The Lens as a Model for Fibrotic Disease - Essay Example

? The Lens as a Model for Fibrotic Disease The Lens as a Model for Fibrotic Disease Fibrosis is associated with contraction, cell transdifferentiation, matrix modification, and hyperprolification (Radisky & Przybylo, 2008). Evidently, fibrosis affects a number of organs. Following this, it is essential to consider finding out the major driver of fibrotic events, which most certainly would help facilitate the development of therapeutic strategies that are more appropriate. The lens is such an elegant, experimental, model for studying the processes that are known to cause fibrosis. Arguably, the cellular, as well as molecular organization of the lens has been well defined. This, thus, implies that modifications that are associated with fibrosis can easily be assessed. Additionally, the no-innervated and avascular properties associated with the lens provide an allowance for the application of effective in Vitro studies to be used. These studies quite compliment in vivo systems, and as well, relate to clinical data. The use of lens as an appropriate model for fibrosis directly affects many individuals, especially those that are affected by lens disorders. It also serves best as an experimental tool for understanding fibrosis per se. Research has shown so far that the lens in such an excellent model for studying fibrosis. This paper discuses this claim with a sole purpose of providing evidence that supports this statement. Introduction Fibrosis refers to ‘a pathological condition by which tissue structures are disrupted thus producing excessive extracellular matrix (ECM)’ (Leask, & Abraham, 2004). Studies show that fibrosis, encompasses multiple organ disorders known to have survival rate that is even worse than cancer (Laurent, McAnulty, Hill & Chambers, 2008). Following this, medics suggest that the conditions of fibrosis cause almost half of all deaths worldwide (McAnulty, 2007). Together with, the enhanced matrix production, the key features for tissue fibrosis include fibroblasts to myofibroblasts, hyperproliferation, matrix contraction, and trnsdifferentiation of the epethilial cells (Lee & Joo, 1999). Myofibroblasts generation has, more often than not, been assumed to the pivot of initiating fibrotic tissue formation, as well as the establishment of the pro-contractile apparatus leading to contraction of the matrix. Recent studies conducted on lens cells, as well as on lung have enlisted reaction among scientist who seems to question the established dogma. They are of the view that rather than employ profibrogenic, the use of myofibroblasts might be used instead in providing protection, in which case, miofibroblasts help in regulating the degree of the fibrotic response (Dawes, Eldred, Anderson, Sleeman, Reddan, Duncan & Wormstone, 2008). This basically implies that elucidating the roles of the signaling mechanism along with myofibroblasts that help in driving fibrotic events is vital as far as the quest to developing strategies for treating fibrotic disorders is concerned. In order to have this realized, appropriate models should be utilized, and the value attributed to the lens need not be underestimated as the best model of fibrosis. The lens as a model for fibrosis. The lens is a biological tool used for investigating various mechanisms that take place in the tissue fibrosis. In order to appreciate the benefits accrued upon the use of the lens, it is essential to understand the features, as well as the organization of a normal lens (consider fig 1a) (Duncan, 2001). The adult lens is often separated from other tissues and lacks either the vascular system or the innervations. It receives virtually all the nutrients it requires from the vitreous and aqueous humors responsible for bathing it. Clearly, the lens is divided into distinctive cellular groups. The cell anterior epithelium has been available since the formation of the cell vesicles during embryogenesis. It is also worthwhile to note that cell division, as well as cell death, is quite small in this population. But, the cells found in the peripheral epithelium can undergo cell division, migrate, and differentiate into the lens fibrer cells, which certainly are the majority in the lens. The cellular compartments markers when in association with these cells are used in defining the cell phenotype. For instant, forkhead transcription factor (FOXE3) is often expressed in the epithelium of the lens, with the eye master gene, and PAX6 (Duncan, 2001). ?-crystallin, on the other hand, serving as an early differentiation marker, while the major intrinsic protein MIP, along with ?-crystallin acting as markers of the mature fibre cell (Hales, Chamberlain & McAvoy, 1995. Normally, in a lens, order is always maintained, however, under certain circumstances, there might be disruption of the integrity of the lens, which might end up provoking a fibrotic change. Monitoring changes in a well defined system is essential to try to understand the nature of the changes in fibrosis, as well as the induction process of wound healing response. The available models for studying fibrosis such as, tissues culture, cell lines, and transgenic models are often well characterized in the lens (Warburton, Guevara, Fanburg, Gaestel & Kayyali, 2007). Moreover, the clinical data alongside post-mortem analysis are of great help in understanding of fibrosis within the lens (Sasaki, Kojima & Ishizaki, 1998). Notably, this information might