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The lens is a vital biological tool to investigate the mechanisms involved in fibrosis. The structure of the lens is bioconvex this shape helps to refract light being focused on the retina and the cornea. The lens is located in the anterior segment of the eye and is held in place by fibres called the zonular. Zonular fibres attach to the lens and are connected to the cilary body. See figure 1.
Figure 1. Schematic of the lens and its cellular organization
Figure 1 shows the structure of lens and its distinct cellular parts(9)
The lens can be separated into distinct cellular parts: the lens capsule, the lens epithelium, and the lens fibres. (4) The lens capsule forms the outer layer of the lens see fig1 and the lens fibres forms most of the interior of the lens. The lens is enclosed in an elastic capsule and this is why they have a spherical shape. This shape is maintained by the zonular fibres. The lens capsule is a basement membrane that surrounds the whole lens. The Anterior section of the lens contains the lens epithelium. They are positioned between the lens capsule and the lens fibres. The cells of the lens epithelium regulate most of the homeostatic functions of the lens. (2)(3)(4) The cells in the anterior portion of the epithelium have been present since lens vesicle formation during embryogenesis. The cells in the peripheral epithelium are capable of migration, cell division and differenating into lens fibre cells that form most of the lens. Many models are available to study fibrosis such as transgenic models and tissue culture and are characterised in the lens. (8)
Fibrosis is a pathological condition where the tissue structure is interrupted by the
Production of excessive extracellular matrix (ECM) (8). Fibrosis is caused by homeostasis being interrupted by infection, inflammation and when the visual function becomes impaired. Homeostasis of the eye depends on the presence of normal vasculture, ECM and other cell types. Fibrosis is also referred to the response of an injury. The injury can result in a wound or metabolic malfunctions such as inflammation and degenerative diseases. Fibrosis can occur in many places in the body for example in the skin it can lead to a formation of a scar. In the eye it can cause problems with vision. Problems with vision will disrupt the visual axis to where cellular functioning is no longer possible. Fibrosis of the cornea can lead to corneal opacification and loss of vision. These conditions of fibrosis in the eye lead to vision loss in millions of individuals worldwide. (1) Two main conditions to be discussed are the anterior subcapsular cataract and posterior capsule opacification.
Anterior subcapsular cataract is the build up of fibrous mass underneath the anterior capsule. It is dense light scattering fibrotic regions below the anterior capsule caused by fibrosis. Anterior subcapsular cataract (ASC) results from the abnormal growth and differentiation of the lens epithelial cells to form fibrotic plaques that disrupt the vision. Plaques in the ASC contain "myofibroblast-like" cells and accumulation of collagenous matrix. Studies on cataract using a technique called immunolabelling have shown there is a presence of cytoskeltal and extracellular matrix proteins not expressed by lens cells. Proteins that have undergone immunolabelling in the fibrotic plaques of ASC are Î±-smooth muscle actin, fibronection, and tenasoin. Î±- smooth muscle actin is a marker for cataract. Anterior subcapsular cataracts are fibrosis opacities that occur near the centre of the lens epithelium. (2) ASC is the least prevalent form of cataract in the United Kingdom. A recent study by lee and joo has shown that transdifferentitaion of lens epithelial cells in ASC causes the production of large amounts of extracellular matrix proteins such as fibronectin, collagen I and III which are not present in the lens capsule. The production and deposition of extracellular matrix is a characteristic of fibrosis. Experiments taken on isolated whole rat lens culture showed fibrotic changes due to the transforming growth factor Î² (TGFÎ²) exposure. Many fibrotic disorders are linked with TGFÎ². Studies on four ex vivo human anterior subcapsular cataracts showed folding and thickening of the anterior lens. The cells in the regions showed positive staining for alpha smooth muscle actin. (8) (2)
Figure 2. A schematic diagram showing the site of the anterior subcapsular cataract. (8)
Figure 2B a schematic diagram showing the formation of fibrotic plaque. (8)
