Topically Applied Cmt-2 Enhances Wound Healing in Streptozotocin Diabetic Rat Skin

Abstract

Delayed wound healing is one of the complications of diabetes mellitus, exhibited by increased wound collagenase and decreased granulation tissues. The current study compared wound healing in normal and diabetic rats, and the effects of topically applied 1 % or 3% concentrations of chemically modified tetracycline-2 (CMT-2) on 6-mm circular full-thickness skin wounds healed by secondary intention. On day 7 after wounding, tissues were removed for biochemical analysis and histology. The wound granulation tissue hydroxyproline was less in the untreated diabetic rat with increased collagenase and gelatinase. Treating the diabetic rat wounds with 3% CMT-2 increased the wound hydroxyproline and decreased activities of gelatinase and collagenase. There was a delay in wound filling by granulation tissue in diabetic rats. In CMT-2-treated diabetic rats, the volume of granulation tissue was greater than that in untreated diabetic rats. CMT-2 appears to normalize wound healing in diabetic rats and may be a valuable adjunct in the treatment of chronic wounds.

Keywords

Diabetes wound healing tetracycline MMPs.

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References

Annette BW , Staiano-Coico L. , Grinnell F. (1993). Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 101 :6468.

Birkedal-Hansen H. (1988). From tadpole collagenase to family of matrix metalloproteinases . J Oral Pathol 17:445-451.

Birkedal-Hansen H. , Moore WG , Bodden MK , Windsor U. , Birkedal-Hansen B. , DeCarlo A. , et al. (1993). Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4:197-250.

Clark Raf (1988). Potential role of fibronectin in cutaneous wound repair. Arch Dermatol 124:201-206.

Davidson JM , Klagsbrun M. , Hill KE , Brewer PS , Woodward SC (1985). Accelerated wound repair, cell proliferation and collagen accumulation are produced by cartilage derived growth factor. J Cell Biol 100:1219-1221.

Eckles TA , Reinhardt RA , Dyer JK , Tussing GJ , Szydlowski WM , Dubois LM (1990). Intra-crevicular application of tetracycline in white petrolatum for the treatment of periodontal disease. J Clin Periodontol 17:454-462.

Fuji A. , Kobayashi S. , Yamamoto H. , Tamura T. (1990). Augmentation of wound healing by royal jelly in streptozotocin-diabetic rats. Jpn J Pharmacol 53:331-337.

Golub LM , Lee HM , Lehrer G. , Nemeroff A. , McNamara T. , Kaplan R. , et al. (1983). Minocycline reduces gingival collagenolytic activity during diabetes: preliminary observation and a proposed new mechanism of action. J Periodont Res 18:516-526.

Golub LM , Ramamurthy NS , McNamara TF , Rifkin B. , Greenwald RA (1991). Tetracycline inhibits connective tissue breakdown: new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 2:297-322.

10.

Golub LM , Evans RT , McNamara TF , Lee HM , Ramamurthy NS (1994). A non-antimicrobial tetracycline inhibits gingival matrix metalloproteinases and bone loss in Porphyromonas gingivalis induced periodontitis in rats. Ann NY Acad Sci 732:96-111.

11.

Goodson WH , Hunt TK ( 1979). Wound healing and the diabetic patient. Surg Gynecol Obstet 149:690-708.

12.

Grotendorst GR , Martin GR , Pencev D. , Sodek J. , Harvey AK (1985). Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. J Clin Invest 76:2323-2329.

13.

Kucine A. , Ramamurthy NS , McClain S. , McNamara TF , Golub LM (1997). A temporal study of wound healing in normal and diabetic rats (abstract). J Dent Res 76(Spec Iss):445.

14.

Liu Y. , Ramamurthy N. , Marecek J. , McNamara T. , Rifkin B. , Kabouridou L. , et al. (1998). Chemically-modified tetracyclines (CMTs) exhibit different pharmacokinetics in vivo (abstract). J Dent Res 77(Spec Iss A):251.

15.

Majno G. , Gabbiani G. , Hirschel BJ , Ryan GB , Statkov PR (1971). Contraction of granulation tissue in vitro: similarity to smooth muscle. Science 173:548-550.

16.

McClain SA , Simon M. , Jones E. , Nandi A. , Gailit J. , Tonnesen MG , et al. (1996). Mesenchymal cell activation is the rate-limiting step of granulation tissue induction. Am J Pathol 149:1257-1270.

17.

Ramamurthy NS , Golub LM (1983). Diabetes increases collagenase activity in extracts of rat gingiva and skin. J Periodont Res 18:23-30.

18.

Stegmann H. (1958). A microcolorimetric assay for hydroxyproline. Hopp-Seylers Z Physiol Chem 311:41-45.

19.

Yu Z. , Ramamurthy NS , Leung M. , Chang KM , McNamara TF , Golub LM (1993). Chemically modified tetracycline normalizes collagen metabolism in diabetic rats: a dose response study. J Periodont Res 28:420-428.