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Essay - first two stages of wound healing
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- Liverpool John Moores University (LJMU)
This document discusses the first two stages of wound healing, how they occur under normoxic and hypoxic conditions.
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Proliferation PhaseProliferation within the wound site results in the build-up of highly vascular connective tissue called
granulation tissue. This process is triggered due to the loss of vascularity resulting in the wound
environment having a low pH, reduced oxygen tension and increased lactate. The wound
environment signals the release of vascular endothelial growth factor (VEGF), basic fibroblast factor
(bFF) and transforming growth factor – β (TGF-β).
The oxygen sensing pathway recognises the hypoxic environment of the wound. Hypoxia-inducible
factor (HIF) is triggered. HIF is a heterodimer consisting of two subunits: HIF-1α and HIF-1β. HIF-1α is
induced in hypoxic conditions whereas HIF-1β is constitutively expressed.
Under normoxic conditions, HIF-1α undergoes proline hydroxylation catalysed by prolyl-4-
hydroxylases (PHDs) at the oxygen-dependent degradation domain on the c-terminus. Von Hipple-
Lindau (VHL) can specifically recognize the hydroxylated form of HIF-1α. However, this does not
occur under hypoxic conditions.
Under hypoxic conditions HIF-1α is exempt from VHL degradation and the stable heterodimer binds
to hypoxia response elements within promoter regions to switch on transcription of target genes
such as VEGF.
To restore vascularity to the wound, endothelial cells secrete enzymes which degrade the
extracellular matrix to the adjacent areas of the wound. This creates tissue defects allowing the
capillary vessels to form a network allowing the formation of arterioles.
With vascular perfusion restored the oxygen tension rises and restores to the normal levels. Oxygen
binds to HIf-1α and inhibits the transcription of VEGF.
Maturation Phase
The new extracellular matrix (ECM) is initiated as cytokines produced by macrophages signals to
fibroblasts to translocate to the wound. Wound fibroblasts have a decreased proliferation rate yet
and increased collagen production rate. The initial fibrin clot is used almost as a scaffold for the
collagen.
If the wound is healing by secondary intention the wound must fill with granulation tissue first prior
to epithelialisation, as epithelial cells can only migrate over moist, vascular tissue. Once the cells
have covered the wound surface, they begin upward migration and differentiation to form the
epidermis. Fibroblasts are activated within the granulation tissue by TGF-β, they acquire α-Smooth
muscle actin (α-SM actin) and form myofibroblasts
The final phase of remodelling can take up to a year depending on the magnitude of the wound.
Myofibroblasts control the breakdown of the wound matrix and the synthesis of the new ECM. The
cells exhibit contractile properties due to the expression of α-SM actin in the microfilaments or
stress fibres which begin to pull the boundaries of the wound in. The progressive remodelling of the
granulation tissue is carried out by metalloproteinases (MMPs) (part of the calcium-dependent zinc-
containing endopeptidase family) and their inhibitors (tissue inhibitors of metalloproteinases
(TIMPS)). Overtime collagen type III is replaced with collagen type I, the main structural component
of the dermis.
The slow process allows the increase in tensile strength. Abnormal scarring may occur if an
imbalance is caused during the final phase interrupting the matrix degradation and synthesis.
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