Posterior capsular opacification (PCO) also known as secondary cataract is another form of cataract that occurs after surgery. It involves abnormal epithelial growth and the formation of fibrotic plaques. Cataract surgery involves the removal of a segment of the anterior capsule and allows light to pass through the lens again allowing vision to be restored. A lens capsular bag is produced that contains the remaining anterior capsule with lens epithelial cells attached. The bag can accommodate an artificial intraocular lens implant. The remaining lens epithelial cells rapidly grow and could invade on the visual axis where light scattering changes induced by the cells can give rise to secondary visual loss also known as PCO.(5)
Figure 3. A Image showing the post surgical capsular bag (B) The growth of rapidly diving epithelial cells invading the visual axis giving rise to PCO.(8)
PCO is the most common fibrotic condition in the lens and is arisen from the lens epithelial cells that are left behind from cataract surgery. In PCO the plaques also contain myofibroblast cells and express some of the abnormal markers found in ASC. PCO can be grouped into 4 categories: Elschnig's pearls, capsular fibrosis, Soemmerring's ring, and lentoid of Thiel. The most common forms of PCO are capsular fibrosis and Elschnig's pearls. Fibrosis is commonly found around the lining of the anterior capsule and the central portion of the posterior capsule, where it is present with capsular wrinkles and folds. The build up of large amounts of extracellular matrix appears to be major cause of opacification in this form of PCO. (6)
Many features are common to both PCO and ACO. Both share similarities with the fibrous opacities and in both PCO and ASC the lens epithelial cells transdifferentiate to myofibroblast-like cells. The main feature in both is the transforming growth factor. (6)
TGF-Î² is a major system of study. It is the major fibrotic molecule. Studies have shown TGF- Î² can initiate myofibroblast formation, fibrosis and cataract formation in transgenic mice. There are different isoforms of the transforming growth factor (1, 2 and 3) and are all present in mammals. These isoforms are multifunctional cytokines that play a role in wound healing and in tissue repair. TGF - Î² exists in both a latent and active form.TGF-_2 is a major isoform within the eye, it plays a critical role in both the short- and long-term development of PCO.It is detected in the aqueous humor and exists in the latent form.TGF_1 and TGF_3 show low levels of expression in the eye under normal circumstances. In a surgical injury active levels of all TGF isoforms can be high. TGF-2 is present in the human capsular bags and also the addition of this growth factor to the medium can induce the matrix and cellular changes exhibited in vivo. Transforming growth factor is an effective inducer of both transdifferentiation and contraction, which are critical processes that support tissue fibrosis. There are many TGF- Î² signal transduction pathways. The major intracellular signalling system identified for TGF- is through translocation of smad proteins. Smad are proteins involved in mediating intracellular signal transduction. Many experiments have been taken on animals to investigate the role of TGF and the role it has on fibrotic disorders of the lens. A study on a rat lens culture model has shown TGF induces anterior subcapsular cataract. (7)(10)Studies on capsular bag following cataract surgery from a donor 1 month of surgery has shown increased levels of TGFÎ²- induced fibrotic markers including the matrix contraction/wrinkling of the posterior capsule.(8)
Fibrotic conditions can be both biological and cellular processes. The mechanisms involved in fibrotic conditions are inflammation and how it can construct the fibrotic process and how the factors can lead to increased matrix production and deposition and the modification eventually defines fibrotic conditions in the lens. (8)
To conclude the conditions of fibrosis in the eye can lead to vision loss in millions of individuals worldwide. The properties of the lens lets us investigate the processes that support fibrosis. TGFÎ² and smad signal pathways are among the useful targets to be inhibited in the prevention and treatment of fibrotic diseases in the eye. Hyper-proliferation following injury, matrix production deposition and contraction and the transdifferentaion to myofibroblasts can be seen using the lens as a study. Myofibroblasts are key mediators of ECM production and deposition and in both ASC and PCO it is a common feature of fibrotic pathologies. Using transgenic animals and tissue culture models in experiments have shown results for fibrosis and therefore the lens is an excellent model to study fibrosis. (8)