title: Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema.
abstract: Development of novel treatments for lymphedema has been limited by the fact that the pathophysiology of this disease is poorly understood. It remains unknown, for example, why limb swelling resulting from surgical injury resolves initially, but recurs in some cases months or years later. Finding answers for these basic questions has been hampered by the lack of adequate animal models. In the current study, we usedCre-loxmice that expressed the human diphtheria toxin receptor (DTR) driven by a lymphatic-specific promoter in order to noninvasively ablate the lymphatic system of the hind limb. Animals treated in this manner developed lymphedema that was indistinguishable from clinical lymphedema temporally, radiographically, and histologically. Using this model and clinical biopsy specimens, we show that the initial resolution of edema after injury is dependent on the formation of collateral capillary lymphatics and that this process is regulated by M2-polarized macrophages. In addition, we show that despite these initial improvements in lymphatic function, persistent accumulation of CD4+cells inhibits lymphangiogenesis and promotes sclerosis of collecting lymphatics, resulting in late onset of edema and fibrosis. Our findings therefore provide strong evidence that inflammatory changes after lymphatic injury play a key role in the pathophysiology of lymphedema.
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardenier
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Hespe
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Raghu P
authors.initials: RP
authors.lastname: Kataru
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Ira L
authors.initials: IL
authors.lastname: Savetsky
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Torrisi
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Gabriela D García
authors.initials: GDG
authors.lastname: Nores
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Dayan
authors.affiliation: Section of Plastic and Reconstructive Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chang
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Zampell
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Inés
authors.initials: I
authors.lastname: Martínez-Corral
authors.affiliation: Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.affiliation: Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Babak J
authors.initials: BJ
authors.lastname: Mehrara
mesh_terms: D000818:Animals; D004167:Diphtheria Toxin / Q000009:adverse effects*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics; D006801:Humans; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels; D008209:Lymphedema / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D004167:Diphtheria Toxin; D066257:Heparin-binding EGF-like Growth Factor