
  9. 9. Zhao C, Chen W, Yang L, et al. PPARγ agonists prevent TGFβ1/Smad3signaling in human hepatic stellate cells [J]. Biochem Biophys Res Commun, 2006, 350(2): 385391.
  10. 10. Abreu JG, Ketpura NI, Reversade B, et al. Connectivetissue growth factor (CTGF) modulates cell signalling by BMP and TGFβ [J]. Nat Cell Biol, 2002, 4(8): 599604.
  11. 11. Sun K, Wang Q, Huang XH. PPAR gamma inhibits growth of rat hepatic stellate cells and TGF betainduced connective tissue growth factor expression [J]. Acta Pharmacol Sin, 2006, 27(6): 715723.
  12. 12. Fonseca C, Abraham D, Black CM. Lung fibrosis [J]. Springer Semin Immunopathol, 1999, 21(4): 453474.
  13. 13. Khalil N, Greenberg AH. The role of TGFbeta in pulmonary fibrosis [J]. Ciba Found Symp, 1991, 157: 194207.
  14. 14. Wen FQ, Kohyama T, Skld CM, et al. Glucocorticoids modulate TGFβ production by human fetal lung fibroblasts [J]. Inflammation, 2003, 27(1): 919.
  15. 15. Sime PJ, Xing Z, Graham FL, et al. Adenovectormediated gene transfer of active transforming growth factorbeta1 induces prolonged severe fibrosis in rat lung [J]. J Clin Invest, 1997, 100(4): 768776.
  16. 16. Yao HW, Xie QM, Chen JQ, et al. TGFβ1 induces alveolar epithelial to mesenchymal transition in vitro [J]. Life Sci, 2004, 76(1): 2937.
  17. 17. Burgess HA, Daugherty LE, Thatcher TH, et al. PPARγ agonists inhibit TGFβ induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis [J]. Am J Physiol Lung Cell Mol Physiol, 2005, 288(6): L1146L1153.
  18. 18. Milam JE, Keshamouni VG, Phan SH, et al. PPARγ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycininduced pulmonary fibrosis [J]. Am J Physiol Lung Cell Mol Physiol, 2008, 294(5): L891L901.
  19. 19. Tan X, Dagher H, Hutton CA, et al. Effects of PPARγ ligands on TGFβ1induced epithelialmesenchymal transition in alveolar epithelial cells [J]. Respir Res, 2010, 11: 2133.
  20. 20. Eddy AA. Molecular basis of renal fibrosis [J]. Pediatr Nephrol, 2000, 15(34): 290301.
  21. 21. Tamaki K, Okuda S. Role of TGFβ in the progression of renal fibrosis [J]. Contrib Nephrol, 2003, 139: 4465.
  22. 22. Wang W, Koka V, Lan HY. Transforming growth factorβ and Smad signalling in kidney diseases [J]. Nephrology (Carlton), 2005, 10(1): 4856.
  23. 23. Yang CW, Hsueh S, Wu MS, et al. Glomerular transforming growth factorβ1 mRNA as a marker of glomerulosclerosisapplication in renal biopsies [J]. Nephron, 1997, 77(3): 290297.
  24. 24. Imai E, Isaka Y, Akagi Y, et al. New therapeutic strategies of molecular intervention in glomerulonephritis [J]. Nephrology, 1997, 3 Suppl 2: S755S757.
  25. 25. Moon JA, Kim HT, Cho IS, et al. IN1130, a novel transforming growth factorβ type Ⅰ receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy [J]. Kidney Int, 2006, 70(7): 12341243.
  26. 26. Guo B, Koya D, Isono M, et al. Peroxisome proliferatoractivated receptorγ ligands inhibit TGFβ1induced fibronectin expression in glomerular mesangial cells [J]. Diabetes, 2004, 53(1): 200208.
  27. 27. Wang W, Liu F, Chen N. Peroxisome proliferatoractivated receptorγ (PPARγ) agonists attenuate the profibrotic response induced by TGFβ1 in renal interstitial fibroblasts [J]. Mediators Inflamm, 2007, 2007: 62641.
  28. 28. Kawai T, Masaki T, Doi S, et al. PPARγ agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGFβ [J]. Lab Invest, 2009, 89(1): 4758.
  29. 29. Bettinger DA, Yager DR, Diegelmann RF, et al. The effect of TGFβ on keloid fibroblast proliferation and collagen synthesis [J]. Plast Reconstr Surg, 1996, 98(5): 827833.
  30. 30. Hsu M, Peled ZM, Chin GS, et al. Ontogeny of expression of transforming growth factorbeta 1 (TGFβ1), TGFβ3, and TGFβ receptors Ⅰ and Ⅱ in fetal rat fibroblasts and skin [J]. Plast Reconstr Surg, 2001, 107(7): 17871794.
