Effects of combined natural hirudin and hyperbaric oxygen therapy on survival of transplanted random-pattern skin flap in rats_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CAI Jieyun ¹ , LIN Bojie ¹ , PAN Xinyuan ² , CUI Jia ¹ , Pradhan Rohan ¹ ,  YIN Guoqian ¹

1. Department of Plastic and Aesthetic Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning Guangxi, 530021, P.R.China;
2. Department of Burn and Plastic Surgery, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning Guangxi, 530001, P.R.China;

Corresponding author：

YIN Guoqian, Email: yingq61@163.com

Keywords：

Natural hirudin; hyperbaric oxygen; random-pattern skin flap; angiogenesis; inflammation response; flap survival; rat

DOI：

10.7507/1002-1892.201711135

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ObjectiveTo investigate the effect of natural hirudin combined with hyperbaric oxygen therapy on the survival of transplanted random-pattern skin flap in rats.MethodsA random-pattern skin flap in size of 10.0 cm×2.5 cm was elevated on the dorsum of 72 Sprague Dawley rats. Then the 72 rats were randomly divided into 4 groups (n=18) according to the therapy method. At immediate and within 4 days after operation, the rats were treated with normal saline injection in control group, normal saline injection combined with hyperbaric oxygen treatment in hyperbaric oxygen group, the natural hirudin injection in natural hirudin group, and the natural hirudin injection combined with hyperbaric oxygen treatment in combined group. The flap survival was observed after operation, and survival rate was evaluated at 6 days after operation. The skin samples were collected for histological analysis, microvessel density (MVD) measurement, and evaluation of tumor necrosis factor α (TNF-α) expression level by the immunohistochemical staining at 2 and 4 days after operation.ResultsPartial necrosis occurred in each group after operation, and the flap in combined group had the best survival. The survival rate of flap was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, and in combined group than in hyperbaric oxygen group and natural hirudin group (P<0.05). There was no significant difference between hyperbaric oxygen group and natural hirudin group (P>0.05). At 2 days, more microvascular structure was observed in hyperbaric oxygen group, natural hirudin group, and combined group in comparison with control group; while plenty of inflammatory cells infiltration in all groups. At 4 days, the hyperbaric oxygen group, natural hirudin group, and the combined group still showed more angiogenesis. Meanwhile, there was still infiltration of inflammatory cells in control group, inflammatory cells in the other groups were significantly reduced when compared with at 2 days. At 2 days, the MVD was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group (P<0.05); the expression of TNF-α was significantly lower in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group (P<0.05). There was no significant difference in above indexes between hyperbaric oxygen group, natural hirudin group, and combined group (P>0.05). At 4 days, the MVD was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, in natural hirudin group and combined group than in hyperbaric oxygen group (P<0.05). The expression of TNF-α was significantly lower in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, in combined group than in natural hirudin group and hyperbaric oxygen group (P<0.05).ConclusionHyperbaric oxygen and natural hirudin therapy after random-pattern skin flap transplantation can improve the survival of flaps. Moreover, combined therapy is seen to exhibit significant synergistic effect. This effect maybe related to promotion of angiogenesis and the reduction of inflammation response.

Citation： CAI Jieyun, LIN Bojie, PAN Xinyuan, CUI Jia, Pradhan Rohan, YIN Guoqian. Effects of combined natural hirudin and hyperbaric oxygen therapy on survival of transplanted random-pattern skin flap in rats. Chinese Journal of Reparative and Reconstructive Surgery, 2018, 32(4): 484-490. doi: 10.7507/1002-1892.201711135 Copy

