Hyperkeratosis in human lower limb lymphedema: the effect of stagnant tissue fluid/lymph.

ABSTRACT

BACKGROUND: Hyperkeratosis of skin in lower limb lymphedema is one of the sequelae of tissue fluid/lymph (TF/L) stasis, but its mechanisms remain unknown. It is noteworthy, nonetheless, that human TF/L contains high levels of growth factors and cytokines, and may serve as the physiological environment for keratinocyte (KC) proliferation. OBJECTIVE: The aim of the study was to investigate the effect of human TF/L on human KC proliferation, differentiation and on the expression of epidermal stem cell markers on them. METHODS: KC were isolated from lymphedema and normal skin, and cultured for 1-14 days in TF/L with neutralized Interleukin 1ß, Interleukin 6, tumour necrosis factor α (TNF-α), keratinocyte growth factor (KGF) or tumour growth factor ß (TGF-ß). Alternatively, KC receptors for these factors were blocked. RESULTS: The number of KC cultured in TF/L was increased, as was the percentage of mitotic figures. There was a higher percentage of p63, CD29, Ki67, PCNA, CK6, CK17, CK16 and a lower of CK10, CK14, filaggrin and involucrin-positive KC. Neutralization of TF/L IL-1ß, IL-6, TNF-α and KGF as well as blockage of their receptors resulted in decreased percentage of mitotic KC. TGF-ß had a limited effect on KC proliferation. CONCLUSION: Hyperkeratosis in lymphedema may be the effect of a high concentration of cytokines in the stagnant TF/L tissue, but not because of presumed changes in the KC.