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Active response of the lymphatic endothelium to acute inflammation vs. chronic lymphedema: in vivo and in vitro studies
Author(s) -
Rutkowski Joseph M,
Yong Carolyn,
Swartz Melody A
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a848-d
Subject(s) - lymphedema , lymphatic system , lymphangiogenesis , inflammation , lymphatic endothelium , in vivo , endothelium , secondary lymphedema , medicine , pathology , lymph , immunology , microbiology and biotechnology , biology , cancer , breast cancer , metastasis
Tissue swelling occurs in both inflammation and in lymphedema. While acute inflammation is reversible, chronic lymphedema is not. One key difference is in the mechanical environment of the lymphatic endothelial cells (LECs): in acute swelling, the lymphatics are functional with increased load and thus LECs should experience heightened shear stress, while in lymphedema, lymphatic blockage effectively halts lymph flow and thus diminishes shear stress on LECs. Using an in vivo model of secondary lymphedema in the mouse tail, we show that LECs actively respond to fluid stagnation in ways that exacerbate the condition, e.g., by proliferating and becoming hyperplastic, upregulating VEGF‐C, and increasing inflammatory mediators. These and other effects were confirmed using gene array studies comparing LECs in vitro under 0 vs. 2 dyn/cm2 shear stress. In contrast, higher shear of 20 dyn/cm2 ‐ as might be experienced in acute inflammatory conditions ‐ led to drainage‐enhancing and anti‐inflammatory responses, including increased expression of key transporter genes, smooth muscle regulators, cell‐matrix adhesion molecules and many others. Our combined in vivo and in vitro results thus establish an active role of the lymphatic endothelium in regulating tissue fluid balance during inflammation, when drainage is increased, and a pathological role in driving chronic tissue lymphedema when drainage is stopped.