156 Homocysteine Associated with Impaired Wound Healing and Decreased Nitric Oxide Production

Abstract

Nitric oxide (NO) is a critical mediator of normal tissue repair and is inhibited by homocysteine (Hcy). Following 8 weeks of lower extremity ulcer (LEU) treatment with human fibroblast-derived dermal substitute (Dermagraft®) for 12 (n = 12) patients, a correlation was observed between patients with a poor wound healing response to Dermagraft and elevated serum homocysteine (Hcy). The responders group (R) to Dermagraft treatment (n = 6) was observed with robust granulation tissue, epidermal migration and a 67% rate of healed ulcerations. All R-group patients (6/6) had normal serum Hcy. The nonresponders (NR) group (n = 6) exhibited poor granulation tissue formation and epidermal migration and a complete absence of healed wounds. Five of the NR patients (5/6) were observed with elevated serum Hcy. There was no significant (p < 0.05) difference between the wound areas (cm2 ± SE) of each group [35.43(±28.99)-R vs. 19.90(±7.55)-NR]. After 2 weeks of treatment, the R-group demonstrated significantly greater %Δwound area than the NR-group [62.17 (±7.96)-R group vs. 23.17(±8.82)-NR group; p < 0.05]. Wound fluid nitrate (WFNOx), a surrogate measurement (μM ± SE) for local NO bioactivity, was significantly lower for the NR-group than the R-group [3.17(±1.46)μM-NR group vs. 12.98(±1.73)μM-R group; p < 0.05]. In a large group of LEU patients (n = 138) we observed a 50% incidence of elevated Hcy; 69% for diabetic neuropathic LEU patients and 47% for nondiabetic LEU patients. Hcy inhibits NO production by multiple pathways and may also inhibit wound repair by occupying the fibronectin domain of fibrin during provisional matrix formation. Our study suggests that elevated serum Hcy is a common finding in chronic LEU patients. The high Hcy may contribute to impaired wound healing by decreasing wound NO production and, perhaps, by inhibition of fibronectin-fibrin-mediated wound matrix development.