EFFECT AND MECHANISM RESEARCH OF HYDROCHLORIC PROPRANOLOL CREAM ON WOUND HEALING IN DIABETIC MICE_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LIUYishu ^1,2 , ZHENGZhifang ^2,3 ,  CHENGBiao ^1,2,3

1. Graduate School, Third Military Medical University, Chongqing, 400038, P.R.China;
2. Department of Plastic Surgery, the Key Laboratory of Trauma Treatment &Tissue Repair of Tropical Area of Chinese PLA, Guangzhou General Hospital of Guangzhou Military Command;
3. Graduate School, Southern Medical University;

Corresponding author：

CHENGBiao, Email: chengbiaocheng@163.com

Keywords：

Hydrochloric propranolol cream; Wound healing; Diabetic ulcer; Mouse

DOI：

10.7507/1002-1892.20160152

Video：

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Objective To investigate the effect of hydrochloric propranolol cream and its possible mechanism on wound healing in diabetic mice. Methods Eighteen 8-week-old BKS.Cg-Dock7m+/+Leprdb/JNju diabetic mice were randomly divided into control group (n=9) and experimental group (n=9). After full-thickness dermal wounds (0.6 cm in diameter) was made, wounds were treated with cream containing hydrochloric propranolol (experimental group) or not containing hydrochloric propranolol (control group) at 2, 5, 7, 10, 14, and 17 days. At 2, 5, 7, 10, 14, 17, and 21 days, wound healing was observed, and healing rate was calculated; HE staining, Masson staining, and toluidine blue staining were used to observe wound re-epithelialization, collagen fibers, and mast cells distribution. Western blot was applied to detect the expressions of interleukin 1β (IL-1β) and angiogenin 2 (Ang2) in wound tissue. Results Wounds healed in 2 groups, but the wounds healing rate of experimental group was significantly higher than that of control group at other time points (P < 0.05) except 21 days (P > 0.05). The histological observation showed that re-epithelialization rate was higher in experimental group than control group, there were less mast cells in the wound. The experimental group was lower than control group in IL-1β expression at 2, 5, 7, 14, 17, and 21 days and in Ang2 expression at 2, 5, 7, 10, 14, 17, and 21 days. Conclusion Hydrochloric propranolol cream can promote wound healing in diabetic mice, which potential mechanism is that propranolol can promote epidermal cell proliferation, reduce inflammation, and benefit angiogenesis.

Citation： LIUYishu, ZHENGZhifang, CHENGBiao. EFFECT AND MECHANISM RESEARCH OF HYDROCHLORIC PROPRANOLOL CREAM ON WOUND HEALING IN DIABETIC MICE. Chinese Journal of Reparative and Reconstructive Surgery, 2016, 30(6): 742-747. doi: 10.7507/1002-1892.20160152 Copy

