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Growth Factors and Ocular Scarring
β have been shown to enhance cellular production of PDGF,
16
which Table 1: Main Growth Factors Involved in Ocular
promotes cell proliferation and migration and has been shown to
Scarring, Suggesting Common Functions of Each
of the Main Growth Factors
have an autocrine effect in RPE, promoting cell growth.
17
Tumour
necrosis factor-alpha (TNF-α) is believed to be inhibitory to PDGF-
induced migration.
18
Growth Primary Roles References
Factor Sources
TGF-β Platelets, mast Chemotaxis, inhibition of 13, 16, 32,
Growth Factors and Scarring in the Cornea
cells, macrophages, endothelial proliferation, 33, 43, 46,
Cytokines and growth factors are key to the maintenance of the
endothelial cells, stimulation of fibroblastic and 66, 67, 88
corneal epithelium. Interactions between epithelial cells and
epithelial cells, epithelial proliferation, activation
stromal fibroblasts involve cell-surface molecules such as integrins
fibroblasts of extracellular cytokines,
and connexins, ECM or cytokines.
19,20
These play an important role in
TIMP synthesis, angiogenesis
the development, homeostasis and wound healing capabilities of
PDGF Platelets, mast Fibroblast, epithelial and endothelial 16, 18
the corneal limbal niche (the principal habitat of the stem cell
cells, macrophages proliferation and chemotaxis,
population that sustains the corneal epithelial mass).
21
angiogenesis, keratinocyte migration,
wound contraction
Deposition of fibrotic tissue and scarring can severely impair normal
EGF Platelets, Fibroblast proliferation 53
function of the cornea and clarity of vision (see
macrophages and migration
Figure 1`). Both the
opaque nature of the scar tissue and corneal contraction hamper
VEGF Platelets, mast Stimulation of endothelial and 93–99,
the focusing of light and, as such, affect the vision of patients.
cells, astrocytes, fibroblastic proliferation, granulation 104–106
macrophages, tissue formation, neovascularisation
The prevention of scarring is therefore crucial, and investigation
Muller cells
of the implicating mechanisms can define the appropriate
FGF Platelets, mast Cellular proliferation 7, 45,
therapeutic strategies.
cells, macrophages and chemotaxis 49–52
CTGF Macrophages, Proliferation, migration, 34, 35,
TGF-β isoforms, which are constantly expressed by the corneal
ECM, fibroblasts wound contraction 67, 88
epithelium,
22,23
have been shown to regulate corneal epithelial,
CTGF = connective tissue growth factor; EGF = epidermal growth factor;
endothelial and fibroblast chemotaxis.
24
TGF-β is a key player in scar
ECM = extracellular matrix; FGF = fibroblast growth factor; PDGF = platelet-derived growth
factor; TGF = transforming growth factor; VEGF = vascular endothelial growth factor.
tissue formation
25,26
in the corneal stroma. Ordinarily, the basement
membrane of the stroma prevents the diffusion of molecules (such as
TGF-β); however, following injury or surgery, this barrier becomes
Figure 1: Corneal and Conjunctival Scarring in
compromised, allowing for diffusion.
Stevens-Johnson Syndrome
TGF-β signalling also contributes to the recruitment of bone-
marrow-derived cells to the wound site,
27
which subsequently
express fibronectin, one of the main ECM components of fibrous
tissue.
28
In addition, TGF-β induces α-smooth muscle actin (α-SMA)
expression by the stromal fibroblasts, which makes them more
contractile and is a typical feature of fibrosis.
29,30
Of the three
isoforms, TGF-β2 has been suggested to play the most vital part in
scar formation during corneal wound healing, and its specific
inhibition has reduced fibrosis.
23
The TGF-βs act via the SMAD
signalling pathways to onset α-SMA expression and actin stress
fibres.
31
SMAD proteins are involved in the signalling and inhibition of
signalling of the TGF family. It is believed that fibronectin deposition
by TGF-β stimulation is mediated by the c-Jun N-terminal kinase
(JNK) pathway, a member of the mitogen-activated protein (MAP)
kinase (MAPK) superfamily.
32,33
Connective tissue growth factor (CTGF) is regulated downstream Scarring of the Lens Capsule and the
of TGF-β and, as such, fibroblast stimulation and ECM deposition by Role of Growth Factors
TGF-β may be under the control of CTGF.
34
CTGF is essential (but not Cataract surgery is the most common eye operation worldwide. The
the sole requirement) for the TGF-β1-mediated transdifferentiation most common complication is posterior capsule opacification (PCO),
of fibroblasts to myofibroblasts following mechanical stress.
35
which can occur in to 20–40% of patients undergoing surgery
34,35
(see
Pharmaceutical intervention of corneal scarring can potentially Figure 2). As with other fibrotic disorders, TGF-β is highly implicated in
focus on the inhibition of CTGF, as opposed to TGF-β, which has PCO development.
more physiological actions than CTGF in healthy tissue.
36
TGF-β, the
key player in corneal scarring, is still the most prominent The lens is an invagination of the surface ectoderm that is formed
pharmaceutical target as effective neutralisation on the wound site during embryogenesis.
38–40
Loss of vision attributed to scar formation
could reduce scarring after surgery or injury;
37
this is especially the in the lens has been attributed to TGF-βs.
19,20
As with other tissues,
case as many of the downstream wound healing processes are TGF-β upregulates the expression of α-SMA, promoting the epithelial-
under the influence of the TGF-βs. to-myofibroblast transition of lens epithelial cells (LECs). Multiple
EUROPEAN OPHTHALMIC REVIEW 59
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