The University of Sydney Disciplines of Anatomy & Histology
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Cataract Prevention Unit
Coral Chamberlain

This laboratory was established in January 2000 by Dr Chamberlain, formerly a member of the Lens Research Laboratory in this Department (1985-1999). As a member of that group she participated in studies that made important contributions to understanding of the role of fibroblast growth factor (FGF) and other growth factors in normal lens biology and the role of transforming growth factor (TGFb) in cataract development.

Cataract, or opacification of the lens of the eye, is a major cause of blindness worldwide. This laboratory was set up to investigate further the normal and abnormal cell biology of the lens from a commercial and humanitarian perspective, with a view to developing strategies for preventing or delaying the onset of cataract. Also a target is a cataract-related condition known as posterior capsule opacification (PCO), an outgrowth of aberrant lens cells that leads to secondary impairment of vision following cataract surgery in many patients. Problems associated with cataract and PCO, which are already significant global health issues, will escalate as the world population ages. Most of the work in this laboratory to date has been strategic research carried out under research agreements with commercial partners. Some recent studies are described below.

Exacerbation of TGFb-induced cataract by FGF in cultured rat lenses
Cerra, Mansfield and Chamberlain

Culturing rat lenses with TGFb results in the formation of anterior, opaque subcapsular plaques, which exhibit many of the features of human subcapsular cataract. In this study it was shown that supplementing a low, barely cataractogenic dose of TGFb2 with 2.5-30 ng/ml FGF-2 promotes a very strong opacification response. The exceptionally large plaques that form in the presence of FGF are similar histologically to those induced by TGFb alone at higher concentrations and show immunoreactivity for cataract markers. Another growth factor, PDGF, at a concentration equivalent to FGF in terms of proliferative potential was ineffective. Addition of FGF inhibitors PSS or suramin reduces the opacification response induced by a cataractogenic dose of TGFb alone. Thus FGF exacerbates the cataractogenic effects of TGFb,  indicating that FGF inhibitors, as well as TGFb inhibitors, have the potential to protect the lens against TGFb-induced cataractous changes.

PCO-like responses in rat lens explants treated sequentially with TGFb and FGF
Mansfield, Cerra and Chamberlain

TGFb plays a key role in PCO development by inducing lens epithelial cells to undergo myofibroblastic/fibroblastic transition. Paradoxically, in rat lens explants, this TGFb-induced transition is followed rapidly by loss of cells due to apoptotic cell death. In this study, it was shown that survival of TGFb2-affected cells is promoted by FGF-2 but not by EGF, PDGF, IGF, or HGF. The cells salvaged by FGF no longer express the lens epithelial marker Pax6 and exhibit immunoreactivity for markers for myofibroblastic/fibroblastic transition (a-smooth muscle actin, type I collagen, and fibronectin) as in PCO. FGF inclusion also promotes ECM production, multilayering, and plaque formation, features of PCO known to contribute to visual loss. This study points to a key role for FGF in the aetiology of PCO and suggests that FGF inhibitors may be useful in preventing PCO.

Effects of dexamethasone on PCO-like changes in a rat lens explant model
Mansfield, Cerra, Chamberlain

In this study it was shown that dexamethasone (DEX), an anti-inflammatory agent widely used before and after cataract surgery, influences the behavior of lens cells under conditions relevant to PCO development. Rat lens epithelial explants, treated according to the sequential TGFb2/FGF model described above, were cultured for up to 30 days with or without DEX at a clinically relevant concentration Changes in lens cell behavior with addition of DEX included rapid formation of long, needle-like cells, less deposition of extracellular matrix on cellular surfaces, and a marked tendency for PCO-like plaques to be surrounded by a monolayer of abnormal migratory cells. This study raises the possibility that the use of DEX as an anti-inflammatory agent at the time of cataract surgery may influence PCO development.

Studies of factors that influence PCO-like changes in a rat explant model
Symonds, Lovicu and Chamberlain

In this study, the rat explant model was used to compare the effects of adding TGFb and FGF simultaneously or sequentially in explants that were initially well covered or poorly covered with cells. Differences between sequential and simultaneous addition, between low and high initial cell coverage explants, and between peripheral and central regions of explants were distinguishable on day 4 of culture, in terms of the extent to which cells were influenced by TGFb. By day 30, however, all explants were well covered with cells, irrespective of treatment and initial cell coverage, and all exhibited diverse PCO-like morphological changes, with expression of PCO markers in virtually all cells. The ability of lens cells to tolerate wide variations in conditions as they undergo PCO-like changes, demonstrated in this study, may contribute to difficulties encountered in eradicating PCO, while subtle differences noted early in the culture period may contribute to the characteristic pleomorphism of PCO.

Comparison of effects of dexamethasone and diclofenac in a rat explant model for PCO
Symonds, Lovicu and Chamberlain

In this study, the effects of the prototype steroidal and non-steroidal anti-inflammatory drugs, dexamethasone (DEX) and diclofenac (DIC), were compared using the above rat explant PCO model with sequential addition of TGFb and FGF. Explants were cultured with or without addition of each of the drugs at clinically relevant doses for up to 30 days. Throughout culture, cell coverage tended to be higher in the DEX-treated group than in the basic model or DIC-treated group, and plaques that formed were surrounded by a migratory monolayer of cells only when DEX was included. With or without drug treatment, most cells became aberrant and expressed PCO markers; however, DEX and DIC both strongly enhanced accumulation of one such marker, type I collagen. Further, DEX, but not DIC, countered TGFb-induced loss of cells from explants treated with TGFb alone. This study has shown that the behaviour of lens cells undergoing PCO-like changes is significantly and differentially affected by the presence of DEX and DIC. It thus highlights the possibility that drugs used to control inflammation associated with cataract surgery, and the clinician’s choice of drugs, may influence PCO development.