Inflammatory manifestations of experimental lymphatic insufficiency.
BACKGROUND
Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic.


RESULTS
We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response.


CONCLUSIONS
We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.
Tabibiazar
Raymond
R
Stanford Center for Lymphatic and Venous Disorders, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
Cheung
Lauren
L
Han
Jennifer
J
Swanson
Jeffrey
J
Beilhack
Andreas
A
An
Andrew
A
Dadras
Soheil S
SS
Rockson
Ned
N
Joshi
Smita
S
Wagner
Roger
R
Rockson
Stanley G
SG
D000818:Animals; D019070:Cell Lineage; D002465:Cell Movement; D003167:Complement Activation / Q000235:genetics; D003872:Dermatitis / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D005355:Fibrosis / Q000235:genetics; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000032:analysis; D006098:Granulocytes / Q000473:pathology / Q000637:transplantation; D007121:Immunocompetence; D007249:Inflammation / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008209:Lymphedema / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D016131:Lymphocyte Subsets / Q000473:pathology / Q000637:transplantation; D061305:Lymphoscintigraphy; D026901:Membrane Transport Proteins; D051379:Mice; D008812:Mice, Hairless; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008863:Microspheres; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D018384:Oxidative Stress / Q000235:genetics; D016133:Polymerase Chain Reaction; D011183:Postoperative Complications / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000473:pathology; D013623:Tail / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D014158:Transcription, Genetic; D014945:Wound Healing / Q000235:genetics
D006023:Glycoproteins; D008156:Luciferases; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C492273:LYVE1 protein, mouse