A vicious circle in chronic lymphoedema pathophysiology? An adipocentric view

F. Cucchi, L. Rossmeislova, L. Simonsen, M. R. Jensen and J. Bülow. Obesity Reviews 18, 1159–1169, October 2017

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A vicious circle in chronic lymphoedema pathophysiology? An Obesity Reviews 18, 1159–1169, October 2017 adipocentric view

Cucchi, L. Rossmeislova, L. Simonsen, M. R. Jensen and J. Bülow.

Chronic lymphoedema is a disease caused by a congenital or acquired damage to the lymphatic system and characterized by complex chains of pathophysiologic events such as lymphatic fluid stasis, chronic inflammation, lymphatic vessels impairment, adipose tissue deposition and fibrosis. These events seem to maintain and reinforce themselves through a positive feedback loop: regardless of the initial cause of lymphatic stasis, the dysfunctional adipose tissue and its secretion products can worsen lymphatic vessels’ function, aggravating lymph leakage and stagnation, which can promote further adipose tissue deposition and fibrosis, similar to what may happen in obesity. In addition to the current knowledge about the tight and ancestral interrelation between immunity system and metabolism, there is evidence for similarities between obesity-related and lymphatic damage-induced lymphoedema. Together, these observations indicate strong reciprocal relationship between lymphatics and adipose tissue and suggest a possible key role of the adipocyte in the pathophysiology of chronic lymphoedema’s vicious circle.

Main findings

  • The hypertrophic adipocyte could be the initiator of the inflammatory process in lymphoedema, and the immune system would contribute to its amplification and perpetuation. This would be true for both obesity-induced lymphoedema and lymphoedema started by lymphatic vasculature damage, because both conditions implicate adipocyte dysfunction and adipose tissue inflammation. Also, the lymph itself might have a direct and indirect role in causing inflammation and cytotoxicity, in addition to its lipogenic function.
  • In chronic high-fat diet-induced obesity the collecting lymphatic vessel function seems likewise to be compromised, because of the increasing perilymphatic inflammation and alteration of LEC gene expression in mice.
  • Progressive weight gain correlates with decreased collecting lymphatic pumping frequency, decreased lymphatic vessel density, increased accumulation of perilymphatic inflammatory cells and expression of inducible nitric oxide synthase. Notably, weight loss reverses these changes, ameliorating the lymphatic and immune dysfunction in mice.
  • Obesity and metabolic syndrome in humans are linked to lymphatic dysfunction and reduced removal capacity of macromolecules from the interstitial space in adipose tissue.
  • The mechanisms eliciting fibrosis in both lymphoedema and obesity could be similar, but are still not described in detail.