{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T15:08:55Z","timestamp":1793718535337,"version":"4.6.1"},"reference-count":83,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T00:00:00Z","timestamp":1586131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["2T32CA009501"],"award-info":[{"award-number":["2T32CA009501"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>An estimated 5 million people in the United States are affected by secondary lymphedema, with most cases attributed to malignancies or malignancy-related treatments. The pathogenesis of secondary lymphedema has historically been attributed to lymphatic injury or dysfunction; however, recent studies illustrate the complexity of lymphedema as a disease process in which many of its clinical features such as inflammation, fibrosis, adipogenesis, and recurrent infections contribute to on-going lymphatic dysfunction in a vicious cycle. Investigations into the molecular underpinning of these features further our understanding of the pathophysiology of this disease and suggests new therapeutics.<\/jats:p>","DOI":"10.3390\/ijms21072546","type":"journal-article","created":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T03:58:39Z","timestamp":1586231919000},"page":"2546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Histopathologic Features of Lymphedema: A Molecular Review"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6246-5899","authenticated-orcid":false,"given":"Claire Y.","family":"Li","sequence":"first","affiliation":[{"name":"The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu P.","family":"Kataru","sequence":"additional","affiliation":[{"name":"The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babak J.","family":"Mehrara","sequence":"additional","affiliation":[{"name":"The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1177\/1358863X9700200408","article-title":"Lymphedema: Anatomy, physiology and pathogenesis","volume":"2","author":"Szuba","year":"1997","journal-title":"Vasc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5213","DOI":"10.1200\/JCO.2008.16.3725","article-title":"Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: Objective measurements","volume":"26","author":"McLaughlin","year":"2008","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_3","first-page":"73","article-title":"Lymphedema following breast cancer treatment, including sentinel lymph node biopsy","volume":"37","author":"Armer","year":"2004","journal-title":"Lymphology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1001\/archsurg.2010.231","article-title":"Risk factors for lymphedema in a prospective breast cancer survivorship study: The pathways study","volume":"145","author":"Kwan","year":"2010","journal-title":"Arch. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ygyno.2010.06.018","article-title":"Risk factors for postoperative lower-extremity lymphedema in endometrial cancer survivors who had treatment including lymphadenectomy","volume":"119","author":"Todo","year":"2010","journal-title":"Gynecol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1158\/1055-9965.EPI-09-1245","article-title":"Risk factors for lymphedema after breast cancer treatment","volume":"19","author":"Norman","year":"2010","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1097\/01.sla.0000143271.32568.2b","article-title":"Lymphedema after complete axillary node dissection for melanoma: Assessment using a new, objective definition","volume":"240","author":"Starritt","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ijrobp.2019.05.002","article-title":"Development and validation of a nomogram to predict lymphedema after axillary surgery and radiation therapy in women with breast cancer from the NCIC CTG MA.20 randomized trial","volume":"105","author":"Gross","year":"2019","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1245\/s10434-012-2290-x","article-title":"Nomograms for predicting the risk of arm lymphedema after axillary dissection in breast cancer","volume":"19","author":"Bevilacqua","year":"2012","journal-title":"Ann. Surg. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5138","DOI":"10.1002\/cncr.25458","article-title":"Lymphedema beyond breast cancer: A systematic review and meta-analysis of cancer-related secondary lymphedema","volume":"116","author":"Cormier","year":"2010","journal-title":"Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Brayton, K.M., Hirsch, A.T., Patricia, J.O., Brien, A.C., Karaca-Mandic, P., and Rockson, S.G. (2014). Lymphedema prevalence and treatment benefits in cancer: Impact of a therapeutic intervention on health outcomes and costs. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114597"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1007\/s12282-013-0481-3","article-title":"Efficacy of manual lymphatic drainage and intermittent pneumatic compression pump use in the treatment of lymphedema after mastectomy: A randomized controlled trial","volume":"22","author":"Uzkeser","year":"2015","journal-title":"Breast Cancer"},{"key":"ref_13","first-page":"344","article-title":"Complex decongestive physiotherapy for patients with chronic cancer-associated lymphedema","volume":"103","author":"Liao","year":"2004","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/S0002-9343(00)00503-9","article-title":"Decongestive lymphatic therapy for patients with cancer-related or primary lymphedema","volume":"109","author":"Szuba","year":"2000","journal-title":"Am. