The contradictory role of androgens in cutaneous and major burn wound healing
- Burns & Trauma Vol. 9, Issue 1, (2021)
- 作者机构：
1. Burns Research Group, ANZAC Research Institute, University of Sydney
2. Andrology, ANZAC Research Institute, University of Sydney
3. Burns and Reconstructive Surgery Unit
4. Adrenal Steroid Laboratory, ANZAC Research Institute, University of Sydney
- 作者简介：
- 基金信息：
DOI：10.1093/burnst/tkaa046
CLC：Published：2021，
Published Online：20 April 2021，
扫 描 看 全 文
Huaikai Shi, Kenny Cheer, Ulla Simanainen, Brian Lesmana, Duncan Ma, Jonathan J Hew, Roxanne J Parungao, Zhe Li, Mark S Cooper, David J Handelsman, Peter K Maitz, Yiwei Wang, The contradictory role of androgens in cutaneous and major burn wound healing, Burns & Trauma, Volume 9, 2021, tkaa046, https://doi.org/10.1093/burnst/tkaa046
Huaikai Shi, Kenny Cheer, Ulla Simanainen, Brian Lesmana, Duncan Ma, Jonathan J Hew, Roxanne J Parungao, Zhe Li, Mark S Cooper, David J Handelsman, Peter K Maitz, Yiwei Wang, The contradictory role of androgens in cutaneous and major burn wound healing, Burns & Trauma, Volume 9, 2021, tkaa046, https://doi.org/10.1093/burnst/tkaa046 DOI：
摘要
Abstract
Wound healing is a complex process involving four overlapping phases: haemostasis
inflammation
cell recruitment and matrix remodeling. In mouse models
surgical
pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-α production and reduce wound re-epithelization and matrix deposition
retarding cutaneous wound healing. Similarly
clinical studies have shown that cutaneous wound healing is slower in men compared to women. However
in major burn injury
which triggers not only local wound-healing processes but also systemic hypermetabolism
the role of androgens is poorly understood. Recent studies have claimed that a synthetic androgen
oxandrolone
increases protein synthesis
improves lean body mass and shortens length of hospital stay. However
the possible mechanisms by which oxandrolone regulates major burn injury have not been reported. In this review
we summarize the current findings on the roles of androgens in cutaneous and major burn wound healing
as well as androgens as a potential therapeutic treatment option for patients with major burn injuries.
关键词
Keywords
Wound healingAndrogenMouse modelOxandroloneCutaneous injuryMajor burn injury
references
1.Hart DW, Wolf SE, Ramzy PI, Chinkes DL, Beauford RB, Ferrando AA, et al. Anabolic effects of oxandrolone after severe burn. Ann Surg. 2001;233:556–64.
2.Chen W, Zouboulis CC, Fritsch M, Blume-Peytavi U, Kodelja V, Goerdt S, et al. Evidence of heterogeneity and quantitative differences of the type 1 5alpha-reductase expression in cultured human skin cells--evidence of its presence in melanocytes. J Invest Dermatol. 1998;110:84–9.
3.Gerst C, Dalko M, Pichaud P, Galey JB, Buan B, Bermard BA. Type-1 steroid 5 alpha-reductase is functionally active in the hair follicle as evidenced by new selective inhibitors of either type-1 or type-2 human steroid 5 alpha-reductase. Exp Dermatol. 2002;11:52–8.
4.Choi J, Psarommatis B, Gao YR, Zheng Y, Handelsman DJ, Simanainen U. The role of androgens in experimental rodent mammary carcinogenesis. Breast Cancer Res. 2014. https://doi.org/10.1186/s13058-014-0483-x.
5.Handelsman DJ. Androgen, Physiology, Pharmaolgy, Use and Misuse. Sauder:Elsevier, 2016.
6.Azzouni F, Godoy A, Li Y, Mohler J. The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. Adv Urol. 2012. https://doi.org/10.1155/2012/530121.
7.Quigley CA, De Bellis A, Marschke KB, El-Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev. 1995;16:271–321.
8.Basaria S, Dobs AS. Hypogonadism and androgen replacement therapy in elderly men. Am J Med. 2001;110:563–72.
9.Grinspoon S. Androgen deficiency and HIV infection. Clin Infect Dis. 2005;41:1804–5.
