Mechanisms of adrenergic β-antagonist for wounds and its application prospect in diabetic foot ulcers_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

SUN Shiyi ¹ , MA Jing ² ,  RAN Xingwu ¹

1. Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;
2. Department of Endocrinology and Metabolism, Gansu Provincial Hospital, Lanzhou Gansu, 730000, P.R.China;

Corresponding?author：

RAN Xingwu, Email: ranxingwu@163.com

Keywords：

Adrenergic β-antagonists; diabetic foot; ulcer; wound healing; mechanism

DOI：

10.7507/1002-1892.202002063

Video：

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Objective To review the research progress of adrenergic β-antagonists on wounds and diabetic chronic cutaneous ulcers healing in recent years, and to investigate its application prospect in diabetic foot ulcer (DFU).Methods The latest literature about the role of adrenergic β-antagonists in wounds and diabetic chronic cutaneous ulcers healing was extensively reviewed, and the mechanisms of adrenergic β-antagonists for wounds and its potential benefit for DFU were analyzed thoroughly.Results The adrenergic β-antagonists can accelerate the wound healing. The possible mechanisms include accelerating re-epithelialization, promoting angiogenesis, improving neuropathy, and regulating inflammation and growth factors, etc. At present clinical research data showed that the adrenergic β-antagonists may be an adjuvant treatment for diabetic chronic cutaneous ulcers.Conclusion Adrenergic β-antagonists maybe promote the healing of wounds and diabetic chronic cutaneous ulcers. However, more long-term follow-up and high-quality randomized control studies are needed to further verify their efficacy and safety for DFU.

Citation： SUN Shiyi, MA Jing, RAN Xingwu. Mechanisms of adrenergic β-antagonist for wounds and its application prospect in diabetic foot ulcers. Chinese Journal of Reparative and Reconstructive Surgery, 2020, 34(12): 1630-1634. doi: 10.7507/1002-1892.202002063 Copy