1.	Tchanque-Fossuo CN, Ho D, Dahle SE, et al. A systematic review of low-level light therapy for treatment of diabetic foot ulcer. Wound Repair Regen, 2016, 24(2): 418-426.
2.	Kum JJ, Khan ZA. Propranolol inhibits growth of hemangioma-initiating cells but does not induce apoptosis. Pediatr Res, 2014, 75(3): 381-388.
3.	Núñz-Villaveirán T, Sánchez M, Millán P, et al. Systematic review of the effect of propanolol on hypermetabilism in burn injuries. Med Intensiva, 2015, 39(2): 101-113.
4.	Brown DA, Gibbons J, Honari S, et al. Propranolol dosing practices in adult burn patients: Implications for safety and efficacy. Journal of Burn Care & Research, 2015. [Epub ahead of print].
5.	Romana-Souza B, Nascimento AP, Monte-Alto-Costa A. Propranolol improves cutaneous wound healing in streptozotocin-induced diabetic rats. Eur J Pharmacol, 2009, 611(1-3): 77-84.
6.	Kunzi-Rapp K. Topical propranolol therapy for infantile hemangiomas. Pediatr Dermatol, 2012, 29(2): 154-159.
7.	肖强, 李勤, 齐向东, 等. 普萘洛尔在婴儿严重血管瘤中的临床应用. 中国美容整形外科杂志, 2011, 22(3): 157-160.
8.	程飚, 袁进. 一种用于治疗婴幼儿血管瘤的盐酸普萘洛尔乳膏及其制备方法: 中国, CN201310003911.5. 2013-4-24.
9.	Cheng B, Liu HW, Fu XB, et al. Recombinant human platelet-derived growth factor enhanced dermal wound healing by a pathway involving ERK and c-fos in diabetic rats. J Dermatol Sci, 2007, 45(3): 193-201.
10.	Kim LR, Whelpdale K, Zurowski M, et al. Sympathetic denervation impairs epidermal healing in cutaneous wounds. Wound Repair and Regeneration, 2009, 6(3): 194-201.
11.	Romana-Souza B, Porto LC, Monte-Alto-Costa A. Cutaneous wound healing of chronically stressed mice is improved through catecholamines blockade. Exp Dermatol, 2010, 19(9): 821-829.
12.	Vestita M, Bonamonte D, Filoni A. Topical propranolol for a chronic recalcitrant wound. Dermatol Ther, 2016.[Epub ahead of print].
13.	Beroukhim K, Rotunda AM. Topical 0.5% timolol heals a recalcitrant irradiated surgical scalp wound. Dermatol Surg, 2014, 40(8): 924-926.
14.	鲍济洪. 糖尿病小鼠全层皮肤缺损创面愈合特征的实验研究. 昆明: 昆明医科大学, 2015.
15.	Pastar I, Stojadinovic O, Yin NC, et al. Epithelialization in Wound Healing: A Comprehensive Review. Adv Wound Care (New Rochelle), 2014, 3(7): 445-464.
16.	Sivamani RK, Pullar CE, Manabat-Hidalgo CG, et al. Stress-mediated increases in systemic and local epinephrine impair skin wound healing: potential new indication for beta blockers. PLoS Med, 2009, 6(1): e12.
17.	Pullar CE, Rizzo A, Isseroff RR. beta-Adrenergic receptor antagonists accelerate skin wound healing: evidence for a catecholamine synthesis network in the epidermis. J Biol Chem, 2006, 281(30): 21225-21235.
18.	肖正华, 张正军, 周倩, 等. 糖尿病足部溃疡患者白介素-1β对成纤维细胞增殖及基质金属蛋白酶-2和基质金属蛋白酶-9的影响. 中国慢性病预防与控制, 2008, 16(6): 581-583.
19.	Qiao L, Lu S L, Dong JY, et al. Abnormal regulation of neo-vascularisation in deep partial thickness scalds in rats with diabetes mellitus. Burns, 2011, 37(6): 1015-1022.
20.	李小强, 胡大海, 刘洋, 等. 负压创面治疗技术对糖尿病大鼠创面血管生成的影响. 中华烧伤杂志, 2013, 29(5): 442-447.
21.	Kämpfer H, Pfeilschifter J, Frank S. Expressional regulation of angiopoietin-1 and -2 and the tie-1 and -2 receptor tyrosine kinases during cutaneous wound healing: a comparative study of normal and impaired repair. Lab Invest, 2001, 81(3): 361-373.
22.	Chen J, Joyal JS, Hatton CJ, et al. Propranolol inhibition of β-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci, 2012, 53(6): 2968-2977.

