Treatment of Elevated Homocysteine to Restore Normal Wound Healing: A Possible Relationship Between Homocysteine, Nitric Oxide, and Wound Repair

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Nitric oxide (NO), a gaseous free radical, is a critical mediator of normal tissue repair.1 A deficiency in NO is associated with diabetes-impaired wound healing.2-4 Angiogenesis,5 granulation tissue formation,6 epidermal migration,7 and collagen deposition8 are all significant healing processes that are regulated by optimal NO bioactivity. Experimental studies also document a biphasic effect of NO on the wound keratinocyte, with cellular proliferation or cytostasis documented as a result of low (basal) or high (toxic) NO tissue concentrations, respectively.9-11
This article presents a case of chronic bilateral, medial ankle venous ulcerations in a patient with type 2 diabetes and an untreated, elevated serum homocysteine (Hcy) level. The patient's wounds had failed to heal after treatment with topical human fibroblast-derived dermal substitute (Dermagraft). Following the reduction of elevated Hcy and reapplication of Dermagraft, however, both wounds healed after 4 weeks of treatment. This case documents an inverse relationship between elevated serum Hcy and decreased wound NO bioactivity by measuring nitrate and nitrite (NOx; the stable oxidation products of NO) in the wound fluid of the treated ulcers.
In experimental and clinical wound healing research, NOx has been used exclusively as a reliable surrogate marker for NO.1-4,6,8 In all cases, NOx levels have been highly sensitive to conditions or factors that reduce NO production and impair normal wound healing, such as diabetes,12 protein-calorie malnutrition,13 cutaneous irradiation,14 steroid therapy,15 and metabolic inhibition of NO synthesis.16 In these cases, decreased wound fluid NOx and impaired wound closure were associated with decreased collagen accumulation,17 wound tensile strength, type I and III collagen gene expression,18 vascular endothelial growth factor expression, granulation tissue formation, and wound microvascular perfusion.19
Although Hcy has been documented to antagonize NO bioactivity, its association with impaired wound healing has not been previously documented. This case presents clinical evidence suggesting that medical treatment of an elevated Hcy level successfully reverses Hcy-mediated inhibition of wound NO bioactivity associated with impaired wound healing.
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