  31. 31. Wang R, Ghahary A, Shen Q, et al. Hypertrophic scar tissues and fibroblasts produce more transforming growth factorβ1 mRNA and protein than normal skin and cells [J]. Wound Repair Regen, 2000, 8(2): 128137.
  32. 32. Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factorβ receptors Ⅰ and Ⅱ and activation of Smad 3 in keloid fibroblasts [J]. Plast Reconstr Surg, 2001, 108(2): 423429.
  33. 33. Ghosh AK, Bhattacharyya S, Lakos G, et al. Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferatoractivated receptor γ [J]. Arthritis Rheum, 2004, 50(4): 13051318.
  34. 34. Zhang GY, Yi CG, Li X, et al. Troglitazone suppresses transforming growth factorβ1induced collagen type Ⅰ expression in keloid fibroblasts [J]. Br J Dermatol, 2009, 160(4): 762770.
  35. 35. Zhang GY, Cheng T, Zheng MH, et al. Peroxisome proliferatoractivated receptorγ (PPARγ) agonist inhibits transforming growth factorbeta1 and matrix production in human dermal fibroblasts [J]. J Plast Reconstr Aesthet Surg, 2010, 63(7): 12091216.
  36. 36. Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling [J]. Pharmacol Ther, 2009, 123(2): 255278.
  37. 37. Laviades C, Varo N, Díez J. Transforming growth factor β in hypertensives with cardiorenal damage [J]. Hypertension, 2000, 36(4): 517522.
  38. 38. Lim H, Zhu YZ. Role of transforming growth factorβ in the progression of heart failure [J]. Cell Mol Life Sci, 2006, 63(22): 25842596.
  39. 39. Lijnen P, Petrov V, Fagard R. Transforming growth factorβ1mediated collagen gel contraction by cardiac fibroblasts [J]. J Renin Angiotensin Aldosterone Syst, 2003, 4(2): 113118.
  40. 40. Brooks WW, Conrad CH. Myocardial fibrosis in transforming growth factor β1 heterozygous mice [J]. J Mol Cell Cardiol, 2000, 32(2): 187195.
  41. 41. Rosenkranz S. TGFβ1 and angiotensin networking in cardiac remodeling [J]. Cardiovasc Res, 2004, 63(3): 423432.
  42. 42. Kawano H, Do YS, Kawano Y, et al. Angiotensin Ⅱ has multiple profibrotic effects in human cardiac fibroblasts [J]. Circulation, 2000, 101(10): 11301137.
  43. 43. Wenzel S, Taimor G, Piper HM, et al. Redoxsensitive intermediates mediate angiotensin Ⅱinduced p38 MAP kinase activation, AP1 binding activity, and TGFβ expression in adult ventricular cardiomyocytes [J]. FASEB J, 2001, 15(12): 22912293.
  44. 44. Chen K, Chen J, Li D, et al. Angiotensin Ⅱ regulation of collagen type Ⅰ expression in cardiac fibroblasts: modulation by PPARγ ligand pioglitazone [J]. Hypertension, 2004, 44(5): 655661.
  45. 45. Zhao SM, Shen LH, Li HW, et al. Downregulation of the expression of angiotensin Ⅱ type 1 receptor in neonatal rat cardiac fibroblast by activation of PPARγ signal pathway [J]. Chin J Physiol, 2008, 51(6): 357362.
  46. 46. Hao GH, Niu XL, Gao DF, et al. Agonists at PPARγ suppress angiotensin Ⅱinduced production of plasminogen activator inhibitor1 and extracellular matrix in rat cardiac fibroblasts [J]. Br J Pharmacol, 2008, 153(7): 14091419.
  47. 47. Shiomi T, Tsutsui H, Hayashidani S, et al. Pioglitazone, a peroxisome proliferatoractivated receptorγ agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction [J]. Circulation, 2002, 106(24): 31263132.
  48. 48. van Westerloo DJ, Florquin S, de Boer AM, et al. Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice [J]. Am J Pathol, 2005, 166(3): 721728.
  49. 49. Peng Y, Liu H, Liu F, et al. Troglitazone inhibits synthesis of transforming growth factorβ1 and reduces matrix production in human peritoneal mesothelial cells [J]. Nephrology (Carlton), 2006, 11(6): 516523.
  50. 50. Fu M, Zhang J, Zhu X, et al. Peroxisome proliferatoractivated receptor γ inhibits transforming growth factor βinduced connective tissue growth factor expression in human aortic smooth muscle cells by interfering with Smad3 [J]. J Biol Chem, 2001, 276(49): 4588845894.
  51. 51. Honda K, Marquillies P, Capron M, et al. Peroxisome proliferatoractivated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model [J]. J Allergy Clin Immunol, 2004, 113(5): 882888.