1.	Karam RA, Rezk NA, Abdel Rahman TM, et al. Effect of negative pressure wound therapy on molecular markers in diabetic foot ulcers. Gene, 2018, 667: 56-61.
2.	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.
3.	Steinkraus V, Mak JC, Pichlmeier U, et al. Autoradiographic mapping of beta-adrenoceptors in human skin. Arch Dermatol Res, 1996, 288(9): 549-553.
4.	Albrecht H, Yang HY, Kiuru M, et al. The beta 2 adrenergic receptor antagonist iimolol improves healing of combined burn and radiation wounds. Radiat Res, 2018, 189(4): 441-445.
5.	Satterfield KR, Chambers CB. Current treatment and management of infantile hemangiomas. Surv Ophthalmol, 2019, 64(5): 608-618.
6.	Thomas B, Kurien JS, Jose T, et al. Topical timolol promotes healing of chronic leg ulcer. J Vasc Surg Venous Lymphat Disord, 2017, 5(6): 844-850.
7.	Dasu MR, Ramirez SR, La TD, et al. Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing. Stem Cells Transl Med, 2014, 3(6): 745-759.
8.	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.
9.	Gulcan E, Ilhan D, Toker S. Nebivolol might be beneficial in the prevention and treatment of diabetic neuropathy. Am J Ther, 2016, 23(1): e240.
10.	Zheng Z, Liu Y, Yang Y, et al. Topical 1% propranolol cream promotes cutaneous wound healing in spontaneously diabetic mice. Wound Repair Regen, 2017, 25(3): 389-397.
11.	Bhadri N, Razdan R, Goswami SK. Nebivolol, a β-blocker abrogates streptozotocin-induced behavioral, biochemical, and neurophysiological deficit by attenuating oxidative-nitrosative stress: a possible target for the prevention of diabetic neuropathy. Naunyn Schmiedebergs Arch Pharmacol, 2018, 391(2): 207-217.
12.	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.
13.	Lev-Tov H, Dahle S, Moss J, et al. Successful treatment of a chronic venous leg ulcer using a topical beta-blocker. J Am Acad Dermatol, 2013, 69(4): e204-e205.
14.	Romana-Souza B, Otranto M, Vieira AM, et al. Rotational stress-induced increase in epinephrine levels delays cutaneous wound healing in mice. Brain Behav Immun, 2010, 24(3): 427-437.
15.	Kuebler U, Wirtz PH, Sakai M, et al. Acute stress reduces wound-induced activation of microbicidal potential of ex vivo isolated human monocyte-derived macrophages. PLoS One, 2013, 8(2): e55875.
16.	Romana-Souza B, Otranto M, Almeida TF, et al. Stress-induced epinephrine levels compromise murine dermal fibroblast activity through β-adrenoceptors. Exp Dermatol, 2011, 20(5): 413-419.
17.	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.
18.	Sivamani RK, Shi B, Griffiths E, et al. Acute wounding alters the beta2-adrenergic signaling and catecholamine synthetic pathways in keratinocytes. J Invest Dermatol, 2014, 134(8): 2258-2266.
19.	Pullar CE, Grahn JC, Liu W, et al. Beta2-adrenergic receptor activation delays wound healing. FASEB J, 2006, 20(1): 76-86.
20.	Koizumi H, Yasui C, Fukaya T, et al. Beta-adrenergic stimulation induces intracellular Ca++ increase in human epidermal keratinocytes. J Invest Dermatol, 1991, 96(2): 234-237.
21.	Tu CL, Celli A, Mauro T, et al. Calcium-sensing receptor regulates epidermal intracellular Ca²⁺ signaling and re-epithelialization after wounding. J Invest Dermatol, 2019, 139(4): 919-929.
22.	Huo J, Sun S, Geng Z, et al. Bone marrow-derived mesenchymal stem cells promoted cutaneous wound healing by regulating keratinocyte migration via β₂-adrenergic receptor signaling. Mol Pharm, 2018, 15(7): 2513-2527.
23.	Pullar CE, Manabat-Hidalgo CG, Bolaji RS, et al. Beta-adrenergic receptor modulation of wound repair. Pharmacol Res, 2008, 58(2): 158-164.
24.	Kim MH, Gorouhi F, Ramirez S, et al. Catecholamine stress alters neutrophil trafficking and impairs wound healing by β2-adrenergic receptor-mediated upregulation of IL-6. J Invest Dermatol, 2014, 134(3): 809-817.
25.	Djanani A, Kaneider NC, Meierhofer C, et al. Inhibition of neutrophil migration and oxygen free radical release by metipranolol and timolol. Pharmacology, 2003, 68(4): 198-203.
26.	O’Leary AP, Fox JM, Pullar CE. Beta-adrenoceptor activation reduces both dermal microvascular endothelial cell migration via a cAMP-dependent mechanism and wound angiogenesis. J Cell Physiol, 2015, 230(2): 356-365.
27.	Tang JC, Dosal J, Kirsner RS. Topical timolol for a refractory wound. Dermatol Surg, 2012, 38(1): 135-138.
28.	Pullar CE, Le Provost GS, O’Leary AP, et al. β2AR antagonists and β2AR gene deletion both promote skin wound repair processes. J Invest Dermatol, 2012, 132(8): 2076-2084.
29.	Spiller KL, Anfang RR, Spiller KJ, et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials, 2014, 35(15): 4477-4488.
30.	Kisiel MA, Klar AS. Isolation and culture of human dermal fibroblasts. Methods Mol Biol, 2019, 1993: 71-78.
31.	Pullar CE, Isseroff RR. The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci, 2006, 119(Pt 3): 592-602.
32.	Souza BR, Santos JS, Costa AM. Blockade of beta1- and beta2-adrenoceptors delays wound contraction and re-epithelialization in rats. Clin Exp Pharmacol Physiol, 2006, 33(5-6): 421-430.
33.	López-López N, González-Curiel I, Trevi?o-Santa Cruz MB, et al. Expression and vitamin D-mediated regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy skin and in diabetic foot ulcers. Arch Dermatol Res, 2014, 306(9): 809-821.
34.	Berlanga-Acosta J, Schultz GS, López-Mola E, et al. Glucose toxic effects on granulation tissue productive cells: the diabetics’ impaired healing. Biomed Res Int, 2013, 2013: 256043.
35.	Shedden AH, Laurence J, Barrish A, et al. Plasma timolol concentrations of timolol maleate: timolol gel-forming solution (TIMOPTIC-XE) once daily versus timolol maleate ophthalmic solution twice daily. Doc Ophthalmol, 2001, 103(1): 73-79.
36.	Khunger N, Pahwa M. Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol, 2011, 164(4): 886-888.
37.	Boos MD, Castelo-Soccio L. Experience with topical timolol maleate for the treatment of ulcerated infantile hemangiomas (IH). J Am Acad Dermatol, 2016, 74(3): 567-570.
38.	Khouri C, Jouve T, Blaise S, et al. Peripheral vasoconstriction induced by β-adrenoceptor blockers: a systematic review and a network meta-analysis. Br J Clin Pharmacol, 2016, 82(2): 549-560.