10.Howell SJ, Radford JA, Adams JE, Smets EM, Warburton R, Shalet SM. Randomized placebo-controlled trial of testosterone replacement in men with wild Leydig cell insufficiency following cytotoxic chemotherapy. Clin Endrocinol (Oxf). 2001;55:315–24.
11.Merza Z, Blumsohn A, Mah PM, Meads DM, McKenna SP, Wylie K, et al. Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Int J Androl. 2006;29:381–91.
12.Demling RH, Seigne P. Metabolic management of patients with severe burns. World J Surg. 2000;24:673–80.
13.Orr R, Singh M F. The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety. Drugs. 2004;64:725–50.
14.Lindblad WJ. Considerations for selecting the correct animal model for dermal wound-healing studies. J Biomater Sci Polym Ed. 2008;19:1087–96.
15.Wong VW, Sorkin M, Glotzbach JP, Longaker MT, Gurtner GC. Surgical approaches to create murine models of human wound healing. J Biomed Biotechnol. 2011. https://doi.org/10.1155/2011/969618.
16.Mestas J, Hughes CCW. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–8.
17.Abdullahi A, Amini-Nik S, Jeschke MG. Animal models in burn research. Cell Mol Life Sci. 2014;71:3241–55.
18.Ashcroft GS, Mills SJ. Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Investig. 2002;110:615–24.
19.Ashcroft GS, Mills SJ, Flanders KC, Lyakh LA, Anzano MA, Gilliver SC, et al. Role of Smad3 in the hormonal modulation of in vivo wound healing responses. Wound Repair Regen. 2003;11:468–73.
20.Gilliver SC, Ashworth JJ, Mills SJ, Hardman MJ, Ashcroft GS. Androgens modulate the inflammatory response during acute wound healing. J Cell Sci. 2006;119:722–32.
21.Gilliver SC, Ruckshanthi JP, Hardman MJ, Nakayama T, Ashcroft GS. Sex dimorphism in wound healing: the roles of sex steroids and macrophage migration inhibitory factor. Endocrinology. 2008;149:5747–57.
22.Gilliver SC, Ashworth JJ, Mills SJ, Hardman MJ, Ashcroft GS. Androgens modulate the inflammatory response during acute wound healing. J Cell Sci. 2006;119:722–32.
23.Lai JJ, Lai KP, Chuang KH, Chang P, Yu IC, Lin WJ, et al. Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression. J Clin Investig. 2009;119:3739–51.
24.Gendt KD, Verhoeven G. Tissue- and cell-specific functions of the androgen receptor revealed through conditional knockout models in mice. Mol Cell Endocrinol. 2012;352:13–25.
25.Shamberger RC, Thistlethwaite PA, Thibault LE, Talbot TL, Brennan MF. The effect of testosterone propionate on wound healing in normal and castrate rats. J Surg Res. 1982;33:58–68.
26.Mukai K, Nakajima Y, Urai T, Komatsu E, Nasruddin, Sugama, J et al. 17β-Estradiol administration promotes delayed cutaneous wound healing in 40-week ovariectomised female mice. Int Wound J. 2016;13:636–44.
27.Hardman MJ, Emmerson E, Campbell L, Ashcroft GS. Selective estrogen receptor modulators accelerate cutaneous wound healing in ovariectomized female mice. Endocrinology. 2008;149:551–7.
28.Lyon MF, Hawkes SG. X-linked gene for testicular feminization in the mouse. Nature. 1970;227:1217–9.
29.Olsen KL, Whalen RE. Hormonal control of the development of sexual behavior in androgen-insensitive (tfm) rats. Physiol Behav. 1981;27:883–6.
30.He WW, Kumar MV, Tindall DJ. A frame-shift mutation in the androgen receptor gene causes complete androgen insensitivity in the testicular-feminized mouse. Nucleic Acids Res. 1991;19:2373–8.
31.Gaspar ML, Meo T, Bourgarel P, Guenet JL, Tosi T. A single base deletion in the Tfm androgen receptor gene creates a short-lived messenger RNA that directs internal translation initiation. Proc Natl Acad Sci U S A. 1991;88:8606–10.
32.Lyon MF, Glenister PH. Reduced reproductive performance in androgen-resistant Tfm/Tfm female mice. Proc R Soc Lond B Biol Sci. 1980;208:1–12.
