• 四川大學(xué)華西醫(yī)院燒傷整形科（成都，610041）;

【摘 要】 目的  對近年TGF-β1/Smad3信號轉(zhuǎn)導(dǎo)通路與創(chuàng)傷后瘢痕形成的相關(guān)研究作一綜述。 方法  廣泛查閱國內(nèi)外近年有關(guān)TGF-β1/Smad3信號轉(zhuǎn)導(dǎo)通路及與創(chuàng)傷后瘢痕形成的文獻，并進行綜述。 結(jié)果  TGF-β1是纖維化疾病的重要影響因子，通過TGF-β1/Smad3信號通路轉(zhuǎn)導(dǎo)產(chǎn)生其生物學(xué)效應(yīng)。該途徑受多種因子調(diào)控并在細胞及分子水平與其他信號通路串話。該途徑參與創(chuàng)傷后早期炎性反應(yīng)、創(chuàng)面愈合及后期病理性瘢痕的形成。在分子水平干預(yù)轉(zhuǎn)導(dǎo)途徑的各個環(huán)節(jié)，可以影響纖維化及細胞外基質(zhì)沉著的進程。 結(jié)論  TGF-β1/Smad3信號轉(zhuǎn)導(dǎo)途徑是影響創(chuàng)傷后瘢痕形成及細胞外基質(zhì)沉著的重要途徑。對該途徑進行深入研究，可為臨床促進創(chuàng)面的愈合及病理性瘢痕的防治奠定理論基礎(chǔ)。

引用本文： 于蓉,岑瑛. TGF-β1/Smad3信號轉(zhuǎn)導(dǎo)通路與創(chuàng)傷后瘢痕形成. 中國修復(fù)重建外科雜志, 2012, 26(3): 330-335. doi: 復(fù)制

1. 46 Takagawa S, Lakos G, Mori Y, et al. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol, 2003, 121(1): 41-50. 47 Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracelluar matrix remodeling and wound healing. J Dermatol Sci, 2004, 35(2): 83-92.
2.
3. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 2000, 103(2): 295-309.
4. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genet, 2001, 29(2): 117-129.
5. Rhett JM, Ghatnekar GS, Palatinus JA, et al. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol, 2008, 26(4): 173-180.
6. Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5(1): 99-118.
7. Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta, 2008, 1782(4): 197-228.
8. 曾惠芬, 王慶文. 轉(zhuǎn)化生長因子-β及其Smad信號轉(zhuǎn)導(dǎo)的研究進展. 中國藥物與臨床, 2010, 10(10): 1145-1147.
9. Khalil N. TGF-beta: from latent to active. J Microbes Infect, 1999, 1(15): 1255-1263.
10. Horimoto M, Kato J, Takimoto R, et al. Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. Br J Cancer, 1995, 72(3): 676-682.
11. Huse M, Chen YG, Massagué J, et al. Crystal structure of the cytoplasmic domain of the type I TGFbeta receptor in complex with FKBP12. Cell, 1999, 96(3): 425-436.
12. Massagué J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-791.
13. Letamendía A, Lastres P, Botella LM, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem, 1998, 273(49): 33011-33019.
14. 趙會平, 肖嶸, 劉伏友, 等. Smad家族與硬皮病. 國外醫(yī)學(xué): 生理、病理科學(xué)與臨床分冊, 2005, 25(2): 169-171.
15. Shi Y, Wang YF, Jayaraman L, et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell, 1998, 94(5): 585-594.
16. Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science, 2000, 287(5450): 92-97.
17. Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem, 2000, 267(24): 6954-6967.
18. Feng XH, Derynck R. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J, 1997, 16(13): 3912-3923.
19. Ishisaki A, Yamato K, Nakao A. et al. Smad7 is an Activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J Biol Chem, 1998, 273(38): 24293-24296.
20. Tan R, He W, Lin X, et al. Smad ubiquitination regulatory factor-2 in the fibrotic kindney: regulation, target specificity, and functional implication. Am J Physiol Renal Physiol, 2008, 294(5): F1076-1083.
21. Dong C, Li Z, Alvarez R Jr, et al. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell, 2000, 5(1): 27-34.
22. Lo RS, Massagué J. Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol, 1999, 1(8): 472-478.
23. Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev, 1999, 13(7): 804-816.
24. Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest, 1999, 103(2): 197-206.
25. Boone B, Haspeslagh M, Brochez L. Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma. J Dermatol Sci, 2009, 53(1): 26-33.