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1002\/(SICI)1097-0142(19981215)83:12B+<2833::AID-CNCR35>3.0.CO;2-3","article-title":"The treatment of lymphedema","volume":"83","author":"Foldi","year":"1998","journal-title":"Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1245\/s10434-017-5964-6","article-title":"Considerations for clinicians in the diagnosis, prevention, and treatment of breast cancer-related lymphedema, recommendations from an expert panel: Part 2: Preventive and therapeutic options","volume":"24","author":"McLaughlin","year":"2017","journal-title":"Ann. Surg. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/tbj.12710","article-title":"Effectiveness of decongestive lymphatic therapy in patients with lymphedema resulting from breast cancer treatment regardless of previous lymphedema treatment","volume":"23","author":"Bozkurt","year":"2017","journal-title":"Breast J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Garza, R., Skoracki, R., Hock, K., and Povoski, S.P. (2017). A comprehensive overview on the surgical management of secondary lymphedema of the upper and lower extremities related to prior oncologic therapies. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3444-9"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1245\/s10434-014-3515-y","article-title":"An effective system of surgical treatment of lymphedema","volume":"21","author":"Granzow","year":"2014","journal-title":"Ann. Surg. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s10549-017-4335-0","article-title":"The efficacy of lymphaticovenular anastomosis in breast cancer-related lymphedema","volume":"165","author":"Winters","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.ygyno.2006.03.055","article-title":"The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: A 12-year experience at memorial sloan-kettering cancer center","volume":"103","author":"Alektiar","year":"2006","journal-title":"Gynecol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1046\/j.0004-8666.2003.00040.x","article-title":"Aetiology and prevalence of lower limb lymphoedema following treatment for gynaecological cancer","volume":"43","author":"Ryan","year":"2003","journal-title":"Aust. N. Z. J. Obstet. Gynaecol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.jaad.2017.03.022","article-title":"Lymphedema: Pathophysiology and clinical manifestations","volume":"77","author":"Grada","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/j.jaad.2012.04.028","article-title":"Stewart-Treves syndrome: Pathogenesis and management","volume":"67","author":"Sharma","year":"2012","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zampell, J.C., Yan, A., Elhadad, S., Avraham, T., Weitman, E., and Mehrara, B.J. (2012). CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049940"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1096\/fj.12-222695","article-title":"Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema","volume":"27","author":"Avraham","year":"2013","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1016\/j.ajpath.2016.04.006","article-title":"prominent lymphatic vessel hyperplasia with progressive dysfunction and distinct immune cell infiltration in lymphedema","volume":"186","author":"Gousopoulos","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.jid.2015.12.001","article-title":"Excess lymphangiogenesis cooperatively induced by macrophages and CD4(+) T cells drives the pathogenesis of lymphedema","volume":"136","author":"Ogata","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1038\/s41467-018-04418-y","article-title":"CD4(+) T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema","volume":"9","author":"Nores","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"518e","DOI":"10.1097\/PRS.0000000000005322","article-title":"Small numbers of CD4+ T cells can induce development of lymphedema","volume":"143","author":"Ly","year":"2019","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1113\/jphysiol.2012.250662","article-title":"Genetic removal of basal nitric oxide enhances contractile activity in isolated murine collecting lymphatic vessels","volume":"591","author":"Scallan","year":"2013","journal-title":"J. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18784","DOI":"10.1073\/pnas.1116152108","article-title":"Impaired lymphatic contraction associated with immunosuppression","volume":"108","author":"Liao","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1097\/01.prs.0000277995.25009.3e","article-title":"Changes in the lymph structure of the upper limb after axillary dissection: Radiographic and anatomical study in a human cadaver","volume":"120","author":"Suami","year":"2007","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"H2113","DOI":"10.1152\/ajpheart.00879.2008","article-title":"TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair","volume":"295","author":"Clavin","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1097\/PRS.0b013e3181adcf4b","article-title":"Fibrosis is a key inhibitor of lymphatic regeneration","volume":"124","author":"Avraham","year":"2009","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nri1412","article-title":"Fibrotic disease and the T(H)1\/T(H)2 paradigm","volume":"4","author":"Wynn","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.trsl.2018.12.003","article-title":"T helper 2 differentiation is necessary for development of lymphedema","volume":"206","author":"Ly","year":"2019","journal-title":"Transl. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"H165","DOI":"10.1152\/ajpheart.00244.2014","article-title":"Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema","volume":"307","author":"Savetsky","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6196","DOI":"10.1038\/ncomms7196","article-title":"TH2 cells and their cytokines regulate formation and function of lymphatic vessels","volume":"6","author":"Shin","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Savetsky, I.L., Ghanta, S., Gardenier, J.C., Torrisi, J.S., Nores, G.D., Hespe, G.E., Nitti, M.D., Kataru, R.P., and Mehrara, B.J. (2015). Th2 cytokines inhibit lymphangiogenesis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126908"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and molecular mechanisms of fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.2353\/ajpath.2010.100594","article-title":"Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair","volume":"177","author":"Avraham","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1089\/lrb.2016.0010","article-title":"Pathological changes of lymphedematous skin: increased mast cells, related proteases, and activated transforming growth factor-beta1","volume":"14","author":"Di","year":"2016","journal-title":"Lymphat. Res. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nri.2017.90","article-title":"Type 2 immunity in tissue repair and fibrosis","volume":"18","author":"Gieseck","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","first-page":"72","article-title":"Indocyanine green lymphography findings in limb lymphedema","volume":"32","author":"Narushima","year":"2016","journal-title":"J. Reconstr. Microsurg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/76996","article-title":"Hepatocyte migration during liver development requires Prox1","volume":"25","author":"Wigle","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e85096","DOI":"10.1172\/jci.insight.85096","article-title":"Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice","volume":"1","author":"Escobedo","year":"2016","journal-title":"JCI insight"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ng1642","article-title":"Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity","volume":"37","author":"Harvey","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/ijo.2016.96","article-title":"Obesity but not high-fat diet impairs lymphatic function","volume":"40","author":"Nores","year":"2016","journal-title":"Int. J. Obes."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1097\/PRS.0b013e3182450b47","article-title":"Regulation of adipogenesis by lymphatic fluid stasis: Part II. Expression of adipose differentiation genes","volume":"129","author":"Aschen","year":"2012","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1097\/PRS.0b013e3182450b2d","article-title":"Regulation of adipogenesis by lymphatic fluid stasis: Part I. Adipogenesis, fibrosis, and inflammation","volume":"129","author":"Zampell","year":"2012","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"H1426","DOI":"10.1152\/ajpheart.01019.2013","article-title":"IL-6 regulates adipose deposition and homeostasis in lymphedema","volume":"306","author":"Cuzzone","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1148\/radiology.180.1.2052688","article-title":"Arm edema in conservatively managed breast cancer: Obesity is a major predictive factor","volume":"180","author":"Werner","year":"1991","journal-title":"Radiology"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Blum, K.S., Karaman, S., Proulx, S.T., Ochsenbein, A.M., Luciani, P., Leroux, J.C., Wolfrum, C., and Detmar, M. (2014). Chronic high-fat diet impairs collecting lymphatic vessel function in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094713"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1159\/000461579","article-title":"High-fat diet in the absence of obesity does not aggravate surgically induced lymphoedema in mice","volume":"58","author":"Gousopoulos","year":"2017","journal-title":"Eur. Surg. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/ijo.2012.98","article-title":"Reduced adipose tissue lymphatic drainage of macromolecules in obese subjects: A possible link between obesity and local tissue inflammation?","volume":"37","author":"Arngrim","year":"2013","journal-title":"Int. J. Obes. (London)"},{"key":"ref_57","first-page":"43","article-title":"The third circulation: Radionuclide lymphoscintigraphy in the evaluation of lymphedema","volume":"44","author":"Szuba","year":"2003","journal-title":"J. Nucl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1097\/PRS.0000000000001271","article-title":"Obesity-induced lymphedema: Clinical and lymphoscintigraphic features","volume":"135","author":"Greene","year":"2015","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"19817","DOI":"10.1038\/srep19817","article-title":"Inhibition of inflammation and iNOS improves lymphatic function in obesity","volume":"6","author":"Torrisi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1001\/jamaoncol.2019.2109","article-title":"Effect of home-based exercise and weight loss programs on breast cancer\u2013related lymphedema outcomes among overweight breast cancer survivors: The WISER survivor randomized clinical trial","volume":"5","author":"Schmitz","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1056\/NEJMoa0810118","article-title":"Weight lifting in women with breast-cancer-related