33.Yeh S, Tsai MY, Xu Q, Mu XM, Lardy H, Huang KE, et al. Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci U S A. 2002;99:13498–503.
34.Walters KA, Simanainen U, Handelsman DJ. Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models. Hum Reprod Update. 2010;16:543–58.
35.Walters KA, Allan CM, Jimenez M, Lim PR, Davey RA, Zajac JD, et al. Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility. Endocrinology. 2007;148:3674–84.
36.Walters KA, McTavish KJ, Seneviratne MG, Jimenez M, McMahon AC, Allan CM, et al. Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function. Endocrinology. 2009;150:3274–82.
37.Markova MS, Zeskand J, McEntee B, Rothstein J, Jimenez SA, Siracusa LD. A role for the androgen receptor in collagen content of the skin. J Invest Dermatol. 2004;123:1052–6.
38.Sauer B. Cre/lox: one more step in the taming of the genome. Endocrine. 2002;19:221–8.
39.Holdcraft RW, Braun RE. Androgen receptor function is required in Sertoli cells for the terminal differentiation of haploid spermatids. Development. 2004;131:459–67.
40.Takahiro M, Ken-ichi T, Takashi S, Shigeaki K. Androgen receptor functions from reverse genetic models. J Steroid Biochem Mol Biol. 2003;85:95–9.
41.De Gendt K, Swinnen JV, Saunders PT, Schoonjans L, Dewerchin M, Devos A, et al. A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci U S A. 2004;101:1327–32.
42.Notini AJ, Davey RA, McManus JF, Bate KL, Zajac JD. Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model. J Mol Endocrinol. 2005;35:547–55.
43.Walters KA, Allan CM, Handelsman DJ. Androgen actions and the ovary. Biol Reprod. 2008;78:380–9.
44.Quigley CA, Evans BA, Simental JA, Marschke KB, Sar M, Lubahn DB, et al. Complete androgen insensitivity due to deletion of exon C of the androgen receptor gene highlights the functional importance of the second zinc finger of the androgen receptor in vivo. Mol Endocrinol. 1992;6:1103–12.
45.Hu Y-C, Wang P-H, Yeh S, Wang R-S, Xie C, Xu Q, et al. Subfertility and defective folliculogenesis in female mice lacking androgen receptor. Proc Natl Acad Sci U S A. 2004;101:11209–14.
46.Kato S. Androgen receptor structure and function from knock-out mouse. Clin Pediatr Endocrinol. 2002;11:1–7.
47.Liu S, Xu S-w, Blumbach K, Eastwood M, Denton CP, Eckes B, et al. Expression of integrin β1 by fibroblasts is required for tissue repair in vivo. J Cell Sci. 2010;123:3674–82.
48.Gilliver SC, Ruckshanthi JP, Hardman MJ, Zeef LA, Ashcroft GS. 5alpha-dihydrotestosterone (DHT) retards wound closure by inhibiting re-epithelialization. J Pathol. 2009;217:73–82.
49.Toraldo G, Bhasin S, Bakhit M, Guo W, Serra C, Safer JD, et al. Topical androgen antagonism promotes cutaneous wound healing without systemic androgen deprivation by blocking β-catenin nuclear translocation and cross-talk with TGF-β signaling in keratinocytes. Wound Repair Regen. 2012;20:61–73.
50.Wojcik SM, Bundman DS, Roop DR. Delayed wound healing in keratin 6a knockout mice. Mol Cell Biol. 2000;20:5248–55.
51.Shengqiang Y, Chiuan-Ren Y, Yuanjie N, Hong-Chiang C, Yu-Chieh T, Harold LM, et al. Altered prostate epithelial development in mice lacking the androgen receptor in stromal fibroblasts. Prostate. 2011;72:437–49.
52.KuoPao L, Shinichi Y, ChiungKuei H, Shuyuan Y, Chawnshang C. Loss of stromal androgen receptor leads to suppressed prostate tumourigenesis via modulation of pro-inflammatory cytokines/chemokines. EMBO Mol Med. 2012;4:791–807.
53.Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010;89:219–29.
