Lymphedema Conference Presentation
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Transcript of Lymphedema Conference Presentation
Func;ons of the lympha;c system
• Tissue fluid balance • Immune cell trafficking • Lipid uptake – Peripheral – Intes;nal
Pepper MS and Skobe M (2003) J Cell Biol 163(2):209-‐213
Structure of the lympha;c system
• Peripheral dermal lympha;cs
• Lympha;c vessels made up of endothelial cells (LECs)
• LECs connected via specialized junc;ons
Alitalo K et al. (2005) Nature 438:946-‐953
Intes;nal lympha;c dysfunc;on
• Chylous ascites: leakage of lipid into abdominal cavity
• Acquired or congenital • Draining and dietary management
• Leakage may also occur in thoracic cavity and around the heart in lymphangiomatosis.
Dietrich S et al. (2009) Case Rep Oncol 2(2):144-‐149
Herman TE and Sigel MJ (2009) J Perinatol 29:178-‐180
Inherited lymphedema and other lympha;c disorders
• Result from rare, inherited chromosomal disorders or muta;ons
• Malforma;ons of the lympha;cs
• Mul;-‐factorial, systemic diseases
Alders M et al. (2012) Mol Syndromol 4:107-‐113
Abnormal lipid accumula;on is a feature of secondary lymphedema
Courtesy of H. Brorson, MD
“Lymphedema is regional obesity.” -‐ Babak J. Mehrara, MD
Animal model of lympha;c dysfunc;on
Harvey NL et al. (2005) Nature Gene>cs 37(10):1072-‐1081
Increased subcutaneous fat deposits and larger adipocytes were observed in the skin.
Many mice died with chylous ascites in the abdominal and thoracic cavi;es soon aYer birth.
Mice that survived became obese as they reached adulthood and had elevated insulin and lipid in the liver.
Animal model of lymphedema
Zampell JC et al. (2012) Plas>c and Rec Surg 129(4):825-‐834
Lipid accumulated in ;ssue in lymphedema condi;on.
Further evidence of ac;ve transport
• The lympha;cs clear cholesterol from the peripheral ;ssue space.
• Transport is specific and transcellular.
• This process helps maintain cholesterol levels and prevents atherosclerosis.
Lim HY et al. (2013) Cell Metab 17(5):671-‐684
Experimental objec;ve
• To inves;gate the ac;ve component of lympha;c lipid transport and its rela;ve importance to overall uptake using in vitro models of the peripheral lympha;cs and the enterocyte-‐lacteal interface.
Transcellular lipid transport
0 mM 10 mM0
20
40
60
80
100
NaN3 Concentration
% fl
ux o
f con
trol *
LECs growing on permeable membrane
Basolateral compartment containing albumin-‐bound bodipy
and dextran
Apical compartment from which sample was collected and fluorescence measured
Transcellular transport of fluorescent lipid was inhibited when cellular fuel was depleted, sugges;ng transport is ac;ve.
Chylomicron transport
0 mM 2 mM 5 mM 10 mM0.00
0.05
0.10
0.15
0.20
Pef
f (µ
m/s
ec)
NaN3 concentration
**
*
0 mM 2 mM 5 mM 10 mM0
20
40
60
80
100
NaN3 concentration
% fl
ux o
f con
trol
*
* *
Total and transcellular transport of chylomicrons was significantly reduced when cellular fuel was depleted, sugges;ng both these process are ac;ve, par;cularly transcellular transport.
Summary
• The lympha;cs play a pivotal role in lipid uptake and movement.
• Abnormal lipid accumula;on is a feature of lympha;c disease and can be modeled in animals.
• An important frac;on of lipid is transported via an ac;ve, transcellular route.
Future direc;ons
• Elucida;ng the molecular mechanisms of transport.
• Op;mizing drug delivery strategies to target the lympha;cs. – Encapsula;ng a chemotherapeu;c agent resulted in increased efficacy in the blood via lympha;c uptake and delivery (A\li-‐Qadri et al. (2013) PNAS Early Ed.
Acknowledgements
• NIH R00HL091133 • Sydney Rowson • Pe;t Undergraduate Research Scholars Program Mentorship Funds
• Timothy Kassis • John McDonald lab