title: Topical synthetic inhibitor of matrix metalloproteinases delays epidermal regeneration of human wounds.
abstract: Matrix metalloproteinases (MMPs) degrade extracellular proteins during epithelialization of wounds. To evaluate the biological significance of MMPs in epidermal healing, the synthetic broad-spectrum MMP inhibitor GM 6001 (also called Galardin and Ilomastat) was applied topically to standardized human wounds. GM 6001 (10 microg/microl) or vehicle alone was applied every second day onto 4 de-roofed 6 mm suction blister wounds on the volar forearm of healthy male volunteers for 12 days. GM 6001 delayed healing by 2-4 days as assessed macroscopically and microscopically. In situ hybridization or immunohistochemistry showed that MMP-1 (interstitial collagenase) was present in and MMP-2 (gelatinase A) close to laterally migrating keratinocytes whereas MMP-9 (gelatinase B) was seen during maturation of new epidermis. MMP-1 was undetectable in blister roofs (normal epidermis) and found in low levels in normal skin. Total MMP-1 activities increased about 100-fold in wounds, independent of treatment, compared to normal skin as analyzed by specific ELISA-based activity assay. By gelatin zymography, MMP-2, but not MMP-9, was detected in blister roofs and wound healing was associated with increased active MMP-2 and latent MMP-9 levels. GM 6001 prevented activation of MMP-2 and increased latent MMP-9 levels. GM 6001 delayed re-appearance of laminin-5, the synthesis of which correlated with epidermal regeneration. Restoration of stratum corneum, measured indirectly by transepidermal water loss, was also impaired (P<0.05) in the GM 6001 group. In conclusion, pharmacological MMP inhibition delayed epidermal regeneration in vivo, suggesting that MMPs are required to restore epidermis after epidermal ablation in humans.
authors.affiliation: Aagren Dermaconsulting ApS, Humlebaek, Denmark. aagrendermaconsulting@yahoo.com
authors.forename: M S
authors.initials: MS
authors.lastname: Agren
authors.forename: U
authors.initials: U
authors.lastname: Mirastschijski
authors.forename: T
authors.initials: T
authors.lastname: Karlsmark
authors.forename: U K
authors.initials: UK
authors.lastname: Saarialho-Kere
mesh_terms: D000328:Adult; D001768:Blister / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004817:Epidermis / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D012038:Regeneration / Q000187:drug effects*; D013396:Suction; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects*; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D004151:Dipeptides; D004791:Enzyme Inhibitors; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D000097794:Kalinin; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide