Infected Chronic Wounds Show Different Local and Systemic Arginine Conversion Compared With Acute Wounds Iris B. J. G. Debats, M.D.,* Darren Booi, M.D.,* Nicolaas E. P. Deutz, M.D., Ph.D.,† Wim A. Buurman, Ph.D.,† Willy D. Boeckx, M.D., Ph.D.,* and Rene R. W. J. van der Hulst, M.D., Ph.D.* ,1 *Department of Plastic and Reconstructive Surgery and †Surgery, Maastricht Academic Hospital, Maastricht, The Netherlands Submitted for publication May 25, 2005 Background. Several experimental studies have shown the importance of arginine in wound healing. How- ever, little is known about its role in human wound healing. In this study, we investigated arginine metab- olism in impaired wound healing. Materials and methods. Twenty patients with chronic wounds and 10 patients with acute wounds were in- cluded in a prospective study. Amino acids, nitrate/ nitrite, and arginase concentrations were determined in plasma and wound fluid using high-performance liquid chromatography and enzyme-linked immuno- sorbent assay. Chronic wounds were divided into two groups: noninfected chronic wounds (n  11) and in- fected chronic wounds (n  9), based on quantitative bacterial analysis of wound fluid samples. Results. Plasma arginine levels, next to total plasma amino acid levels, were significantly decreased in pa- tients with infected chronic wounds compared with patients having acute or noninfected wounds. Citrul- line and ornithine levels were significantly increased in infected chronic wounds and related to decreased nitrate/nitrite levels, whereas wound fluid arginine levels were similar in all groups. In addition, wound fluid arginase levels of infected chronic wounds were significantly enhanced. Conclusions. This study demonstrates that patients with infected chronic wounds have decreased plasma arginine levels and suggests enhanced arginine con- version in the wound. In contrast to noninfected chronic wounds, arginine seems to be mainly metabo- lized by arginase in infected chronic wounds. In con- clusion, our hypothesis is that impaired wound heal- ing is related to an altered arginine usage. © 2006 Elsevier Inc. All rights reserved. Key Words: arginine; wound healing; chronic wounds; human; acute wounds; metabolism; infection. INTRODUCTION Patients with chronic wounds are a major problem in health care. The resulting prolonged hospital stay gen- erates high costs and impairs the well-being of the patient. The high prevalence of chronic wounds leads to a financial burden in health care; for example, in the United States, 1.5 to 3 million patients are affected by pressure ulcers [1, 2]. Although the development of chronic wounds is multifactorial, nutritional factors have an important role in their development [3]. Sup- plementation of high amounts of proteins and vitamins to malnourished patients with chronic wounds initially improves wound healing, although complete healing is not observed [4–6]. Recent studies suggest the need of specific amino acids instead of supplementation of high amounts of proteins to stimulate wound healing [7–10]. In this context, the amino acids arginine and ornithine are suggested to be of great importance in wound healing [10 –14]. The effect of arginine supplementation has been attributed to enhanced synthesis of nitric oxide (NO) [10, 12, 13, 15–18]. NO is a signal molecule in- volved in immune responsiveness, angiogenesis, epi- thelialisation and formation of granulation tissue, and has been shown to be critical for healing [19 –23]. Ornithine is the precursor for proline, an essential amino acid for collagen synthesis [24] and for poly- amines, key components in cell growth and differenti- ation [14, 25–29]. Supplementation of ornithine also has shown to enhance wound healing. The mechanism 1 To whom correspondence and reprint requests should be ad- dressed at Department of Plastic and Reconstructive Surgery, Maas- tricht Academic Hospital, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: RVH@spch.azm.nl. Journal of Surgical Research 134, 205–214 (2006) doi:10.1016/j.jss.2006.03.005 205 0022-4804/06 $32.00 © 2006 Elsevier Inc. All rights reserved.