1.	陶晓晓, 吴森敏, 林上进, 等. 长春西汀对大鼠随意型皮瓣成活的影响. 中华烧伤杂志, 2012, 28(3): 231-233.
2.	Guo ZN, XU L, Hu Q, et al. Hyperbaric oxygen preconditioning attenuates hemorrhagic transformation through reactive oxygen species/thioredoxin-interacting protein/nod-like receptor protein 3 pathway in hyperglycemic middle cerebral artery occlusion rats. Crit Care Med, 2016, 44(6): e403-411.
3.	Wee HY, Lim SW, Chio CC, et al. Hyperbaric oxygen effects on neuronal apoptosis associations in a traumatic brain injury rat model. J Surg Res, 2015, 197(2): 382-389.
4.	Long Y, Liang F, Gao C, et al. Hyperbaric oxygen therapy reduces apoptosis after spinal cord injury in rats. Int J Clin Exp Med, 2014, 7(11): 4073-4081.
5.	Shapira R, Solomon B, Efenkel S, et al. Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg-AD mouse model by attenuating neuroinflammation. Neurobiol Aging, 2017, 62: 105-119.
6.	Gould LJ, May T. The science of hyperbaric oxygen for flaps and grafts. Surg Technol Int, 2016, 28: 65-72.
7.	Francis A, Baynosa RC. Hyperbaric oxygen therapy for the compromised graft or flap. Adv Wound Care (New Rochelle), 2017, 6(1): 23-32.
8.	Liu X, Liang F, Yang J, et al. Effects of stromal cell derived factor-1 and CXCR4 on the promotion of neovascularization by hyperbaric oxygen treatment in skin flaps. Mol Med Rep, 2013, 8(4): 1118-1124.
9.	Richards L, ineaweaver WC, Stile F, et al. Effect of hyperbaric oxygen therapy on the tubed pedicle flap survival in a rat model. Ann Plast Surg, 2003, 50(1): 51-56.
10.	韩志强, 殷国前, 韦淑怡, 等. 天然水蛭素对大鼠背部随意皮瓣早期断蒂后成活的影响. 中国修复重建外科杂志, 2013, 27(6): 738-742.
11.	Peng L, Pan X, Yin G. Natural hirudin increases rat flap viability by anti-inflammation via PARs/p38/NF-kappaB pathway. Biomed Res Int, 2015, 2015: 597264.
12.	朱江英, 殷国前, 庞进军, 等. 高压氧预处理超长皮瓣组织血管内皮生长因子、转化生长因子 β 的表达. 中国组织工程研究, 2016, 20(11): 1525-1531.
13.	袁相斌, 陈卫平, 杨勇, 等. 随意超薄皮瓣的超薄层次及长宽比例的实验研究. 中国修复重建外科杂志, 1994, 8(2): 71-73.
14.	Zhang Y, Zhao H, Zhao D, et al. SDF-1/CXCR4 axis in myelodysplastic syndromes: correlation with angiogenesis and apoptosis. Leuk Res, 2012, 36(3): 281-286.
15.	Liu X, Yang J, Li Z, et al. Hyperbaric oxygen preconditioning promotes neovascularization of transplanted skin flaps in rats. Int J Clin Exp Pathol, 2014, 7(8): 4734-4744.
16.	Zhang T, Gong W, Li Z, et al. Efficacy of hyperbaric oxygen on survival of random pattern skin flap in diabetic rats. Undersea Hyperb Med, 2007, 34(5): 335-339.
17.	Yang Y, Wei H, Zhou X, et al. Hyperbaric oxygen promotes neural stem cell proliferation by activating vascular endothelial growth factor/extracellular signal-regulated kinase signaling after traumatic brain injury. Neuroreport, 2017, 28(18): 1232-1238.
18.	Sheikh AY, Gibson JJ, Rollins MD, et al. Effect of hyperoxia on vascular endothelial growth factor levels in a wound model. Arch Surg, 2000, 135(11): 1293-1297.
19.	Erlich JH, Boyle EM, Labriola J, et al. Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. Am J Pathol, 2000, 157(6): 1849-1862.
20.	Pan XY, Peng L, Han ZQ, et al. Hirudin promotes angiogenesis by modulating the cross-talk between p38 MAPK and ERK in rat ischemic skin flap tissue. Tissue Cell, 2015, 47(3): 301-310.
21.	Kraft AD, McPherson CA, Harry GJ. Heterogeneity of microglia and TNF signaling as determinants for neuronal death or survival. Neurotoxicology, 2009, 30(5): 785-793.
22.	Tanabe K, Matsushima-Nishiwaki R, Yamaguchi S, et al. Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells. J Neuroinflammation, 2010, 7: 16.
23.	Min JK, Kim YM, Kim SW, et al. TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells. J Immunol, 2005, 175(1): 531-540.
24.	Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ, 2017, 24(7): 1184-1195.
25.	Gordon A, Kozin ED, Keswani SG, et al. Permissive environment in postnatal wounds induced by adenoviral-mediated overexpression of the anti-inflammatory cytokine interleukin-10 prevents scar formation. Wound Repair Regen, 2008, 16(1): 70-79.
26.	Kang N, Hai Y, Yang J, et al. Hyperbaric oxygen intervention reduces secondary spinal cord injury in rats via regulation of HMGB1/TLR4/NF-κB signaling pathway. Int J Clin Exp Pathol, 2015, 8(2): 1141-1153.
27.	Yu X, Li YG, He XW, et al. Hyperbaric oxygen reduces inflammatory response in acute pancreatitis by inhibiting NF-kappaB activation. Eur Surg Res, 2009, 42(2): 130-135.
28.	Shapira R, Solomon B, Efrati S, et al. Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg-AD mouse model by attenuating neuroinflammation. Neurobiol Aging, 2017, 62: 105-119.
29.	Yang Z, Nandi J, Wang J, et al. Hyperbaric oxygenation ameliorates indomethacin-induced enteropathy in rats by modulating TNF-alpha and IL-1beta production. Dig Dis Sci, 2006, 51(8): 1426-1433.