54.Efron PA, Moldawer LL. Cytokines and wound healing: the role of cytokine and anticytokine therapy in repair response. J Burn Care Rehabil. 2004;25:149–60.
55.Angele MK, Knoferl MW, Schwacha MG, Ayala A, Cioffi WG, Bland KI, et al. Sex steroids regulate pro- and anti-inflammatory cytokine release by macrophages after trauma-hemorrhage. Am J Physiol. 1999;277:C35–42.
56.D'Agostino P, Milano S, Barbera C, Bella G, Rosa M, Ferlazzo V, et al. Sex hormones modulate inflammatory mediators produced by Macrophages. Ann N Y Acad Sci. 1999;876:426–9.
57.Cheon SS, Wei Q, Gurung A, Youn A, Bright T, Poon R, et al. Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing. FASEB J. 2006;20:692–701.
58.Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, et al. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol. 2005;167:59–69.
59.Schultz GS, Ladwig G, Wysocki A. Extracellular matrix: review of its roles in acute and chronic wounds. World Wide Wounds. 2005. www.worldwide wounds.com/2005/august/Schultz/Extrace-Matric-Acute-Chronic-Wounds.html.
60.Moali C, Hulmes DJ. Extracellular and cell surface proteases in wound healing: new players are still emerging. Eur J Dermatol. 2009;19:552–64.
61.Gilliver SC, Ruckshanthi JP, Atkinson SJ, Ashcroft GS. Androgens influence expression of matrix proteins and proteolytic factors during cutaneous wound healing. Lab Invest. 2007;87:871–81.
62.Hart DW, Wolf SE, Mlcak R, Chinkes DL, Ramzy PI, Obeng MK, et al. Persistence of muscle catabolism after severe burn. Surgery. 2000;128:312–9.
63.Wray CJ, Mammen JMV, Hasselgren P. Catabolic response to stress and potential benefits of nutrition support. Nutrition. 2002;18:971–7.
64.Jeschke MG. Post-burn hypermetabolism: past, present and future. J Burn Care Res. 2016;37:86–96.
65.Thomas S, Wolf SE, Murphy KD, Chinkes DL, Herndon DN. The long-term effect of oxandrolone on hepatic acute phase proteins in severely burned children. J Trauma. 2004;56:37–44.
66.Jeschke MG, Finnerty CC, Suman OE, Kulp G, Mlcak RP, Herndon DN. The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. Ann Surg. 2007;246:351–60.
67.Orr R, Fiatarone SM. The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety. Drugs. 2004;64:725–50.
68.Maisniemi K, Lassus P, Kluger N, Koljonen V. Rapid decrease in total serum testosterone levels in burn victims. Eur J Plast Surg. 2013;36:135–6.
69.Ferrando AA, Sheffield-Moore M, Wolf SE, Herndon DN, Wolfe RR. Testosterone administration in severe burns ameliorates muscle catabolism. Crit Care Med. 2001;29:1936–42.
70.Demling RH. Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe burn injury. Burns. 1999;25:215–21.
71.Jeschke MG, Finnerty CC, Suman OE, Kulp G, Mlcak RP, Herndon DN. The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn. Ann Surg. 2007;246:351–60.
72.Przkora R, Jeschke MG, Barrow RE, Suman OE, Meyer WJ, Finnerty CC, et al. Metabolic and hormonal changes of severely burned children receiving long-term oxandrolone treatment. Trans Meet Am Surg Assoc. 2005;123:85–91.
73.Cochran A, Thuet W, Holt B, Faraklas I, Smout RJ, Horn SD. The impact of oxandrolone on length of stay following major burn injury: a clinical practice evaluation. Burns. 2013;39:1374–9.
74.Demling RH, DeSanti L. The rate of restoration of body weight after burn injury, using the anabolic agent oxandrolone, is not age dependent. Burns. 2001;27:46–51.
75.Demling RH, DeSanti L. Oxandrolone induced lean mass gain during recovery from severe burns is maintained after discontinuation of the anabolic steroid. Burns. 2003;29:793–7.
76.Demling RH, Orgill DP. The anticatabolic and wound healing effects of the testosterone analog oxandrolone after severe burn injury. J Crit Care. 2000;15:12–7.
77.Murphy KD, Thomas S, Mlcak RP, Chinkes DL, Klein GL, Herndon DN. Effects of long-term oxandrolone administration in severely burned children. Surgery. 2004;136:219–24.
