Progress in Animal Models of Secondary Lymphedema

doi:10.12300/j.issn.1674-5817.2021.081

Abstract

Abstract:

Secondary lymphedema (SL) seriously affects the physiological and psychosocial status of cancer patients. The establishment of appropriate animal models for basic research is crucial to study the pathogenesis and treatment of SL. At present, there are many animal models of SL, but the lack of uniformity results in slow progress of mechanism research. Based on the research progress of SL animal models, this paper analyzes the types of experimental animals and the intervention methods of modeling in SL research. The analysis results showed that rodents (especially rats) are ideal experimental animals, and a stable and durable chronic SL model can be prepared by combining surgery with two times of preoperative and postoperative radiation, which has been confirmed in daily scientific research work.

Key words: Secondary lymphedema, Animal model, Radiation, Surgery

CLC Number:

Q95-33

Xing YANG,Xingfang PAN,Tianyi ZHAO,et al. Progress in Animal Models of Secondary Lymphedema[J]. Laboratory Animal and Comparative Medicine, 2022, 42(1): 62-67. DOI: 10.12300/j.issn.1674-5817.2021.081.

Figures/Tables 2

References 35

1	SZOLNOKY G, DOBOZY A, KEMÉNY L. Towards an effective management of chronic lymphedema[J]. Clin Dermatol, 2014, 32(5):685-691. DOI:10.1016/j.clindermatol.2014.04.017 .
2	PASKETT E D, DEAN J A, OLIVERI J M, et al. Cancer-related lymphedema risk factors, diagnosis, treatment, and impact: a review[J]. J Clin Oncol, 2012, 30(30):3726-3733. DOI:10.1200/JCO.2012.41.8574 .
3	SUNG C, WANG S, HSU J, et al. Current understanding of pathological mechanisms of lymphedema[J]. Adv Wound Care (New Rochelle), 2021:2021 Nov 25. DOI:10.1089/wound.2021.0041 .
4	朱雅群. 乳腺癌患者治疗后上肢淋巴水肿发病情况及危险因素的临床研究[D]. 苏州: 苏州大学, 2015.
5	KATARU R P, WISER I, BAIK J E, et al. Fibrosis and secondary lymphedema: chicken or egg? [J]. Transl Res, 2019, 209:68-76. DOI:10.1016/j.trsl.2019.04.001 .
6	KANTER M A, SLAVIN S A, KAPLAN W. An experimental model for chronic lymphedema[J]. Plast Reconstr Surg, 1990, 85(4):573-580. DOI:10.1097/00006534-199004000-00012 .
7	REFINETTI R, KENAGY G J. Diurnally active rodents for laboratory research[J]. Lab Anim, 2018, 52(6):577-587. DOI:10.1177/0023677218771720 .
8	HARB A A, LEVI M A, CORVI J J, et al. Creation of a rat lower limb lymphedema model[J]. Ann Plast Surg, 2020, 85(S1 ): S129-S134. DOI:10.1097/SAP.0000000000002323 .
9	AKSOYLER D, BITIK O, MENKU OZDEMIR F D, et al. A new experimental lymphedema model: reevaluating the efficacy of rat models and their clinical translation for chronic lymphedema studies[J]. Ann Plast Surg, 2021, 86(6):707-713. DOI:10.1097/SAP.0000000000002479 .
10	TRIACCA V, PISANO M, LESSERT C, et al. Experimental drainage device to reduce lymphoedema in a rat model[J]. Eur J Vasc Endovasc Surg, 2019, 57(6):859-867. DOI:10.1016/j.ejvs.2018.04.014 .
11	HASSANEIN A H, SINHA M, NEUMANN C R, et al. A murine tail lymphedema model[J]. Vis Exp, 2021:168. DOI:10.3791/61848 .
12	WEILER M J, CRIBB M T, NEPIYUSHCHIKH Z, et al. A novel mouse tail lymphedema model for observing lymphatic pump failure during lymphedema development[J]. Sci Rep, 2019, 9(1):10405. DOI:10.1038/s41598-019-46797-2 .
13	SUAMI H, SCAGLIONI M F. Lymphatic territories (lymphosomes) in the rat: an anatomical study for future lymphatic research[J]. Plast Reconstr Surg, 2017, 140(5):945-951. DOI:10.1097/PRS.0000000000003776 .
14	SUAMI H, SHIN D, CHANG D W. Mapping of lymphosomes in the canine forelimb: comparative anatomy between canines and humans[J]. Plast Reconstr Surg, 2012, 129(3):612-620. DOI:10.1097/PRS.0b013e3182402c6d .
