Effect of tranilast on wound healing and administration time on scar hyperplasia of deep partial-thickness burn in mice_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

HU Zhenzhen ¹ , CHEN Bin ^2△ , LI Yang ¹ , JIANG Wei ³ , WEN Lihong ¹ , JI Fukang ¹ , YANG Xiao ¹ , WANG Jinhuang ¹ ,  LIU Dalie ¹

1. Department of Plastic Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou Guangdong, 510280, P.R.China;
2. Department of Plastic Surgery, the Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou Worker’s Hospital, Liuzhou Guangxi, 545005, P.R.China;
3. Department of Plastic Surgery, Southern Hospital of Southern Medical University, Guangzhou Guangdong, 510515, P.R.China;

Corresponding author：

LIU Dalie, Email: liudalie@hotmail.com

Keywords：

Tranilast; scar hyperplasia; wound healing; transforming growth factor β₁; mast cells; mouse

DOI：

10.7507/1002-1892.201611033

Video：

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Objective To investigate the effect of tranilast on wound healing and the mechanism of inhibiting scar hyperplasia in mice, and to study the relationship between the inhibiting ability of tranilast on scar hyperplasia and administration time. Methods Sixty-six Kunming mice were selected to build deep II degree burn model, and were randomly divided into the control group (18 mice), the early intervention group (18 mice), the medium intervention group (18 mice), and the late intervention group (12 mice). The mice in the early intervention group, the medium-term intervention group, and the late intervention group were given tranilast 200 mg/(kg·d) by gastrogavage at immediate, 7 days, and 14 days after burn respectively, and the mice in the control group were managed with same amount of normal saline every day. The wound healing was observed regularly. At 14, 28, and 42 days in the early and medium intervention groups and at 28 and 42 days in the late intervention group, fresh tissues were taken from 6 mice to observe the shape of mast cells by toluidine blue staining, collagen content by Masson staining; the collagen type I and collagen type III content were measured to calculate the I/III collagen content ratio by immunohistochemistry method, the contents of transforming growth factor β₁ (TGF-β₁) and histamine were detected by ELISA; and the ultrastructure of fibroblasts was observed under transmission electron microscope. Results There was no significant difference in wound healing time between groups (F=1.105,P=0.371). The mast cells number, collagen content, TGF-β₁ content, histamine content, and the I/III collagen content ratio in the early intervention group were significantly less than those in the other groups (P<0.05). Significant difference was found in mast cells number, collagen content, and histamine content between control group and medium or late intervention group at the other time points (P<0.05) except between control group and late intervention group at 42 days (P>0.05). Compared with the control group, the activity of fibroblasts in the early intervention group was obviously inhibited, and the arrangement of the fibers was more regular; the fibroblast activity in the medium and late intervention groups was also inhibited obviously. Conclusion Tranilast has no obvious effect on the wound healing time in mice. Tranilast intervention shows the inhibitory effect on the scar hyperplasia which can significantly reduce the number of mast cells, the content of histamine and TGF-β₁, inhibit the ability of fibroblasts synthetic collagen and adjust the proportion of collagen synthesis. The immediate tranilast intervention may have the best inhibitory effect on scar hyperplasia.

Citation： HU Zhenzhen, CHEN Bin, LI Yang, JIANG Wei, WEN Lihong, JI Fukang, YANG Xiao, WANG Jinhuang, LIU Dalie. Effect of tranilast on wound healing and administration time on scar hyperplasia of deep partial-thickness burn in mice. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(4): 465-472. doi: 10.7507/1002-1892.201611033 Copy

1.	Fan C, Dong Y, Xie Y, et al. Shikonin reduces TGF-β₁-induced collagen production and contraction in hypertrophic scar-derived human skin fibroblasts. Int J Mol Med, 2015, 36(4): 985-991.
2.	Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med, 2007, 4(9): e234.
3.	Lawrence JW, Mason ST, Schomer K, et al. Epidemiology and impact of scarring after burn injury: a systematic review of the literature. J Burn Care Res, 2012, 33(1): 136-146.
4.	陈彬, 首家保, 杨小辉, 等. 口服曲尼司特防治烧伤瘢痕增生的临床研究. 中国美容医学, 2014, 23(3): 173-175.
5.	黎凤明, 许学文, 于蓉, 等. 曲尼司特对大鼠深Ⅱ度烫伤创面愈合及瘢痕形成的作用. 华西药学杂志, 2008, 23(4): 426-428.
6.	Huang D, Shen KH, Wang HG. Pressure therapy upregulates matrix metalloproteinase expression and downregulates collagen expression in hypertrophic scar tissue. Chin Med J (Engl), 2013, 126(17): 3321-3324.
7.	Gauglitz GG, Korting HC, Pavicic T, et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Molecular Medicine, 2010, 17(1-2): 113-125.
8.	Liu BH, Chen L, Li SR, et al. Smac/DIABLO regulates the apoptosis of hypertrophic scar fibroblasts. Int J Mol Med, 2013, 32(3): 615-622.
9.	Butzelaar L, Ulrich MM, Mink van der Molen AB, et al. Currently known risk factors for hypertrophic skin scarring: A review. J Plast Reconstr Aesthet Surg, 2016, 69(2): 163-169.
10.	Yin L, Zhao X, Ji S, et al. The use of gene activated matrix to mediate effective SMAD2 gene silencing against hypertrophic scar. Biomaterials, 2014, 35(8): 2488-2498.
11.	Liu J, Wang Y, Pan Q, et al. Wnt/β-catenin pathway forms a negative feedback loop during TGF-β₁ induced human normal skin fibroblast-to-myofibroblast transition. J Dermatol Sci, 2012, 65(1): 38-49.
12.	Qiu SS, Dotor J, Hontanilla B. Effect of P144® (Anti-TGF-β) in an "In Vivo” Human Hypertrophic Scar Model in Nude Mice. PLoS One, 2015, 10(12): e0144489.
13.	Wilgus TA, Wulff BC. The Importance of Mast Cells in Dermal Scarring. Adv Wound Care (New Rochelle), 2014, 3(4): 356-365.
14.	Wulff BC, Wilgus TA. Examining the role of mast cells in fetal wound healing using cultured cellsin vitro. Methods Mol Biol, 2013, 1037: 495-506.
15.	Chen L, Schrementi ME, Ranzer MJ, et al. Blockade of mast cell activation reduces cutaneous scar formation. PLoS One, 2014, 9(1): e85226.
16.	冯小倩, 张纲, 张慧宇, 等. 组胺及组胺受体1在大鼠牙周炎发病中表达差异的研究. 牙体牙髓牙周病学杂志, 2015, 25(1): 15-19.
17.	Gutiérrez-Venegas G, Rodriguez-Pérez CE. Toll-like receptor 3 activation promotes desensitization of histamine response in human gingival fibroblasts: Poly (I:C) induces histamine receptor desensitization in human gingival fibroblasts. Cell Immunol, 2012, 273(2): 150-157.
18.	Prud’homme GJ. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest, 2007, 87(11): 1077-1091.
19.	Darakhshan S, Pour AB. Tranilast: a review of its therapeutic application. Pharmacol Res, 2015, 91(10): 15-28.

