Letter to the Editor

To the Editor; olite nitrate in fasting urine and serum samples in the healed ulcer patients as compared to the unhealed ulcer The editorial discussion by Drs. Davidson and Mustoe ‘‘Oxygen in wound healing: More than a nutrient’’ group. This preliminary study offered reasonable evidence to suggest that endogenous NO activity may pre(Wound Rep Reg 2001;9:175-7) offers an enlightening biological perspective on our understanding of the role of dict diabetic wound repair with becaplermin and that a biological synergy between NO and platelet-derived oxygen and hyperoxia following hyperbaric oxygen (HBO) therapy. At our center, we are also investigating growth factor (PDGF) may be an important aspect of diabetic wound healing. A more recent clinical study of mechanisms of HBO responsible for enhanced wound repair, especially for the diabetic ulcer patient with imhuman dermal fibroblasts in diabetic and nondiabetic donors by Reenstra et al.2 generally supports our hypothpaired wound healing. While not mentioned by the authors of the editorial, we believe that the ubiquitous, esis and suggest that dermal fibroblasts from diabetic donors display a decreased proliferative response to gaseous free radical and vasodilator nitric oxide (NO) should receive strong consideration as an oxygengrowth factors secondary to a deficiency of growth factor receptor expression, and that expression of PDGF recepmediated cellular signal, which may be responsible for several of the vulnerary aspects of HBO therapy. NO is tor and epidermal growth factor (EGF) receptor, as well as proliferation, may be regulated by NO. These findings formed by the enzymatic combination of free oxygen and the semi-essential amino acid L-arginine. Since mammafurther implicate a synergy of NO with PDGF and, perhaps, EGF in the diabetic and non-diabetic wound. Addilian cells were discovered to produce NO, it has been implicated in the regulation of blood pressure, platelet tionally, there are also significant relationships between NO and vascular endothelial growth factor (VEGF)-mediadhesion, neutrophil aggregation and neurotransmission. Wound healing studies of NO have also shown it to proated angiogenesis that require consideration. Recent experimental studies have shown that endothelial-NOS may mote enhanced wound fibroblast collagen deposition and maintenance of optimal endothelial thromboregulation play a predominant role in VEGF-induced angiogenesis and collateral blood flow development,3 and that inand microvascular homeostasis, which is balanced with its macrophage and neutrophil-mediated cytotoxicity. creased inducible-NOS expression may mediate the survival of ischemic tissue by enhancement of VEGF Our consideration of NO as a ‘‘critical’’ regulator of wound repair began with a clinical, retrospective study of production and its angiogenic response.4 However, VEGF (121)-induced enhancement of vascular remodeling and 10 diabetic ulcer patients who had received becaplermin therapy for 20 weeks under well-controlled conditions.1 collateral-dependent flow production after peripheral arterial ischemia is dependent upon normal NO producHalf of these patients healed completely within 20 weeks with becaplermin and the remaining half were unhealed tion.5 After reviewing our early findings on the possible at the end of this period. Both groups were well matched and clinically could not be distinguished in their initial role of NO in diabetic wound healing, the clinical and experimental evidence needed to propose NO as a medipresentations. The question we posed was, ‘‘Why would diabetic ulcer patients who appeared clinically similar ating factor responsible for the promotion of wound healing with HBO was not difficult to obtain. We have recently display such a variable response when treated with becaplermin?’’ With the understanding that all diabetic papublished our examination of the likely relationship between NO, HBO, and diabetic wound healing.6 Currently, tients exhibit a variable reduction in the expression of nitric oxide synthase (NOS), we hypothesized that the our center is involved in prospective studies of wound healing with and without HBO in diabetic and nondifference between the healing observed between these groups might be related to the presence of a critical, diabetic ulcer patients where NO metabolite and enzyme profiles are being analyzed. We agree that there are probthreshold level of endogenous NO activity present in the healed ulcer group that was not present in the unhealed ably multiple foci of intercellular signals interacting within the wound environment and that oxygen-mediated ulcer group. Our study results supported this hypothesis by showing significantly elevated levels of the NO metabevents related to NO activity are not the entire source of