1. Tchanque-Fossuo CN, Ho D, Dahle SE, et al. A systematic review of low-level light therapy for treatment of diabetic foot ulcer. Wound Repair Regen, 2016, 24(2): 418-426.
2. Kum JJ, Khan ZA. Propranolol inhibits growth of hemangioma-initiating cells but does not induce apoptosis. Pediatr Res, 2014, 75(3): 381-388.
3. Núñz-Villaveirán T, Sánchez M, Millán P, et al. Systematic review of the effect of propanolol on hypermetabilism in burn injuries. Med Intensiva, 2015, 39(2): 101-113.
4. Brown DA, Gibbons J, Honari S, et al. Propranolol dosing practices in adult burn patients: Implications for safety and efficacy. Journal of Burn Care & Research, 2015. [Epub ahead of print].
5. Romana-Souza B, Nascimento AP, Monte-Alto-Costa A. Propranolol improves cutaneous wound healing in streptozotocin-induced diabetic rats. Eur J Pharmacol, 2009, 611(1-3): 77-84.
6. Kunzi-Rapp K. Topical propranolol therapy for infantile hemangiomas. Pediatr Dermatol, 2012, 29(2): 154-159.
7. 肖强, 李勤, 齐向东, 等. 普萘洛尔在婴儿严重血管瘤中的临床应用. 中国美容整形外科杂志, 2011, 22(3): 157-160.
8. 程飚, 袁进. 一种用于治疗婴幼儿血管瘤的盐酸普萘洛尔乳膏及其制备方法: 中国, CN201310003911.5. 2013-4-24.
9. Cheng B, Liu HW, Fu XB, et al. Recombinant human platelet-derived growth factor enhanced dermal wound healing by a pathway involving ERK and c-fos in diabetic rats. J Dermatol Sci, 2007, 45(3): 193-201.
10. Kim LR, Whelpdale K, Zurowski M, et al. Sympathetic denervation impairs epidermal healing in cutaneous wounds. Wound Repair and Regeneration, 2009, 6(3): 194-201.
11. Romana-Souza B, Porto LC, Monte-Alto-Costa A. Cutaneous wound healing of chronically stressed mice is improved through catecholamines blockade. Exp Dermatol, 2010, 19(9): 821-829.
12. Vestita M, Bonamonte D, Filoni A. Topical propranolol for a chronic recalcitrant wound. Dermatol Ther, 2016.[Epub ahead of print].
13. Beroukhim K, Rotunda AM. Topical 0.5% timolol heals a recalcitrant irradiated surgical scalp wound. Dermatol Surg, 2014, 40(8): 924-926.
14. 鲍济洪. 糖尿病小鼠全层皮肤缺损创面愈合特征的实验研究. 昆明: 昆明医科大学, 2015.
15. Pastar I, Stojadinovic O, Yin NC, et al. Epithelialization in Wound Healing: A Comprehensive Review. Adv Wound Care (New Rochelle), 2014, 3(7): 445-464.
16. Sivamani RK, Pullar CE, Manabat-Hidalgo CG, et al. Stress-mediated increases in systemic and local epinephrine impair skin wound healing: potential new indication for beta blockers. PLoS Med, 2009, 6(1): e12.
17. Pullar CE, Rizzo A, Isseroff RR. beta-Adrenergic receptor antagonists accelerate skin wound healing: evidence for a catecholamine synthesis network in the epidermis. J Biol Chem, 2006, 281(30): 21225-21235.
18. 肖正华, 张正军, 周倩, 等. 糖尿病足部溃疡患者白介素-1β对成纤维细胞增殖及基质金属蛋白酶-2和基质金属蛋白酶-9的影响. 中国慢性病预防与控制, 2008, 16(6): 581-583.
19. Qiao L, Lu S L, Dong JY, et al. Abnormal regulation of neo-vascularisation in deep partial thickness scalds in rats with diabetes mellitus. Burns, 2011, 37(6): 1015-1022.
20. 李小强, 胡大海, 刘洋, 等. 负压创面治疗技术对糖尿病大鼠创面血管生成的影响. 中华烧伤杂志, 2013, 29(5): 442-447.
21. Kämpfer H, Pfeilschifter J, Frank S. Expressional regulation of angiopoietin-1 and -2 and the tie-1 and -2 receptor tyrosine kinases during cutaneous wound healing: a comparative study of normal and impaired repair. Lab Invest, 2001, 81(3): 361-373.
22. Chen J, Joyal JS, Hatton CJ, et al. Propranolol inhibition of β-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci, 2012, 53(6): 2968-2977.

Chinese Journal of Reparative and Reconstructive Surgery

EFFECT AND MECHANISM RESEARCH OF HYDROCHLORIC PROPRANOLOL CREAM ON WOUND HEALING IN DIABETIC MICE

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