Peng_Ellis_EU_Ophthalmic_Layout 1 22/01/2010 12:10 Page 61
Growth Factors and Ocular Scarring
The contraction part of conjunctival scarring has been attributed Figure 4: Severe Proliferative Vitreoretinopathy
to the action of TGF-β on fibroblasts, where it is believed to act via the
Leading to Total Retinal Detachment
Rho-associated kinase (ROCK) signalling network. Inhibitors of ROCK
have been shown to reduce both cell tension and α-SMA expression
in fibroblasts, thus reducing the ability of fibroblasts to transform into
myofibroblasts and contract collagen.
66
As such, ROCK provides an
interesting target for pharmaceutical intervention of glaucoma
scarring as, by inhibiting ROCK, the TGF-β-mediated scar formation
may be inhibited.
The downstream activities of TGF-β in glaucoma, as with other wound
healing situations, are influenced by CTGF. CTGF has been shown to
be necessary for TGF-β stimulation of myofibroblast differentiation
and collagen contraction;
67
therefore, as with CTGF in the cornea,
treatments may be possible to inhibit this growth factor, thus limiting
the scarring potential of fibroblasts directly.
68
The potential involvement of p38MAPK via its effects on CTGF and of
the monocyte chemoattractant protein (MCP-1) has been studied.
66
Therefore, the inhibition of p38MAPK has also been proposed as a
possible future therapeutic option. early as 24 hours after retinal detachment.
78
During retinal scaring,
both growth factors and cytokines have been shown to influence the
PDGF may also play an important role in post-GFS scarring. It expression of MMPs by RPE; in vitro RPEs express MMPs 1, 2, 3 and
stimulates fibroblasts, making them proliferate, migrate and produce 9.
79
In addition, retinal membranes from PVR patients have been
ECM molecules, causing contraction, fibrosis and development of shown to have elevated levels of those MMPs.
80
fibrotic membranes such as those observed in proliferative
vitreoretinopathy. Agents capable of blocking PDGF
BB
have been The vitreous of patients with PVR has been shown to be high in both
tested in animal models of proliferative vitreoretinopathy (PVR) and MMP-2 and MMP-9.
4
Neutralisation of a combination of MMPs using
may also be useful in glaucoma surgery. antibodies was shown to be required to inhibit RPE-mediated gel
contraction; individual MMP antibodies were not effective.
71
A broad-
Related to the TGF-βs are the bone morphogenic proteins (BMPs); spectrum MMP inhibitor (ilomastat) was shown to inhibit collagen gel
these growth factors play an important role not only in embryonic contraction by RPEs more effectively than the combined antibodies.
development but also in cell proliferation, differentiation, apoptosis, The effects of ilomastat were shown to be reversible after
angiogenesis and other biological functions.
64,65
Increased expression replacement of the media, suggesting effective, reversible inhibition
of BMP-6 mRNA and protein levels have been observed in scarred of contraction. MMPs are, as such, a valuable target for PVR
conjunctiva. The inhibition of BMPs could be a future therapeutic development. It may be feasible to inhibit both the proliferation of RPE
option for the control of scarring after GFS.
69
and MMP activity using a combination of a broad-spectrum MMP
inhibitor plus an anti-inflammatory.
71
Growth Factors in Proliferative Vitreoretinopathy
PVR is a major complication that occurs in approximately 10% of Aside from the importance of cytokines such as TNF-α, which is
patients presenting with retinal detachment (RD). Retinal detachment believed to control intergrin expression and promote migration of
is a clinical emergency where the retina becomes detached from the RPE,
77
growth factors play an important role in the formation of PVR.
RPE layer. RD may result from physical trauma to the eye resulting in It has been suggested that HGF is important in the early stages of
tractional pull of the retina. The fibrous scar (epiretinal membrane) that PVR development.
81
This was realised based on the strong cellular
forms during PVR development dramatically increases the chance of staining of HGF on PVR specimens and relatively weak staining on
failure of reattachment surgery due to the stiffness of the membrane. scar tissue. Hinton et al. suggested that HGF, which acts mainly on
The effect of the epiretinal membrane (EM) formation is dependent on epithelial cells, promotes cell division and migration of RPE in PVR. It
the site of scarring. EM formation proximal to or at the site of the has been hinted that HGF acts via an autocrine system in RPEs as they
macular can lead to vision loss and visual distortion and monocular express both HGF and its receptors.
82
HGF is suggested to promote
dipilopia (see Figure 4).
70
The migration and proliferation of many cell the breakdown of RPE tight junctions,
83
possibly as a result of
types, including RPE, fibroblasts and Müller glia, have been attributed downregulation of zona occuldens 1 (zo-1, a tight junction protein that
to PVR development;
33,69–72
RPE cells are believed to dedifferentiate and is involved in cell–cell signalling).
adopt a fibroblastic phenotype during PVR development.
71
TGF-β probably plays the most important role in the scaring response
Where RPE migration is concerned, a tear in the retina or of the retina. Of the three TGF-βs expressed in mammals, TGF-β2 is
rhegmatogenous detachment allows growth-factor- and cytokine- the most important isoform for retinal scarring; indeed, a significant
rich
72–75
vitreous fluid to come into contact with the RPE layer and RPE correlation exists between the levels of TGF-β2 expression and the
cells, promoting their proliferation
76
and migration
77
into the vitreous severity of retinal scarring.
84
TGF-β2 mediates RPE production of
and onto the retina where they form scar tissue (EM) on both sides of collagen I and fibronectin,
85,86
and promotes cell migration
86
and the
the retina. In a cat model of PVR, proliferation of RPE was shown as transition of RPE into the fibroblastic phenotype.
87
CTGF again
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