Delayed repair: the role of glutathione in a rat incisional wound model.
Glutathione is a low molecular weight tripeptide that is a major intracellular antioxidant, modulates DNA synthesis, and may regulate signal transduction mechanisms. Our previous studies in rats suggested that intracellular stores of glutathione were sensitive to skin ischemia and, therefore, may regulate the early temporal course of wound healing. A 4-cm incision was placed on a rat's back and in vivo wound strength was measured over time. Animals were depleted of glutathione using L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of the enzyme gamma-glutamylcysteine synthetase. Some animals were treated in combination with allopurinol/BSO or with allopurinol alone. The data demonstrated at 4 days that BSO treatment produced a fourfold reduction in glutathione (3.51 +/- 1.78) over baseline (16.15 +/- 2.18) levels and twofold reduction (5.0 +/- 1.1) over untreated sham controls (11.1 +/- 2.3) (P < 0.05). Allopurinol provided no protection to glutathione levels. BSO treatment alone reduced wound burst strength compared to the other groups (P < 0.05). Allopurinol treatment enhanced wound strength over sham controls and BSO groups at 9 days after wounding (P < 0.05). Hydroxyproline content in wounds accumulated faster by Day 4 in the BSO-treatment groups compared to sham controls (P < 0.05), whereas the BSO-treatment groups had lower hydroxyproline levels measured at Day 6 (P < 0.05). These data provide the first evidence that wound healing is related to the temporal course of glutathione metabolism. The effect may not be related to oxidant stress since allopurinol provided enhanced wound burst strength without protecting wound glutathione levels.
Adamson
B
B
Section of Plastic Surgery, University of Michigan, Ann Arbor 48109-0340, USA.
Schwarz
D
D
Klugston
P
P
Gilmont
R
R
Perry
L
L
Fisher
J
J
Lindblad
W
W
Rees
R
R
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000502:physiology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D000493:Allopurinol; D014969:Xanthine Oxidase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione