Heparin-like inhibitory activity to fibroblast growth factor-2 in wound fluids of patients with chronic skin ulcers and its modulation during wound healing

Fibroblast growth factors are potent mitogens and angiogenic factors which play a critical role in wound healing. Fibroblast growth factors require he paran sulfates as cofactors In order to activate their cognate receptors an d exert their cellular and biological effects. Heparan sulfates were extrac ted from wound fluids of 5 patients with chronic diabetic foot ulcers or ch ronic venous stasis ulcers and tested for their capacity to modulate fibrob last growth factor-receptor binding, during the course of the ulcers' resol ution, until complete healing (3-8 months). Total heparan sulfates concentr ation measured as iduronic acid equivalents, decreased In wound fluids from 1.1 +/- 0.3 mug/ml to 0.26 +/- 0.1 mug/ml as wound healing progressed. The se heparan sulfates exhibited a predominant inhibitory effect on fibroblast growth factor-2 binding to fibroblast growth factor receptor-1, when teste d in cells deficient in cell surface heparan sulfates. During wound healing , there was a marked decrease in the relative inhibitory activity of the ex tracted heparan sulfates on fibroblast growth factor-2-receptor binding. He paran sulfates extracted from chronic skin ulcers of different etiologies s uch as diabetic foot or chronic venous stasis ulcers showed the same patter n of alternating balance in heparan sulfates mediated activity. The presenc e of fibroblast growth factor inhibitory factors which possess heparin-like activity in fluids of chronic skin ulcers and their ability to modulate fi broblast growth factor-receptor activity throughout the process of wound he aling, may significantly contribute to the mechanism of chronicity, Treatme nts to counter this inhibition may offer new possibilities for healing chro nic wounds.