1. 陶晓晓, 吴森敏, 林上进, 等. 长春西汀对大鼠随意型皮瓣成活的影响. 中华烧伤杂志, 2012, 28(3): 231-233.
2. Guo ZN, XU L, Hu Q, et al. Hyperbaric oxygen preconditioning attenuates hemorrhagic transformation through reactive oxygen species/thioredoxin-interacting protein/nod-like receptor protein 3 pathway in hyperglycemic middle cerebral artery occlusion rats. Crit Care Med, 2016, 44(6): e403-411.
3. Wee HY, Lim SW, Chio CC, et al. Hyperbaric oxygen effects on neuronal apoptosis associations in a traumatic brain injury rat model. J Surg Res, 2015, 197(2): 382-389.
4. Long Y, Liang F, Gao C, et al. Hyperbaric oxygen therapy reduces apoptosis after spinal cord injury in rats. Int J Clin Exp Med, 2014, 7(11): 4073-4081.
5. Shapira R, Solomon B, Efenkel S, et al. Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg-AD mouse model by attenuating neuroinflammation. Neurobiol Aging, 2017, 62: 105-119.
6. Gould LJ, May T. The science of hyperbaric oxygen for flaps and grafts. Surg Technol Int, 2016, 28: 65-72.
7. Francis A, Baynosa RC. Hyperbaric oxygen therapy for the compromised graft or flap. Adv Wound Care (New Rochelle), 2017, 6(1): 23-32.
8. Liu X, Liang F, Yang J, et al. Effects of stromal cell derived factor-1 and CXCR4 on the promotion of neovascularization by hyperbaric oxygen treatment in skin flaps. Mol Med Rep, 2013, 8(4): 1118-1124.
9. Richards L, ineaweaver WC, Stile F, et al. Effect of hyperbaric oxygen therapy on the tubed pedicle flap survival in a rat model. Ann Plast Surg, 2003, 50(1): 51-56.
10. 韩志强, 殷国前, 韦淑怡, 等. 天然水蛭素对大鼠背部随意皮瓣早期断蒂后成活的影响. 中国修复重建外科杂志, 2013, 27(6): 738-742.
11. Peng L, Pan X, Yin G. Natural hirudin increases rat flap viability by anti-inflammation via PARs/p38/NF-kappaB pathway. Biomed Res Int, 2015, 2015: 597264.
12. 朱江英, 殷国前, 庞进军, 等. 高压氧预处理超长皮瓣组织血管内皮生长因子、转化生长因子 β 的表达. 中国组织工程研究, 2016, 20(11): 1525-1531.
13. 袁相斌, 陈卫平, 杨勇, 等. 随意超薄皮瓣的超薄层次及长宽比例的实验研究. 中国修复重建外科杂志, 1994, 8(2): 71-73.
14. Zhang Y, Zhao H, Zhao D, et al. SDF-1/CXCR4 axis in myelodysplastic syndromes: correlation with angiogenesis and apoptosis. Leuk Res, 2012, 36(3): 281-286.
15. Liu X, Yang J, Li Z, et al. Hyperbaric oxygen preconditioning promotes neovascularization of transplanted skin flaps in rats. Int J Clin Exp Pathol, 2014, 7(8): 4734-4744.
16. Zhang T, Gong W, Li Z, et al. Efficacy of hyperbaric oxygen on survival of random pattern skin flap in diabetic rats. Undersea Hyperb Med, 2007, 34(5): 335-339.
