Homocysteine– A Stealth Mediator of Impaired Wound Healing: A Preliminary Study

Joseph V. Boykin, Jr., MD,1,2 and Chris Baylis, PhD3

Nitric oxide (NO), a gaseous free radical, is a critical mediator of normal tissue repair.1 Angiogenesis,2 granulation tissue formation,3 epidermal migration,4 and collagen deposition5 are all significant wound repair processes that are regulated by NO bioactivity. General somatic and wound NO bioactivity may be evaluated by measuring nitrate and nitrite (NOx, the stable oxidation products of NO) from plasma and urine and from wound fluid NOx, respectively. In experimental and clinical wound healing research, NOx has been used extensively as a reliable surrogate marker for NO.1,3,5–8 In all cases, NOx determinations have been highly sensitive to conditions or factors that reduce NO production and impair normal wound healing, such as diabetes,9 protein-calorie malnutrition,10 cutaneous irradiation,11 steroid therapy,12 and metabolic inhibition of NO synthesis.13 In these cases, decreased wound fluid NOx and impaired wound closure were associated with decreased collagen accumulation,14 wound tensile strength, type I and III collagen gene expression,15 vascular endothelial growth factor (VEGF) expression, granulation tissue formation, and wound microvascular perfusion.16
Elevated homocysteine (Hcy) is widely accepted as a novel risk factor associated with atherosclerotic cardiovascular disease (CVD) in the coronary, cerebral, and peripheral vascular beds.17 Homocysteine also is believed to antagonize NO bioactivity by multiple pathways but has not been identified as a risk factor for wound repair. This preliminary study was designed to prospectively document the relationship between impaired wound healing, wound NO bioactivity evaluated by wound fluid NOx measurement, and elevated Hcy while using topical human fibroblast-derived dermal substitute (Dermagraft® Human Fibroblast-Derived Dermal Substitute, Smith & Nephew Inc., Largo, Fla) for the treatment of chronic lower-extremity ulcers.


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