78.Porro LJ, Herndon DN, Rodriguez NA, Jennings K, Klein GL, Mlcak RP, et al. Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy. J Am Coll Surg. 2012;214:489–502.
79.Przkora R, Herndon DN, Suman OE. The effects of oxandrolone and exercise on muscle mass and function in children with severe burns. Pediatrics. 2007;119:e109–16.
80.Tuvdendorj D, Chinkes DL, Zhang XJ, Suman OE, Aarsland A, Ferrando A, et al. Long-term oxandrolone treatment increases muscle protein net deposition via improving amino acid utilization in pediatric patients 6 months after burn injury. Surgery. 2011;149:645–53.
81.Wolf SE, Edelman LS, Kemalyan N, Donison L, Cross J, Underwood M, et al. Effects of oxandrolone on outcome measures in the severely burned: a multicenter prospective randomized double-blind trial. J Burn Care Res. 2006;27:131–9.
82.Wolf SE, Thomas SJ, Dasu MR, Ferrando AA, Chinkes DL, Wolfe RR, et al. Improved net protein balance, lean mass, and gene expression changes with oxandrolone treatment in the severely burned. Ann Surg. 2003;237:801–10.
83.Pereira CT, Murphy KD, Herndon DN. Altering metabolism. J Burn Care Rehabil. 2005;26:194–9.
84.Chao T, Porter G, Herndon DN, Siopi A, Ideker H. Propranolol and oxandrolone therapy accelerated muscle recovery in burned children. Med Sci Sports Exerc. 2018;50:427–35.
85.Pham TN, Klein MB, Gibran NS, Arnoldo BD, Gamelli RL, Silver GM, et al. Impact of oxandrolone treatment on acute outcomes after severe burn injury. J Burn Care Res. 2008;29:902–6.
86.Przkora R, Jeschke MG, Barrow RE, Suman OE, Meyer WJ, Finnerty CC, et al. Metabolic and hormonal changes of severely burned children receiving long-term oxandrolone treatment. Ann Surg. 2005;242:384–9.
87.Reeves PT, Herndon DN, Tanksley JD, Jennings K, Klein GL, Mlcak RP, et al. Five-year-outcomes after long-term oxandrolone administration in severely burned children: a randomized clinical trial. Shock. 2016;45:367–74.
88.Barrow RE, Dasu MR, Ferrando AA, Spies M, Thomas SJ, Perez-Polo JR, et al. Gene expression patterns in skeletal muscle of thermally injured children treated with oxandrolone. Ann Surg. 2003;237:422–8.
89.McCullough MC, Namias N, Schulman C, Gomez E, Manning R, Goldberg S, et al. Incidence of hepatic dysfunction is equivalent in burn patients receiving oxandrolone and controls. J Burn Care Res. 2007;28:412–20.
90.Hamdi MM, Mutungi G. Dihydrotestosterone stimulates amino acid uptake and the expression of LAT2 in mouse skeletal muscle fibres through an ERK1/2-dependent mechanism. J Physiol. 2011;589:3623–40.
91.Wendowski O, Redshaw Z, Mutungi G. Dihydrotestosterone treatment reduces the decline in protein synthesis as a result of sarcopenia in isolated mouse skeletal muscle fibres. J Cachexia Sarcopenia Muscle. 2017;8:48–56.
92.Shi H, Lo K, Simanainen U, Ma D, Lesmana B, Condor B, et al. Dihydrotestosterone (DHT) enhances major burn injury wound healing by regulating the inflammatory response in mice. J Endocr Soc. 2019. https://doi.org/10.1210/js.2019-SAT-006.
93.Shi H, Lo T, Ma D, Condor B, Lesmana B, Parungao J, et al. Dihydrotestosterone (DHT) enhances wound healing of major burn injury by accelerating resolution of inflammation in mice. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21176231.
0
Views
0
下载量
0
CSCD
- L-PDFDownload
- Meta-XMLDownload
- BibTeXDownload
- EndnoteDownload
- RefMan Download
- NoteExpressDownload
- NoteFirstDownload
Publicity Resources
Related Articles
Related Author
Related Institution
- Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19
京公网安备11010802024621 - It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
- Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.
