Baseline lymphatic dysfunction amplifies the effect of lymphatic injury
Catherine L. Ly, MD1, Geoffrey E. Hespe, MD1, Raghu P. Kataru, PhD1, Guillermo Oliver, PhD2, Babak J. Mehrara, MD1.
1Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2Northwestern University, Chicago, IL, USA.
BACKGROUND: Lymphedema is a common complication of oncologic therapy that is becoming increasingly prevalent. Management of this morbid disease remains limited due to the lack of an accurate risk stratification system and difficulties in prognosticating disease severity. Some patients are diagnosed with lymphedema after trivial lymphatic injury (e.g., sentinel lymph node biopsy), while others never develop the disease despite having multiple known risk factors (e.g., obesity, infection, radiation, and extensive surgical dissection). Similarly, certain patients display slow, smoldering disease in contrast to others who present with rapidly progressive disease regardless of treatment compliance. These discrepancies suggest that some patients may be predisposed to lymphedema following lymphatic injury, possibly due to underlying subclinical lymphatic abnormalities. However, the cellular mechanisms underlying this hypothesis remain unknown. Therefore, this study sought to utilize a mouse model with known baseline lymphatic dysfunction to determine how these defects contribute to the development of lymphedema.
METHODS: Baseline lymphatic morphology, leakiness, pumping, and immune cell trafficking, as well as local tissue inflammation and fibroadipose deposition, were established in female Prox1-haploinsufficient (Prox1+/-) and wild-type (WT) mice using a variety of measures. In subsequent experiments, Prox1+/- and WT mice underwent popliteal lymph node dissection (PLND) to induce lymphatic injury. Repeat testing of the previously assessed variables was conducted four weeks later for comparison.
RESULTS: Prox1+/- mice had dilated, leaky lymphatic vessels with baseline lymphatic dysfunction corresponding to decreased lymphatic vessel pumping frequency, transport of macromolecules to lymph nodes, and immune cell trafficking, as compared to WT mice (p<0.05 for all quantifiable variables). These mice also had a greater amount of inflammation (p<0.005), but no increase in fibroadipose deposition. PLND resulted in evidence of lymphedema in both Prox1+/- and WT mice, but PLND-treated Prox1+/- mice had decreased lymphatic pumping frequency and increased inflammation compared to their WT counterparts (p<0.05 for both).
CONCLUSIONS: Baseline lymphatic dysfunction exacerbates the effect of lymphatic injury through the amplification of the tissue inflammatory response. This results in a more severe form of lymphedema even after trivial lymphatic injury. These findings are clinically significant, as the evaluation of baseline lymphatic function may allow for more accurate patient risk stratification.
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