1. Karam RA, Rezk NA, Abdel Rahman TM, et al. Effect of negative pressure wound therapy on molecular markers in diabetic foot ulcers. Gene, 2018, 667: 56-61.
2. 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.
3. Steinkraus V, Mak JC, Pichlmeier U, et al. Autoradiographic mapping of beta-adrenoceptors in human skin. Arch Dermatol Res, 1996, 288(9): 549-553.
4. Albrecht H, Yang HY, Kiuru M, et al. The beta 2 adrenergic receptor antagonist iimolol improves healing of combined burn and radiation wounds. Radiat Res, 2018, 189(4): 441-445.
5. Satterfield KR, Chambers CB. Current treatment and management of infantile hemangiomas. Surv Ophthalmol, 2019, 64(5): 608-618.
6. Thomas B, Kurien JS, Jose T, et al. Topical timolol promotes healing of chronic leg ulcer. J Vasc Surg Venous Lymphat Disord, 2017, 5(6): 844-850.
7. Dasu MR, Ramirez SR, La TD, et al. Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing. Stem Cells Transl Med, 2014, 3(6): 745-759.
8. 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.
9. Gulcan E, Ilhan D, Toker S. Nebivolol might be beneficial in the prevention and treatment of diabetic neuropathy. Am J Ther, 2016, 23(1): e240.
10. Zheng Z, Liu Y, Yang Y, et al. Topical 1% propranolol cream promotes cutaneous wound healing in spontaneously diabetic mice. Wound Repair Regen, 2017, 25(3): 389-397.
11. Bhadri N, Razdan R, Goswami SK. Nebivolol, a β-blocker abrogates streptozotocin-induced behavioral, biochemical, and neurophysiological deficit by attenuating oxidative-nitrosative stress: a possible target for the prevention of diabetic neuropathy. Naunyn Schmiedebergs Arch Pharmacol, 2018, 391(2): 207-217.
12. 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.
13. Lev-Tov H, Dahle S, Moss J, et al. Successful treatment of a chronic venous leg ulcer using a topical beta-blocker. J Am Acad Dermatol, 2013, 69(4): e204-e205.
14. Romana-Souza B, Otranto M, Vieira AM, et al. Rotational stress-induced increase in epinephrine levels delays cutaneous wound healing in mice. Brain Behav Immun, 2010, 24(3): 427-437.
15. Kuebler U, Wirtz PH, Sakai M, et al. Acute stress reduces wound-induced activation of microbicidal potential of ex vivo isolated human monocyte-derived macrophages. PLoS One, 2013, 8(2): e55875.
16. Romana-Souza B, Otranto M, Almeida TF, et al. Stress-induced epinephrine levels compromise murine dermal fibroblast activity through β-adrenoceptors. Exp Dermatol, 2011, 20(5): 413-419.
17. 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.
18. Sivamani RK, Shi B, Griffiths E, et al. Acute wounding alters the beta2-adrenergic signaling and catecholamine synthetic pathways in keratinocytes. J Invest Dermatol, 2014, 134(8): 2258-2266.
19. Pullar CE, Grahn JC, Liu W, et al. Beta2-adrenergic receptor activation delays wound healing. FASEB J, 2006, 20(1): 76-86.
20. Koizumi H, Yasui C, Fukaya T, et al. Beta-adrenergic stimulation induces intracellular Ca++ increase in human epidermal keratinocytes. J Invest Dermatol, 1991, 96(2): 234-237.
21. Tu CL, Celli A, Mauro T, et al. Calcium-sensing receptor regulates epidermal intracellular Ca²⁺ signaling and re-epithelialization after wounding. J Invest Dermatol, 2019, 139(4): 919-929.
