title: Establishment of an Acquired Lymphedema Model in the Mouse Hindlimb: Technical Refinement and Molecular Characteristics.
abstract: BACKGROUND
  The pathophysiology of secondary lymphedema remains poorly understood. This study aimed to establish a consistent mouse hindlimb lymphedema model for further investigation of the mechanism and treatment of lymphedema.
  
  
  METHODS
  The authors developed a novel postsurgical lymphedema model in the mouse hindlimb by modifying previously described methods. Lymphedema in the hindlimb was created by removing both the inguinal and popliteal lymph nodes together with the surrounding fat pads, followed by silicone splint placement in the inguinal region. Using this modified mouse model, the authors analyzed lymphatic function, histologic changes, and the expression of lymphangiogenic factors including vascular endothelial growth factor C at various time points.
  
  
  RESULTS
  The splinted lymphedema model showed a significant increase of edema formation in the hindlimb compared with the sham surgery control animals. Indocyanine green lymphography revealed lymphatic drainage impairment shown by dermal backflow and rerouting of lymph flow in the lymphedema model. Histopathologic and immunohistochemical examinations showed a significant increase of skin thickness and abnormally dilated lymphatics in the lymphedema model. The expression of lymphangiogenic factors in lymphedematous tissues of the splinted lymphedema model was significantly increased compared with controls, depending on the degree of lymphedema.
  
  
  CONCLUSIONS
  This splinted lymphedema model closely simulates the volume response, histopathology, and lymphography characteristics of human acquired lymphedema. Given these similarities to human lymphedema, this refinement of a mouse hindlimb model of acquired lymphedema represents a promising platform for the study of lymphatic vascular insufficiency and for the evaluation of new therapeutic modalities.
authors.affiliation: Sapporo, Hokkaido, Japan.|From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Hokkaido.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iwasaki
authors.affiliation: Sapporo, Hokkaido, Japan.|From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Hokkaido.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Sapporo, Hokkaido, Japan.|From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Hokkaido.
authors.forename: Naoki
authors.initials: N
authors.lastname: Murao
authors.affiliation: Sapporo, Hokkaido, Japan.|From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Hokkaido.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oyama
authors.affiliation: Sapporo, Hokkaido, Japan.|From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Hokkaido.
authors.forename: Emi
authors.initials: E
authors.lastname: Funayama
authors.affiliation: Sapporo, Hokkaido, Japan.|From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Hokkaido.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006614:Hindlimb; D018398:Homeodomain Proteins / Q000032:analysis; D007150:Immunohistochemistry; D007208:Indocyanine Green; D008196:Lymph / Q000502:physiology; D008198:Lymph Nodes / Q000601:surgery; D008208:Lymphatic System / Q000502:physiology; D008209:Lymphedema / Q000209:etiology / Q000473:pathology; D008220:Lymphography; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000032:analysis; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D000098551:Prospero-Related Homeobox 1 Protein; D012313:RNA; D040321:Vascular Endothelial Growth Factor Receptor-3; D007208:Indocyanine Green