17. Yang Y, Wei H, Zhou X, et al. Hyperbaric oxygen promotes neural stem cell proliferation by activating vascular endothelial growth factor/extracellular signal-regulated kinase signaling after traumatic brain injury. Neuroreport, 2017, 28(18): 1232-1238.
18. Sheikh AY, Gibson JJ, Rollins MD, et al. Effect of hyperoxia on vascular endothelial growth factor levels in a wound model. Arch Surg, 2000, 135(11): 1293-1297.
19. Erlich JH, Boyle EM, Labriola J, et al. Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. Am J Pathol, 2000, 157(6): 1849-1862.
20. Pan XY, Peng L, Han ZQ, et al. Hirudin promotes angiogenesis by modulating the cross-talk between p38 MAPK and ERK in rat ischemic skin flap tissue. Tissue Cell, 2015, 47(3): 301-310.
21. Kraft AD, McPherson CA, Harry GJ. Heterogeneity of microglia and TNF signaling as determinants for neuronal death or survival. Neurotoxicology, 2009, 30(5): 785-793.
22. Tanabe K, Matsushima-Nishiwaki R, Yamaguchi S, et al. Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells. J Neuroinflammation, 2010, 7: 16.
23. Min JK, Kim YM, Kim SW, et al. TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells. J Immunol, 2005, 175(1): 531-540.
24. Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ, 2017, 24(7): 1184-1195.
25. Gordon A, Kozin ED, Keswani SG, et al. Permissive environment in postnatal wounds induced by adenoviral-mediated overexpression of the anti-inflammatory cytokine interleukin-10 prevents scar formation. Wound Repair Regen, 2008, 16(1): 70-79.
26. Kang N, Hai Y, Yang J, et al. Hyperbaric oxygen intervention reduces secondary spinal cord injury in rats via regulation of HMGB1/TLR4/NF-κB signaling pathway. Int J Clin Exp Pathol, 2015, 8(2): 1141-1153.
27. Yu X, Li YG, He XW, et al. Hyperbaric oxygen reduces inflammatory response in acute pancreatitis by inhibiting NF-kappaB activation. Eur Surg Res, 2009, 42(2): 130-135.
28. Shapira R, Solomon B, Efrati S, et al. Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg-AD mouse model by attenuating neuroinflammation. Neurobiol Aging, 2017, 62: 105-119.
29. Yang Z, Nandi J, Wang J, et al. Hyperbaric oxygenation ameliorates indomethacin-induced enteropathy in rats by modulating TNF-alpha and IL-1beta production. Dig Dis Sci, 2006, 51(8): 1426-1433.

Chinese Journal of Reparative and Reconstructive Surgery

Effects of combined natural hirudin and hyperbaric oxygen therapy on survival of transplanted random-pattern skin flap in rats

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