Local Administration of L-Arginine Accelerates Wound Closure

Document Type : Original Article


1 Department of Physiology, Medical School, Namazi Hospital, Tissue Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Physiology, Bushehr University of Medical Sciences, Bushehr, Iran

3 Department of Pathology, Medical School, Namazi Hospital, Tissue Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


The process of wound healing involves tightly integrated events including inflammation, granulation tissue formation and remodeling. Systemic administration of L-arginine promotes wound healing but its global side effects are undesirable. To confine the action of L-arginine at the site of injury, we tested the effects of local administration of L-arginine on the healing of excisional wound in the rat.
Materials and Methods
Full thickness excisional wounds were generated on the dorsum of adult male rats. The test wounds received 200 pm or 400 pm of L-arginine on day 3 and 5 post-wounding. Normal saline was injected into the sham wounds which were otherwise treated as the test wounds. Control wounds remained unmanipulated. The wound size was monitored daily by imaging. To determine the rate of wound closure, wound images were scanned and the rate of size reduction was analyzed and quantified by ScnImage software. The repaired tissues were harvested on day 12 post-wounding. The tissue sections were prepared and stained for microscopic examination.
Wounds treated with L-arginine showed a significant increase in the rate of wound closure. The morphology of basal keratinocytes was altered, and the thickness of neoepidermis was markedly reduced in the wounds treated with L-arginine. Both tested dose of L-arginine were equally effective.
Local administration of L-arginine accelerates wound closure and has profound effects on keratinocytes performance during the process of healing. Therefore, it can be potentially used for treatment of skin disorders, in particular, those characterized by hyperkeratosis.


1.Oberyszvn TM. Inflammation and wound healing. Front Biosci 2007; 12: 2993-2999.
2.Desmouliere A, and Gabbiani G. In: The molecular and cellular biology of wound repair. 2nd edn. New York: Plenum Press, 1996, PP: 391-423.
3.Mutsaers SE, Bishop JE, McGrouther G, et al. Mechanism of tissue repair: from wound healing to fibrosis. Int J Biochem Cell Biol 1997; 29: 5-17.
4.Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007; 127: 526-537.
5.Kdolsky RK, Mohr W, Savidis-Dacho H, et al. The influence of oral L- arginine on fracture healing: an animal study. Wien Klin Wochenschr 2005; 117: 693-701.
6.Stechmiller JK, Childress B, Crowan RN. Arginine supplementation and wound healing. Nutr Clin Pract 2005; 20: 52-61.
7.Williams JZ, Abumorad N, Barbul A. Effect of a specialized amino acid mixture on human collagen deposition. Ann Surg 2002; 236: 360-374.
8.Witte MB, Thornton FJ, Tantry U, Barbul A. L-Arginine supplementation enhances diabetic wound healing: involvement of the nitric oxide synthase and arginase pathways. Metabolism 2002; 51: 1269-1273.
9.Schaffer MR, Tantry U, Thornton FJ, Barbul A. Inhibition of nitric oxide synthesis in wounds: Pharmacology and effect on accumulation of collagen in wounds in mice. Eur J Surg 1999; 165: 262-267.
10.Witte MB, Barbul A. Role of nitric oxide in wound repair. Am J Surg 2002; 183: 406-412.
11.Lee RH, Efron D, Tantry U, Barbul A. Nitric oxide in the healing wound: A time- course study. J Surg Res 2001; 101: 104-108.
12.Albina JE, Mills CD, Barbul A, Thrikill, CA, Henry WL, Masterofrrancesco B, Caldwell MD. Arginine metabolism in wounds. Am J Physiol 1988; 254: 459-467.
13.Albina JE, Mills CD, Henry WL, Caldwell MD. Temporal expression of different pathways of L-arginine metabolism in healing wounds. J Immunol 1990; 144: 3877-3880.
14.Kapoor M, Kojima F, Appleton I, et al. Major enzymatic pathways in dermal wound healing: current understanding and future therapeutic targets. Curr Opin Investing Drugs 2006; 7: 418-422.
15.Shearer JD, Richards JR, Mills CD, Caldwell MD. Differential regulation of macrophage arginine metabolism: a proposed role in wound healing. Am J Physiol 1997; 272: E181-E190.
16.Lee PC, Salyapongse NA, Bragdon GA, Shears II LL, Watkins SC, Edington HDJ, Billiar TR. Impaired wound healing and angiogenesis in e-NOs-deficient mice. Am J Physiol 1999; 277: H1600-H1608.
17.Yamassaki K, Edington HDJ, Mc Closky C, Tzeng E, Lizonova A, Kovesdi I, Steed DL, Billiar TR. Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Invest 1998; 101: 967-971.
18.Shi HP, Efron DT, Most D. Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice. Surgery 2000; 128: 374-378.
19.Noiri E, Peresleni T, Srivastava N, Weber P, Bahou WF, Peunova N, Goligorsky MS. Nitric oxide is necessary for a switch from stationary to locomoting phenotype in epithelial cells. Am J Physiol 1996; 270: C794-C802.
20.Currie GA, Gyure L, Cifuentes L. Microenvironmental arginine depletion by macrophages in vivo. Br J Cancer 1979; 39: 613-620
21.Varedi M, Englander EW. TGF-beta 1 latency associated peptide promotes remodeling of healing cutaneous wounds in the rat. I J M S 2006; 31: 65-69.
22.Amadeu TP, Costa AM. Nitric oxide synthesis inhibition alters rat cutaneous wound healing. J cutan Pathol 2006; 33: 465-473.
23.Gosselink MP, Darby M, Zimmerman DD, et al. Treatment of chronic anal fissure by application of L-arginine gel: a phase II study in 15 patients. Dis Colon Rectum. 2005; 48:4 832-837.
24.Debats IB, Booi D, Deutz NE, et al. Infected chronic wounds show different local and systemic arginine conversion compared with acute wounds. J Surg Res 2006; 134: 205-214.
25.Bruch-Gerharz D, Schnorr O, Suschek C, et al. Arginase 1 overexpression in psoriasis. Am J Path. 2003; 162: 203-211.