15	CHEN H C, PRIBAZ J J, O'BRIEN B M, et al. Creation of distal canine limb lymphedema[J]. Plast Reconstr Surg, 1989, 83(6):1022-1026. DOI:10.1097/00006534-198906000-00016 .
16	SOTO-MIRANDA M A, SUAMI H, CHANG D W. Mapping superficial lymphatic territories in the rabbit[J]. Anat Rec (Hoboken), 2013, 296(6):965-970. DOI:10.1002/ar.22699 .
17	FERNÁNDEZ PEÑUELA R, CASANÍ ARAZO L, MASIÁ AYALA J. Outcomes in vascularized lymph node transplantation in rabbits: a reliable model for improving the surgical approach to lymphedema[J]. Lymphat Res Biol, 2019, 17(4):413-417. DOI:10.1089/lrb.2018.0038 .
18	ITO R, SUAMI H. Lymphatic territories (lymphosomes) in swine: an animal model for future lymphatic research[J]. Plast Reconstr Surg, 2015, 136(2):297-304. DOI:10.1097/PRS. 0000000000001460 .
19	TERVALA T V, HARTIALA P, TAMMELA T, et al. Growth factor therapy and lymph node graft for lymphedema[J]. J Surg Res, 2015, 196(1):200-207. DOI:10.1016/j.jss.2015.02.031 .
20	JIN D P, AN A, LIU J, et al. Therapeutic responses to exogenous VEGF-C administration in experimental lymphedema: immunohistochemical and molecular characterization[J]. Lymphat Res Biol, 2009, 7(1):47-57. DOI:10.1089/lrb.2009.0002 .
21	SOMMER T, MEIER M, BRUNS F, et al. Quantification of lymphedema in a rat model by 3D-active contour segmentation by magnetic resonance imaging[J]. Lymphat Res Biol, 2012, 10(1):25-29. DOI:10.1089/lrb.2011.0010 .
22	STASZYK C, BOHNET W, GASSE H, et al. Blood vessels of the rat tail: a histological re-examination with respect to blood vessel puncture methods[J]. Lab Anim, 2003, 37(2):121-125. DOI:10.1258/00236770360563750 .
23	FERNÁNDEZ PEÑUELA R, PONS PLAYA G, CASANÍ ARAZO L, et al. An experimental lymphedema animal model for assessing the results of lymphovenous anastomosis[J]. Lymphat Res Biol, 2018, 16(3):234-239. DOI:10.1089/lrb. 2016.0068 .
24	TOBBIA D, SEMPLE J, BAKER A, et al. Lymphedema development and lymphatic function following lymph node excision in sheep[J]. J Vasc Res, 2009, 46(5):426-434. DOI:10.1159/000194273 .
25	OLSZEWSKI W. Induction of experimental lymphatic edema[J]. Pol Przegl Chir, 1967, 39(9):926-929.
26	JOSEPH W J, ASCHEN S, GHANTA S, et al. Sterile inflammation after lymph node transfer improves lymphatic function and regeneration[J]. Plast Reconstr Surg, 2014, 134(1):60-68. DOI:10.1097/PRS.0000000000000286 .
27	FRUEH F S, GOUSOPOULOS E, REZAEIAN F, et al. Animal models in surgical lymphedema research: a systematic review[J]. J Surg Res, 2016, 200(1):208-220. DOI:10.1016/j.jss.2015.07.005 .
28	DAS S K, FRANKLIN J D, O'BRIEN B M, et al. A practical model of secondary lymphedema in dogs[J]. Plast Reconstr Surg, 1981, 68(3):422-428.
29	孙一宇, 崔春晓, 戴婷婷, 等. 改良小鼠后肢淋巴水肿模型的构建[J]. 组织工程与重建外科杂志, 2016, 12(6):349-352. DOI:10.3969/j.issn.1673-0364.2016.06.005 .
30	YANG C, NGUYEN D H, WU C W, et al. Developing a lower limb lymphedema animal model with combined lymphadenectomy and low-dose radiation[J]. Plast Reconstr Surg Glob Open, 2014, 2(3): e121. DOI:10.1097/GOX. 0000000000000064 .
31	JØRGENSEN M G, TOYSERKANI N M, HANSEN C R, et al. Quantification of chronic lymphedema in a revised mouse model[J]. Ann Plast Surg, 2018, 81(5):594-603. DOI:10.1097/SAP.0000000000001537 .
32	柴凡, 梁燕, 姜军. 动物前肢淋巴水肿模型构建的实验研究[J]. 中华乳腺病杂志(电子版), 2011, 5(4):466-473. DOI:10.3969/j.issn.1674-0807.2011.04.011 .
33	侯传强, 金星, 吴学君, 等. 慢性肢体淋巴水肿动物模型的构建[J]. 泰山医学院学报, 2012, 33(9):651-653. DOI:10.3969/j.issn.1004-7115.2012.09.003 .
34	吴国君. 腋窝淋巴结清扫术后上肢继发性淋巴水肿动物模型建立的实验研究[D]. 济南: 山东大学, 2017.
35	CONGDON C C. The destructive effect of radiation on lymphatic tissue[J]. Cancer Res, 1966, 26(6):1211-1220.

