A common
feature of compromised wounds is that they appear arrested at the stage
of inflammation and granulation tissue formation (Table
1). Non-resolution of inflammation and the presence of bacteria
(Trengrove, 1996) results in generation of wound exudates containing
a disordered cytokine/growth factor network and high levels of proteolytic
enzymes (proteases) that destroy tissue proteins, growth factors and
ECM (Table
2). (Brantigan, 1996). Because the ECM is degraded proliferating
keratinocytes at the wound margin cannot migrate over the wound bed
to achieve wound closure.
Proteases
The majority
of cell types present in wound tissue have the capacity to produce proteases
and normally both their secretion and proteolytic activity is tightly
controlled. Proteases are required to destroy necrotic tissue, temporarily
break down ECM to allow cell and capillary migration and to remodel
ECM in scar tissue so that it achieves maximum strength. However in
compromised wounds there is a shortage of regulatory factors that act
to inhibit protease activity as well as an overproduction of proteases.
Additionally many compromised wounds are contaminated with bacteria
that also have the ability to add to the pool of proteases in the wound.
For instance, Pseudomonas aeruginosa, which is found in 20-30% of venous
leg ulcers can secrete both elastases and proteases to disrupt healing
(Schmidtchen, 2001). The resulting overall loss of control of protease
activity has great potential to compromise the healing process
Growth
factors and Extracellular matrix
Increased
protease activity in compromised wounds results in degradation of growth
factors (Yager, 1997) needed for regulation of healing and crucially,
in destruction of ECM (Grinnell, 1996).
ECM is primarily
manufactured by fibroblasts in the skin and interlaced fibres of the
proteins collagen and elastin produce its structural strength and elasticity.
Other specialised proteins such as fibronectin and laminin with a combination
of proteins and polysaccharides known as proteoglycans are found in
various combinations depending on wound age. Whilst the mechanical properties
of ECM are important for skin function it is clear that ECM also plays
a major role in regulating healing by acting as a reservoir for growth
factors to be called on when required during healing (Appleton, 1993).
Additionally ECM components such as fibronectin or vitronectin bind
to keratinocytes and induce them to migrate over granulation tissue
as part of wound re-epithelialisation (O'Toole, 2001).
Destruction
of ECM by uncontrolled proteases is considered to be a major contributory
factor preventing healing of compromised wounds (Fray 2003). Protease
activity is a good example of how intrinsic factors required for normal
healing (Steffenson, 2001) negatively impact on healing when acting
in an uncontrolled manner outside normal regulatory circuits. This leads
to the concept that restoration of normal regulation will induce healing
(Schultz, 2003).
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