22. Huo J, Sun S, Geng Z, et al. Bone marrow-derived mesenchymal stem cells promoted cutaneous wound healing by regulating keratinocyte migration via β₂-adrenergic receptor signaling. Mol Pharm, 2018, 15(7): 2513-2527.
23. Pullar CE, Manabat-Hidalgo CG, Bolaji RS, et al. Beta-adrenergic receptor modulation of wound repair. Pharmacol Res, 2008, 58(2): 158-164.
24. Kim MH, Gorouhi F, Ramirez S, et al. Catecholamine stress alters neutrophil trafficking and impairs wound healing by β2-adrenergic receptor-mediated upregulation of IL-6. J Invest Dermatol, 2014, 134(3): 809-817.
25. Djanani A, Kaneider NC, Meierhofer C, et al. Inhibition of neutrophil migration and oxygen free radical release by metipranolol and timolol. Pharmacology, 2003, 68(4): 198-203.
26. O’Leary AP, Fox JM, Pullar CE. Beta-adrenoceptor activation reduces both dermal microvascular endothelial cell migration via a cAMP-dependent mechanism and wound angiogenesis. J Cell Physiol, 2015, 230(2): 356-365.
27. Tang JC, Dosal J, Kirsner RS. Topical timolol for a refractory wound. Dermatol Surg, 2012, 38(1): 135-138.
28. Pullar CE, Le Provost GS, O’Leary AP, et al. β2AR antagonists and β2AR gene deletion both promote skin wound repair processes. J Invest Dermatol, 2012, 132(8): 2076-2084.
29. Spiller KL, Anfang RR, Spiller KJ, et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials, 2014, 35(15): 4477-4488.
30. Kisiel MA, Klar AS. Isolation and culture of human dermal fibroblasts. Methods Mol Biol, 2019, 1993: 71-78.
31. Pullar CE, Isseroff RR. The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci, 2006, 119(Pt 3): 592-602.
32. Souza BR, Santos JS, Costa AM. Blockade of beta1- and beta2-adrenoceptors delays wound contraction and re-epithelialization in rats. Clin Exp Pharmacol Physiol, 2006, 33(5-6): 421-430.
33. López-López N, González-Curiel I, Trevi?o-Santa Cruz MB, et al. Expression and vitamin D-mediated regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy skin and in diabetic foot ulcers. Arch Dermatol Res, 2014, 306(9): 809-821.
34. Berlanga-Acosta J, Schultz GS, López-Mola E, et al. Glucose toxic effects on granulation tissue productive cells: the diabetics’ impaired healing. Biomed Res Int, 2013, 2013: 256043.
35. Shedden AH, Laurence J, Barrish A, et al. Plasma timolol concentrations of timolol maleate: timolol gel-forming solution (TIMOPTIC-XE) once daily versus timolol maleate ophthalmic solution twice daily. Doc Ophthalmol, 2001, 103(1): 73-79.
36. Khunger N, Pahwa M. Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol, 2011, 164(4): 886-888.
37. Boos MD, Castelo-Soccio L. Experience with topical timolol maleate for the treatment of ulcerated infantile hemangiomas (IH). J Am Acad Dermatol, 2016, 74(3): 567-570.
38. Khouri C, Jouve T, Blaise S, et al. Peripheral vasoconstriction induced by β-adrenoceptor blockers: a systematic review and a network meta-analysis. Br J Clin Pharmacol, 2016, 82(2): 549-560.

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Mechanisms of adrenergic β-antagonist for wounds and its application prospect in diabetic foot ulcers

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