文献来源	动物	方式	部位	手术操作	持续时间
Hassanein等^[11](2021)	小鼠	手术	尾部	全层切除和淋巴管夹断	超过15 d
Weiler等^[12](2019)	小鼠	手术	尾部	单血管结扎	70 d
Randolfo等^[23](2018)	兔	手术	耳部	全皮肤剥脱和破坏淋巴通道	15 d
Tobbia等^[24](2009)	羊	手术	后肢	切除淋巴结，结扎淋巴管	16周

文献来源	动物	方式	部位	手术操作	持续时间
Hassanein等^[11](2021)	小鼠	手术	尾部	全层切除和淋巴管夹断	超过15 d
Weiler等^[12](2019)	小鼠	手术	尾部	单血管结扎	70 d
Randolfo等^[23](2018)	兔	手术	耳部	全皮肤剥脱和破坏淋巴通道	15 d
Tobbia等^[24](2009)	羊	手术	后肢	切除淋巴结，结扎淋巴管	16周

文献来源	动物种类	方式	部位	手术操作	放射剂量	持续时间
Harb等^[8](2020)	大鼠	手术和放射	后肢	腹股沟淋巴结切除术、圆周皮肤和皮下组织切除术	22.7 Gy/40.5 Gy	未报告
Triacca等^[10](2019)	大鼠	手术和放射	后肢	手术切除腘窝和腹股沟淋巴结	22.7 Gy	至少8周
Sommer等^[21](2012)	大鼠	手术和放射	后肢	切除体表腹股沟和腘窝淋巴结及邻近淋巴管	15 Gy	未报告
孙一宇，等^[29](2016)	小鼠	手术和放射	后肢	摘除腘窝淋巴结，结扎淋巴管，烧灼皮肤	4.5 Gy	24周
吴国君^[34](2017)	猕猴	手术和放射	上肢	腋窝淋巴结清扫术	30 Gy	12个月
柴凡，等^[32](2011)	兔	手术和放射	前肢	切除右侧腋窝、胸肌外缘及锁骨下淋巴结，破坏淋巴管	15 Gy	18周

文献来源	动物种类	方式	部位	手术操作	放射剂量	持续时间
Harb等^[8](2020)	大鼠	手术和放射	后肢	腹股沟淋巴结切除术、圆周皮肤和皮下组织切除术	22.7 Gy/40.5 Gy	未报告
Triacca等^[10](2019)	大鼠	手术和放射	后肢	手术切除腘窝和腹股沟淋巴结	22.7 Gy	至少8周
Sommer等^[21](2012)	大鼠	手术和放射	后肢	切除体表腹股沟和腘窝淋巴结及邻近淋巴管	15 Gy	未报告
孙一宇，等^[29](2016)	小鼠	手术和放射	后肢	摘除腘窝淋巴结，结扎淋巴管，烧灼皮肤	4.5 Gy	24周
吴国君^[34](2017)	猕猴	手术和放射	上肢	腋窝淋巴结清扫术	30 Gy	12个月
柴凡，等^[32](2011)	兔	手术和放射	前肢	切除右侧腋窝、胸肌外缘及锁骨下淋巴结，破坏淋巴管	15 Gy	18周

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