Can Doxycycline Have An Impact As An Agent For ‘Wound Chemotherapy’?

Editor’s note: This blog is co-authored by Nicholas A. Giovinco, DPM, and Julia Bernardini, DPM.

Doxycycline is a semi-synthetic tetracycline compound. Classically, this drug is used in podiatry and wound care for its properties of antibiosis and antisepsis. However, there have been some investigations of doxycycline and other chemically modified tetracycline species (CMTS), which demonstrate its potential as an inflammatory modulator. These qualities may prove useful within a wound environment. This is particularly so as doxycycline is an inhibitor of nitric oxide (NO) production, matrix metalloprotease (MMP) activity, and tissue necrosis factor alpha converting enzyme (TACE).

Matrix metalloprotease activity has been identified as a key player in the environment of chronic wounds as well. Although MMPs are part of the normal breakdown and remodeling of tissues within the human body, non-healing ulcers are particularly less governed by regulatory mechanisms. Therefore, one will see an overabundance of MMP activity and subsequent persistence of inflammation and degradation of the epithelial matrix in situ. Researchers have investigated the chemical structure of doxycycline and it demonstrates satisfactory results as an inhibitor of such zinc catalyzed protease activity. By inhibiting the activity of various MMP species in a wound bed, the breakdown of wound matrix may be prevented.

Similar to MMP inhibition, TACE (otherwise known as ADAM17) is a member of the same metalloprotease superfamily and thus inhibition works by zinc binding as well. As a surface bound enzymatic protein, TACE degrades pre-TNF-a, thereby converting it to a biologically active form. Doxycycline has demonstrated convincing results in lowering the conversion of pre-TNF-a to its active form. Since TNF-a has long been known as a powerful member of the entourage of inflammatory cytokines of chronic wounds, the ability to suppress its expression could potentially be to the patient's advantage.

Next, the presence of nitric oxide within a wound environment is made possible by its production via the iNOS enzyme. The mRNA molecule, which codes for iNOS, is expressed during times of cytokine and inflammatory stimulation. This mRNA molecule has a relatively short half life, which is presumed to be for regulatory purposes, and is stabilized by the presence of p38 MAPK binding to one of several "AUUA" motifs. When doxycycline prevents p38 MAPK from stabilizing inducible nitric oxide synthase (iNOS) mRNA via competitive binding to metallic ions, subsequent degradation of the iNOS mRNA molecule takes place and therefore acts to decrease the concentration of nitric oxide within the wound environment.

Although further investigation is needed to ascertain the true beneficial value of doxycycline as a wound chemotherapeutic agent, laboratory data is highly suggestive of this possibility.

References

1. Scimeca CL, Bharara M, Fisher TK, Giovinco N, Armstrong DG. Novel use of doxycycline in continuous-instillation negative pressure wound therapy as ‘wound chemotherapy.’ Foot Ankle Spec. Jun 8.
2. Hanemaaijer R, Visser H, Koolwijk P, et al. Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res. 1998;12(2):114-118.
3. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye. Exp Eye Res. 2006;83(3):526-535.
4. Winzen R, Kracht M, Ritter B, et al. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J. 1999;18(18):4969-4980.
5. Hoyt JC, Ballering J, Numanami H, Hayden JM, Robbins RA. Doxycycline modulates nitric oxide production in murine lung epithelial cells. J Immunol. 2006;176(1):567-572.
6. Abdul-Hussien H, Hanemaaijer R, Verheijen JH, van Bockel JH, Geelkerken RH, Lindeman JH. Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content. J Vasc Surg. 2009;49(3):741-749.
7. Hanemaaijer R, Sorsa T, Konttinen YT, et al. Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. Regulation by tumor necrosis factor-alpha and doxycycline. J Biol Chem. 1997;272(50):31504-31509.

Editor’s note: Check out the accompanying PodiatryLIVE video at www.podiatrylive.com/doxycycline_agent_wound_chemotherapy

This blog has been adapted with permission. It originally appeared at www.diabeticfootonline.blogspot.com.



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