Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice.
BACKGROUND
Although generation of nitric oxide (NO) from inducible nitric oxide synthase (iNOS) has been shown to be required for cutaneous wound healing, no differences have been noted in incisional healing between iNOS knockout (iNOS-KO) and wild type (WT) mice. Because supplemental dietary arginine enhances cutaneous healing in normal rodents and is the sole substrate for NO synthesis, we studied whether arginine can enhance cutaneous wound healing in iNOS-KO mice.


METHODS
Twenty iNOS-KO and 20 WT mice, all on a C57BL/6 background, were divided into 4 groups of 10 animals each. Ten animals with each trait were randomized to receive either normal food and tap water or food and water each supplemented with 0.5% arginine (w/w). All animals underwent a 2.5-cm dorsal skin incision with implantation of four 20-mg polyvinyl alcohol sponges into subcutaneous pockets. On postoperative day 14 the animals were killed. The dorsal wound was harvested for breaking strength determination and the wound sponges were assayed for hydroxyproline content and total wound fluid nitrite/nitrate concentration.


RESULTS
Dietary arginine supplementation enhanced both wound breaking strength and collagen deposition in WT but not iNOS-KO mice. Wound fluid nitrite/nitrate levels were higher in WT than iNOS-KO animals but were not significantly influenced by additional arginine.


CONCLUSIONS
These data demonstrate that supplemental dietary arginine enhances wound healing in normal mice. The loss of a functional iNOS gene abrogates the beneficial effect of arginine in wound healing. This suggests that the metabolism of arginine via the NO pathway is one mechanism by which arginine enhances wound healing.
Departments of Surgery, Sinai Hospital of Baltimore and the Johns Hopkins Medical Institutions, Baltimore, MD 21215, USA.
H P
HP
Shi
D T
DT
Efron
D
D
Most
U S
US
Tantry
A
A
Barbul
D000596:Amino Acids / Q000097:blood; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology*; D003094:Collagen / Q000235:genetics; D019587:Dietary Supplements; D006909:Hydroxyproline / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009566:Nitrates / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000032:analysis; D014158:Transcription, Genetic; D015430:Weight Gain; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014947:Wounds and Injuries / Q000097:blood / Q000503:physiopathology*
D000596:Amino Acids; D009566:Nitrates; D009573:Nitrites; D003094:Collagen; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006909:Hydroxyproline