Proteases
It is well
documented that chronic wounds exhibit elevated protease levels compared
to healing acute wounds (Agren, 1994). Protease activity is regulated
in part by naturally occurring inhibitors known as TIMPs (Tissue Inhibitor
of Metalloprotease) and the levels of these are reduced in chronic wound
exudate (Bullen, 1995). As VLU heal in response to compression therapy
levels of Matrix Metalloproteases (MMPs) decrease from levels that may
be 30 fold higher than in acute wounds (Trengrove,1999). Assuming that
this change is not an epi-phenomenon then reduction of protease levels
may make an attractive therapeutic target which if treated would prevent
ECM destruction and aid re-epithelialisation.
This rationale is one of the proposed mechanisms of action of a new
dressing marketed as a protease modulating matrix, for the treatment
of compromised wounds. It is composed of a mixture of freeze dried cellulose
and oxidised regenerated cellulose (Cullen 2002a)) and in addition to
inactivating proteases in wound exudate (Cullen 2002b) also acts to
bind growth factors and protect them form proteolytic degradation (Clark,
2002). Evidence of clinical efficacy for this dressing has been demonstrated
by an accelerated rate of decrease in VLU wound area of 55% in 8 weeks
treatment compared to a control group decrease of 36% (Vin, 2002).
An alternative
means of achieving protease inhibition is to use pharmacologically active
compounds that target these enzymes. There is currently interest in
this type of compound because of the potential therapeutic application
for treatment of a number of diseases including rheumatoid arthritis
and cancer metastasis (Rudek, 2002). This approach may also prove valuable
in treatment of chronic wounds. However, although proteases play a role
in the pathogenesis of chronic wounds they also have a role to play
in normal healing with involvement in autolytic debridement, cell migration
and ECM re-modelling. Their levels are elevated early after injury and
rapidly decrease in the absence of infection but activity is still detectable
in normal human surgical wounds 6 days post-operatively (Tarlton, 1999).
Thus it may not be desirable to induce total protease inhibition to
achieve healing. One approach may be to use highly specific protease
inhibitors so that only those enzymes associated with non-healing are
inhibited whilst those associated with healing are unaffected. This
property has recently been ascribed to a synthetic compound which targets
MMP-3 mediated ECM degradation whilst leaving those enzymes associated
with cell migration unaffected (Fray,2003).
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