lymphedema","volume":"361","author":"Schmitz","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1002\/cncr.22994","article-title":"A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema","volume":"110","author":"Shaw","year":"2007","journal-title":"Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1093\/qjmed\/hcg126","article-title":"Lymphoedema: An underestimated health problem","volume":"96","author":"Moffatt","year":"2003","journal-title":"Qjm"},{"key":"ref_64","first-page":"113","article-title":"Symptom burden and infection occurrence among individuals with extremity lymphedema","volume":"45","author":"Ridner","year":"2012","journal-title":"Lymphology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9377","DOI":"10.1186\/1757-1626-2-9377","article-title":"Challenges of cellulitis in a lymphedematous extremity: A case report","volume":"2","author":"Connor","year":"2009","journal-title":"Cases J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.ijsu.2011.01.007","article-title":"Mathematical model to predict risk for lymphoedema after treatment of cutaneous melanoma","volume":"9","author":"Campanholi","year":"2011","journal-title":"Int. J. Surg."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1111\/j.1365-2133.2007.08423.x","article-title":"Lymphatic abnormalities demonstrated by lymphoscintigraphy after lower limb cellulitis","volume":"158","author":"Soo","year":"2008","journal-title":"Br. J. Dermatol."},{"key":"ref_68","first-page":"177","article-title":"Lymphoscintigraphic evaluation in patients after erysipelas","volume":"33","author":"Valente","year":"2000","journal-title":"Lymphology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"eaam7964","DOI":"10.1126\/scitranslmed.aam7964","article-title":"Methicillin-resistant staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction","volume":"10","author":"Jones","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jid.2017.09.011","article-title":"Regulatory T cells mediate local immunosuppression in lymphedema","volume":"138","author":"Nores","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e89081","DOI":"10.1172\/jci.insight.89081","article-title":"Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function","volume":"1","author":"Gousopoulos","year":"2016","journal-title":"JCI Insight"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.4049\/jimmunol.1103545","article-title":"Impaired humoral immunity and tolerance in K14-VEGFR-3-Ig mice that lack dermal lymphatic drainage","volume":"189","author":"Thomas","year":"2012","journal-title":"J. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Huang, J.J., Gardenier, J.C., Hespe, G.E., Nores, G.D., Kataru, R.P., Ly, C.L., Martinez-Corral, I., Ortega, S., and Mehrara, B.J. (2016). Lymph node transplantation decreases swelling and restores immune responses in a transgenic model of lymphedema. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168259"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e84095","DOI":"10.1172\/jci.insight.84095","article-title":"Diphtheria toxin\u2013mediated ablation of lymphatic endothelial cells results in progressive lymphedema","volume":"1","author":"Gardenier","year":"2016","journal-title":"JCI Insight"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"eaal3920","DOI":"10.1126\/scitranslmed.aal3920","article-title":"Leukotriene B4 antagonism ameliorates experimental lymphedema","volume":"9","author":"Tian","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e123775","DOI":"10.1172\/jci.insight.123775","article-title":"Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema","volume":"3","author":"Rockson","year":"2018","journal-title":"JCI Insight"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1038\/nm1689","article-title":"Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation","volume":"13","author":"Tammela","year":"2007","journal-title":"Nat. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.mvr.2006.05.009","article-title":"Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9","volume":"72","author":"Rutkowski","year":"2006","journal-title":"Microvasc. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1161\/CIRCULATIONAHA.110.965384","article-title":"Growth factor therapy and autologous lymph node transfer in lymphedema","volume":"123","author":"Honkonen","year":"2011","journal-title":"Circulation"},{"key":"ref_80","unstructured":"(2020, January 02). A Phase I Study with Lymfactin\u00ae in the Treatment of Patients with Secondary Lymphedema, Available online: https:\/\/ClinicalTrials.gov\/show\/NCT02994771."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Nakamura, K., Radhakrishnan, K., Wong, Y.M., and Rockson, S.G. (2009). Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0008380"},{"key":"ref_82","unstructured":"(2020, January 02). Ubenimex in Adult Patients with Lymphedema of the Lower Limb (ULTRA), Available online: https:\/\/ClinicalTrials.gov\/show\/NCT02700529."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"14345","DOI":"10.1038\/ncomms14345","article-title":"Topical tacrolimus for the treatment of secondary lymphedema","volume":"8","author":"Gardenier","year":"2017","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2546\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:15:53Z","timestamp":1760174153000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,6]]},"references-count":83,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21072546"],"URL":"https:\/\/doi.org\/10.3390\/ijms21072546","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,6]]}}}