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

Abstract

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. 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. KC were isolated from lymphedema and normal skin, and cultured for 1-14 days in TF/L with neutralized Interleukin 1β, Interleukin 6, tumour necrosis factor α (TNF-α), keratinocyte growth factor (KGF) or tumour growth factor β (TGF-β). Alternatively, KC receptors for these factors were blocked. 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-1β, IL-6, TNF-α and KGF as well as blockage of their receptors resulted in decreased percentage of mitotic KC. TGF-β had a limited effect on KC proliferation. 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.