Metalloproteinase inhibitors and wound healing: a novel enhancer of wound strength.
BACKGROUND
Wound strength is a balance between collagen synthesis and degradation. The role of collagen breakdown in wound healing is still not well understood. We investigated the role of collagenases (metalloproteinases [MMPs]) in wound healing in using GM6001, a novel inhibitor of MMPs.


METHODS
We used the dorsal skin incision model with implantation of polyvinyl alcohol sponges. Twenty male Sprague-Dawley rats were randomly assigned to receive either GM6001 (10 mg/kg body weight) or 2 mL saline subcutaneously. Ten days after operation the animals were killed and fresh wound breaking strength, scar and sponge hydroxyproline content, and collagen type I gene expression in sponges were assayed. In addition, the inflammatory response and the wound fluid cytokine (tumor necrosis factor-alpha [TNF-alpha] and transforming growth factor-beta 1 [TGF-beta 1]) profile were studied.


RESULTS
GM6001 significantly increased wound strength (422 +/- 59 vs 302 +/- 33 g, P < .05), whereas scar collagen content did not differ. In the sponge granulomas the inflammatory infiltrate, the collagen content, and the collagen type I gene expression were all significantly decreased by GM6001.


CONCLUSIONS
Inhibition of MMP activity during acute wound healing enhances wound strength even though new collagen synthesis and the inflammatory response are significantly decreased. This could be achieved by decreasing collagen turnover or increasing collagen maturation and crosslinking, or both.
Department of Surgery, Sinai Hospital of Baltimore, MD 21215, USA.
M B
MB
Witte
F J
FJ
Thornton
T
T
Kiyama
D T
DT
Efron
G S
GS
Schulz
L L
LL
Moldawer
A
A
Barbul
D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000032:analysis; D062109:Dermatologic Surgical Procedures; D004151:Dipeptides / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000737:chemistry / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D015745:Granuloma, Foreign-Body / Q000201:enzymology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011142:Polyvinyl Alcohol; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000201:enzymology / Q000293:injuries; D015503:Surgical Sponges; D016212:Transforming Growth Factor beta / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014945:Wound Healing / Q000502:physiology*
D016207:Cytokines; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D011142:Polyvinyl Alcohol; D003094:Collagen; D008666:Metalloendopeptidases