26. 張斌, 馬顯杰, 劉賓, 等. JNK和TGF-β信號途徑協(xié)同介導(dǎo)CTGF在瘢痕疙瘩成纖維細胞中過度表達. 中國美容醫(yī)學(xué), 2009, 18(4): 506-509.
27. Cuschieri J, Maier RV. Mitogen-activated protein kinase (MAPK). Crit Care Med, 2005, 33(12 Suppl): S417-419.
28. Palmer EM, Beilfuss BA, Naqai T, et al. Human helper T cell activation and differentiation is suppressed by porcine small intestinal submucosa. Tissue Eng, 2002, 8(5): 893-900.
29. 邱振中, 李銳, 魏振雪. 皮膚傷口愈合中轉(zhuǎn)化生長因子β 信號轉(zhuǎn)導(dǎo)分子表達. 中國燒傷創(chuàng)瘍雜志, 2003, 15(3): 173-175.
30. 陳偉, 付小兵, 王海濱, 等. 增生性瘢痕形成和成熟過程中轉(zhuǎn)化生長因子-β1及下游信號分子的基因表達變化. 中華實驗外科雜志, 2005, 22(6): 740-742.
31. Xia W, Phan TT, Lim IJ, et al. Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived cells. Wound Repair Regen, 2004, 12(5): 546-556.
32. 羅梅, 姬永忠. 反義TGF-β1 抑制兔耳增生性瘢痕的實驗研究. 中國美容醫(yī)學(xué), 2004, 13(1): 18-21.
33. Schultze-Mosqau S, Blaese MA, Grabenbauer G, et al. Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1) -treatment in irradiated rat tissue. Radiother Oncol, 2004, 70(3): 249-259.
34. 龐久玲, 馬征, 劉軍, 等. Smad3和轉(zhuǎn)化生長因子β1在瘢痕疙瘩、增生性瘢痕及正常皮膚中的表達: 48∶40∶40例標本病理檢測. 中國組織工程研究與臨床康復(fù), 2010, 14(11): 1927-1930.
35. 孫燚, 宋建星, 汪滋民, 等. TGF-βRⅠ、Smad2、Smad3及Smad7在瘢痕疙瘩中的表達. 中華整形外科雜志, 2006, 22(5): 368-370.
36. 安綱, 蔡景龍, 董紅, 等. 轉(zhuǎn)化生長因子-β1Ⅱ型受體基因在瘢痕疙瘩中改變的實驗研究. 中國美容整形外科雜志, 2006, 17(5): 328-331.
37. Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg, 2001, 108(2): 423-429.
38. Bock O, Yu H, Zitron S, et al. Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloids and hypertrophic scars. Acta Derm Venereol, 2005, 85(3): 216-220.
39. Goldberg HJ, Huszár T, Mózes MM, et al. Overexpression of the type II transforming growth factor-beta receptor inhibits fibroblast proliferation and activates extracellular signal regulated kinase and c-Jun N-terminal kinase. Cell Biol Int, 2002, 26(2): 165-174.
40. Bran GM, Goessler UR, Schardt CS, et al. Effect of the abrogation of TGF-beta1 by antisense oligonucleotides on the expression of TGF-beta-isoforms and their receptors I and II in isolated fibroblasts from keloid scars. Int J Mol Med, 2010, 25(6): 915-921.
41. Wang Y, Moges H, Bharucha Y, et al. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Exp Neurol, 2007, 203(1): 168-184.
42. 毛春明, 楊曉, 張莉, 等. Smad3基因缺失加快小鼠皮膚創(chuàng)面收縮速度機制研究. 中國臨床康復(fù), 2004, 8(26): 5538-5540.
43. Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol, 2002, 160(3): 1057-1068.
44. 但洋, 沈為民, 果磊. shRNA抑制Smad3基因的表達對瘢痕疙瘩成纖維細胞Smad7表達的影響. 第三軍醫(yī)大學(xué)學(xué)報, 2009, 31(12): 1172-1176.
45. 但洋, 沈為民. shRNA對瘢痕疙瘩成纖維細胞Smad3及Ⅰ型膠原表達的影響. 激光雜志, 2009, 30(2): 78-80.
46. 劉波, 張恒術(shù), 果磊. siRNA沉默Smad3對人KFB細胞增殖、凋亡及合成MMP3的影響. 免疫學(xué)雜志, 2009, 25(3): 301-307.
47. Yu H, Bock O, Bayat A, et al. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. J Plast Reconstr Aesthet Surg, 2006, 59(3): 221-229.
48. Saika S, Yamanaka O, Nishikawa-Ishida I, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse mode. Arch Ophtalmol, 2007, 125(5): 647-654.
49. Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A, 2007, 104(9): 3432-3437.
50. Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J, 2003, 22(10): 2443-2452.
51. Zhang ZF, Zhang YG, Hu DH, et al. Smad interacting protein 1 as a regulator of skin fibrosis in pathological scars. Burns, 2011, 37(4): 665-672.
52. Phan TT, Lim IJ, Chan SY, et al. Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma, 2004, 57(5): 1032-1037.
53. Wendling J, Marchand A, Mauviel A, et al. 5-fluorouracil blocks transforming growth feator-beta-induced alpha 2 type Ⅰcollagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 actvation. Mol Pharmacol, 2003, 64(3): 707-713.
54. Suzawa H, Kikuchi S, Arai N, et al. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol, 1992, 60(2): 91-96.
55. Tang B, Zhu B, Liang Y, et al. Asiaticoside suppresses collagen expression and TGF-β/Smad signaling through inducing Smad7 and inhibiting TGF-βRI and TGF-βRII in keloid fibroblasts. Arch Dermatol Res, 2011, 303(8): 563-572.
  1. 1. 46 Takagawa S, Lakos G, Mori Y, et al. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol, 2003, 121(1): 41-50. 47 Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracelluar matrix remodeling and wound healing. J Dermatol Sci, 2004, 35(2): 83-92.
  2. 2.
  3. 3. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 2000, 103(2): 295-309.
  4. 4. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genet, 2001, 29(2): 117-129.
  5. 5. Rhett JM, Ghatnekar GS, Palatinus JA, et al. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol, 2008, 26(4): 173-180.
  6. 6. Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5(1): 99-118.
  7. 7. Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta, 2008, 1782(4): 197-228.
  8. 8. 曾惠芬, 王慶文. 轉(zhuǎn)化生長因子-β及其Smad信號轉(zhuǎn)導(dǎo)的研究進展. 中國藥物與臨床, 2010, 10(10): 1145-1147.
  9. 9. Khalil N. TGF-beta: from latent to active. J Microbes Infect, 1999, 1(15): 1255-1263.
  10. 10. Horimoto M, Kato J, Takimoto R, et al. Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. Br J Cancer, 1995, 72(3): 676-682.
  11. 11. Huse M, Chen YG, Massagué J, et al. Crystal structure of the cytoplasmic domain of the type I TGFbeta receptor in complex with FKBP12. Cell, 1999, 96(3): 425-436.
  12. 12. Massagué J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-791.
  13. 13. Letamendía A, Lastres P, Botella LM, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem, 1998, 273(49): 33011-33019.
  14. 14. 趙會平, 肖嶸, 劉伏友, 等. Smad家族與硬皮病. 國外醫(yī)學(xué): 生理、病理科學(xué)與臨床分冊, 2005, 25(2): 169-171.
  15. 15. Shi Y, Wang YF, Jayaraman L, et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell, 1998, 94(5): 585-594.
  16. 16. Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science, 2000, 287(5450): 92-97.
  17. 17. Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem, 2000, 267(24): 6954-6967.
  18. 18. Feng XH, Derynck R. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J, 1997, 16(13): 3912-3923.
  19. 19. Ishisaki A, Yamato K, Nakao A. et al. Smad7 is an Activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J Biol Chem, 1998, 273(38): 24293-24296.
  20. 20. Tan R, He W, Lin X, et al. Smad ubiquitination regulatory factor-2 in the fibrotic kindney: regulation, target specificity, and functional implication. Am J Physiol Renal Physiol, 2008, 294(5): F1076-1083.
  21. 21. Dong C, Li Z, Alvarez R Jr, et al. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell, 2000, 5(1): 27-34.
  22. 22. Lo RS, Massagué J. Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol, 1999, 1(8): 472-478.
  23. 23. Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev, 1999, 13(7): 804-816.
  24. 24. Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest, 1999, 103(2): 197-206.
  25. 25. Boone B, Haspeslagh M, Brochez L. Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma. J Dermatol Sci, 2009, 53(1): 26-33.
  26. 26. 張斌, 馬顯杰, 劉賓, 等. JNK和TGF-β信號途徑協(xié)同介導(dǎo)CTGF在瘢痕疙瘩成纖維細胞中過度表達. 中國美容醫(yī)學(xué), 2009, 18(4): 506-509.
  27. 27. Cuschieri J, Maier RV. Mitogen-activated protein kinase (MAPK). Crit Care Med, 2005, 33(12 Suppl): S417-419.