1. Fan C, Dong Y, Xie Y, et al. Shikonin reduces TGF-β₁-induced collagen production and contraction in hypertrophic scar-derived human skin fibroblasts. Int J Mol Med, 2015, 36(4): 985-991.
2. Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med, 2007, 4(9): e234.
3. Lawrence JW, Mason ST, Schomer K, et al. Epidemiology and impact of scarring after burn injury: a systematic review of the literature. J Burn Care Res, 2012, 33(1): 136-146.
4. 陈彬, 首家保, 杨小辉, 等. 口服曲尼司特防治烧伤瘢痕增生的临床研究. 中国美容医学, 2014, 23(3): 173-175.
5. 黎凤明, 许学文, 于蓉, 等. 曲尼司特对大鼠深Ⅱ度烫伤创面愈合及瘢痕形成的作用. 华西药学杂志, 2008, 23(4): 426-428.
6. Huang D, Shen KH, Wang HG. Pressure therapy upregulates matrix metalloproteinase expression and downregulates collagen expression in hypertrophic scar tissue. Chin Med J (Engl), 2013, 126(17): 3321-3324.
7. Gauglitz GG, Korting HC, Pavicic T, et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Molecular Medicine, 2010, 17(1-2): 113-125.
8. Liu BH, Chen L, Li SR, et al. Smac/DIABLO regulates the apoptosis of hypertrophic scar fibroblasts. Int J Mol Med, 2013, 32(3): 615-622.
9. Butzelaar L, Ulrich MM, Mink van der Molen AB, et al. Currently known risk factors for hypertrophic skin scarring: A review. J Plast Reconstr Aesthet Surg, 2016, 69(2): 163-169.
10. Yin L, Zhao X, Ji S, et al. The use of gene activated matrix to mediate effective SMAD2 gene silencing against hypertrophic scar. Biomaterials, 2014, 35(8): 2488-2498.
11. Liu J, Wang Y, Pan Q, et al. Wnt/β-catenin pathway forms a negative feedback loop during TGF-β₁ induced human normal skin fibroblast-to-myofibroblast transition. J Dermatol Sci, 2012, 65(1): 38-49.
12. Qiu SS, Dotor J, Hontanilla B. Effect of P144® (Anti-TGF-β) in an "In Vivo” Human Hypertrophic Scar Model in Nude Mice. PLoS One, 2015, 10(12): e0144489.
13. Wilgus TA, Wulff BC. The Importance of Mast Cells in Dermal Scarring. Adv Wound Care (New Rochelle), 2014, 3(4): 356-365.
14. Wulff BC, Wilgus TA. Examining the role of mast cells in fetal wound healing using cultured cellsin vitro. Methods Mol Biol, 2013, 1037: 495-506.
15. Chen L, Schrementi ME, Ranzer MJ, et al. Blockade of mast cell activation reduces cutaneous scar formation. PLoS One, 2014, 9(1): e85226.
16. 冯小倩, 张纲, 张慧宇, 等. 组胺及组胺受体1在大鼠牙周炎发病中表达差异的研究. 牙体牙髓牙周病学杂志, 2015, 25(1): 15-19.
17. Gutiérrez-Venegas G, Rodriguez-Pérez CE. Toll-like receptor 3 activation promotes desensitization of histamine response in human gingival fibroblasts: Poly (I:C) induces histamine receptor desensitization in human gingival fibroblasts. Cell Immunol, 2012, 273(2): 150-157.
18. Prud’homme GJ. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest, 2007, 87(11): 1077-1091.
19. Darakhshan S, Pour AB. Tranilast: a review of its therapeutic application. Pharmacol Res, 2015, 91(10): 15-28.

Chinese Journal of Reparative and Reconstructive Surgery

Effect of tranilast on wound healing and administration time on scar hyperplasia of deep partial-thickness burn in mice

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