Growth factors in proliferative vitreoretinopathy
Surgical repair of retinal detachment complicated by proliferative vitreoretinopathy (PVR) remains complex and time consuming. Visual results of such surgery are frequently disappointing. Dissecting the network of growth factors/cytokines involved in PVR is a comparable challenge which may eventually result in improved anatomical and visual outcomes.
Several lines of evidence point to a role for soluble mediators (“growth factors”) in the process of periretinal membrane formation seen in PVR. Firstly, studies of cellular healing responses in other tissues have demonstrated a role for a number of growth factors (sometimes termed “fibrogenic cytokines”) in mediating cellular chemotaxis and proliferation, neovascularisation, extracellular matrix production, wound remodelling, and contraction, processes essential to the normal wound healing response.1 2 Secondly, several in vitro investigations have demonstrated that retinal pigment epithelium and retinal glia are responsive to a number of growth factors.3-6 The in vitro retinal pigment epithelium mediated contraction of collagen gels has also been shown to be growth factor dependent.7 8 Thirdly, analysis of specimens from eyes with PVR9 reveals the presence of elevated growth factor levels in vitreous10-13 and growth factor deposition in epiretinal membranes.14-19 Cells in PVR epiretinal membranes have also been shown to express growth factor mRNA20 which together with in vitro work on retinal pigment epithelium secretion of growth factors4 21-23suggests that there may be local growth factor production within PVR epiretinal membranes and a potential autocrine action on retinal pigment epithelium function. Lastly, experimental studies have demonstrated the induction of a PVR-like response by intraocular injection of platelet derived growth factor (PDGF).24
The paper by Cassidy and co-workers in this issue of BJO(p 181) adds useful new information to the growing literature on growth factor involvement in PVR. Their essential finding is that levels of both PDGF and basic fibroblast growth factor (bFGF) are significantly raised in the vitreous of eyes with retinal detachment and PVR but not in eyes with retinal detachment without PVR. Both growth factors are known to be involved in the upregulation of wound healing1 2 and the findings support previous observations that PDGF protein and its receptor are present on PVR epiretinal membranes16 and in vitro work suggesting a role for PDGF and bFGF in PVR.3 5 22 An association between raised PDGF levels and vitreous haemorrhage was also documented. Vitreous haemorrhage is considered a risk factor for PVR25 although in this context it may in fact simply serve as a marker for blood-retinal barrier breakdown. The trend towards higher levels of PDGF in grade A PVR is also of interest, suggesting differing growth factors may be active at the various stages of progression of the process of membrane formation. Further work is necessary to clarify this point.
As knowledge of the involvement of growth factors in PVR expands, additional questions are raised. The relative contributions of individual “fibrogenic” (for example, PDGF, bFGF, transforming growth factor β) and “inflammatory” (for example, interleukins 1 and 6, tumour necrosis factor α) growth factors are unknown and potentially single growth factors may hold the key to the PVR process. It is uncertain whether the growth factor profile in PVR represents a qualitative or quantitative difference from that of the processes of retinal repair seen in uncomplicated retinal reattachment. As manipulation of growth factor responses becomes a clinical reality a fundamental issue is to determine if specific targeting of growth factors can provide a means of treating and/or preventing PVR. Until effective adjunctive treatment is available for PVR the single option of vitreoretinal surgeons will continue to be direct surgical relief of vitreoretinal traction and retinal foreshortening.