  28. 28. Palmer EM, Beilfuss BA, Naqai T, et al. Human helper T cell activation and differentiation is suppressed by porcine small intestinal submucosa. Tissue Eng, 2002, 8(5): 893-900.
  29. 29. 邱振中, 李銳, 魏振雪. 皮膚傷口愈合中轉(zhuǎn)化生長因子β 信號轉(zhuǎn)導(dǎo)分子表達. 中國燒傷創(chuàng)瘍雜志, 2003, 15(3): 173-175.
  30. 30. 陳偉, 付小兵, 王海濱, 等. 增生性瘢痕形成和成熟過程中轉(zhuǎn)化生長因子-β1及下游信號分子的基因表達變化. 中華實驗外科雜志, 2005, 22(6): 740-742.
  31. 31. Xia W, Phan TT, Lim IJ, et al. Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived cells. Wound Repair Regen, 2004, 12(5): 546-556.
  32. 32. 羅梅, 姬永忠. 反義TGF-β1 抑制兔耳增生性瘢痕的實驗研究. 中國美容醫(yī)學(xué), 2004, 13(1): 18-21.
  33. 33. Schultze-Mosqau S, Blaese MA, Grabenbauer G, et al. Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1) -treatment in irradiated rat tissue. Radiother Oncol, 2004, 70(3): 249-259.
  34. 34. 龐久玲, 馬征, 劉軍, 等. Smad3和轉(zhuǎn)化生長因子β1在瘢痕疙瘩、增生性瘢痕及正常皮膚中的表達: 48∶40∶40例標本病理檢測. 中國組織工程研究與臨床康復(fù), 2010, 14(11): 1927-1930.
  35. 35. 孫燚, 宋建星, 汪滋民, 等. TGF-βRⅠ、Smad2、Smad3及Smad7在瘢痕疙瘩中的表達. 中華整形外科雜志, 2006, 22(5): 368-370.
  36. 36. 安綱, 蔡景龍, 董紅, 等. 轉(zhuǎn)化生長因子-β1Ⅱ型受體基因在瘢痕疙瘩中改變的實驗研究. 中國美容整形外科雜志, 2006, 17(5): 328-331.
  37. 37. Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg, 2001, 108(2): 423-429.
  38. 38. Bock O, Yu H, Zitron S, et al. Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloids and hypertrophic scars. Acta Derm Venereol, 2005, 85(3): 216-220.
  39. 39. Goldberg HJ, Huszár T, Mózes MM, et al. Overexpression of the type II transforming growth factor-beta receptor inhibits fibroblast proliferation and activates extracellular signal regulated kinase and c-Jun N-terminal kinase. Cell Biol Int, 2002, 26(2): 165-174.
  40. 40. Bran GM, Goessler UR, Schardt CS, et al. Effect of the abrogation of TGF-beta1 by antisense oligonucleotides on the expression of TGF-beta-isoforms and their receptors I and II in isolated fibroblasts from keloid scars. Int J Mol Med, 2010, 25(6): 915-921.
  41. 41. Wang Y, Moges H, Bharucha Y, et al. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Exp Neurol, 2007, 203(1): 168-184.
  42. 42. 毛春明, 楊曉, 張莉, 等. Smad3基因缺失加快小鼠皮膚創(chuàng)面收縮速度機制研究. 中國臨床康復(fù), 2004, 8(26): 5538-5540.
  43. 43. Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol, 2002, 160(3): 1057-1068.
  44. 44. 但洋, 沈為民, 果磊. shRNA抑制Smad3基因的表達對瘢痕疙瘩成纖維細胞Smad7表達的影響. 第三軍醫(yī)大學(xué)學(xué)報, 2009, 31(12): 1172-1176.
  45. 45. 但洋, 沈為民. shRNA對瘢痕疙瘩成纖維細胞Smad3及Ⅰ型膠原表達的影響. 激光雜志, 2009, 30(2): 78-80.
  46. 46. 劉波, 張恒術(shù), 果磊. siRNA沉默Smad3對人KFB細胞增殖、凋亡及合成MMP3的影響. 免疫學(xué)雜志, 2009, 25(3): 301-307.
  47. 47. Yu H, Bock O, Bayat A, et al. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. J Plast Reconstr Aesthet Surg, 2006, 59(3): 221-229.
  48. 48. Saika S, Yamanaka O, Nishikawa-Ishida I, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse mode. Arch Ophtalmol, 2007, 125(5): 647-654.
  49. 49. Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A, 2007, 104(9): 3432-3437.
  50. 50. Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J, 2003, 22(10): 2443-2452.
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