not necessary bring out clearly the causal factors, but essentially, the data serve as a blueprint of noticeable changes commonly observed in patients. This, thus, implies that this information on clinical disorders is fundamental in directing researchers to make sure whichever the experimental system used has relevance to specific changes that are observed in patients. Adopting the appropriate model would help make sure that the mechanisms that give rise to the said change becomes easily determined and will help in advancing knowledge. It is worth noting that fibrotic disorders of the lens has affected many people globally (Marcantonio, Syam & Duncan, 2003), thus for purposes of the review, the best two characterized conditions: posterior capsule opacification PCO and the anterior subcapsular, shall be discussed. Fig1 Figure 1. (a) The schematic diagram that illustrates the cellular organization of a human lens. The figure (b) depicts the site for anterior subcapsular cataract, where ASC is often associated with modifying the epithelium, known to be clinically observed often as a fibrotic plaque The Anterior subcapsular cataract Anterior Subcapsular Cataract (ASC) is often characterized by a dense, light scattering fibrotic region found under the anterior capsule (fig1). The anterior Subcapsular cataract has been reported to be the least prevalent cataract in the United Kingdom having a prevalence of 2 – 3per cent (Dawes, 2009). The ASC has a high prevent among the eastern societies such as Singapore and Japan (Fisher, 1981). The occurrence of Anterior Subcapsular Cataract is closely associated with a number of conditions involving ocular trauma, such as the eye irritation or inflammation, impact injury, atopic dermatits among others (Fisher, 1981). Recently, analyses of animal model studies (Hales, Chamberlain & McAvoy, 1995), alongside the human anterior subcapsular material have been done with an aim of determining the cellular and molecular mechanisms underpinning the ASC formation. Marcantonio et al (2003) did a cystochemical analysis of the four ex vivo ASCs for humans. He observed the thickening and folding of the capsule anterior lens, while the cells found in this region exhibited a typical myofibroblast morphology that is elongated, and spindle shaped. They exhibited a positive staining for the alpha smooth muscle actin. In yet another study, Lee and Joo (1999) showed that transdifferentiation of the lens’ epithelial cells found in ASC leads to the production of enoumours amounts of ECM proteins such as fibronectin, collagen I and collagen III, which are never present within the lens capsule. Excessive deposition of ECM, along with the production of ECM, shows that the fibrotic changes that have so far been described can be mimicked because of the transformimg growth factor ? (TGF?) exposures (fig 2) (Leask, & Abraham, 2004). Just like the case of fibrotic disorders, the transforming growth factor has become the main area of study. Posterior capsule opacification Posterior capsule operation has been reported to be the most common condition within the lens that often develops after a cataract surgery Warburton et al. 2007). Currently, surgical intervention is the only means through which cataract is treated and initially, it was known to help in the restoration of high visual quality. However, PCO is disadvantageous to patients since it has been known to develop in a large proportion of patients to the extent that it causes a secondary loss of patient’s vision. The modern cataract operation leads to a capsular bag that comprises of a certain proportion of the entire and anterior posterior capsule. As often, the bag does remain in situ partitioning the vitreuos and aqueous humours. In many cases, it houses the intraocular lens. During surgery, there is the production of the capsular bag that allows free passage of light in the visual axis via a transparent intraocular lens, along with the acellular posterior capsule (Warburton, et al. 2007). As concerns, the other anterior capsule, the lens epithelial cells reside even though they endure the rigor surgical trauma. The resilient cells start re-colonizing the denuded anterior capsule regions, encroaching into the surface of the intraocular lens. They end up occupying the regions for the outer anterior capsule in the vent colonizing the free posterior capsule found before them. These groups of cells continue dividing while covering the posterior capsule ultimately encroaching on the visual axis. During this process, there is a thin cover of cells, which is somewhat insufficient in effecting the light path, but can subsequently bring change to the matrix, as well as the cell organization thus giving rise to a light scatter. Fig 2 (a) without the TGFB lenses, which remained clear, (b) corresponding cellular plaques, (c) did retain its normal histology having an epithelia cells monolayer and (d) with the arrow head, underlies the lens capsule. PCO is the classical fibrotic disease that exhibits hyperproliferation when responding to any injury, contration, muofibroblast formation, and matrix formation (Warburton, et al. 2007). There are various methods that can be used in studying PCO. One such method is the cell lines, which give abundant and reliable source of materials that help in investigating the relationship existing between the functional effects and signaling pathways (Dawes, et al, 2008). Tissue culture models, as well serve well for this research. The models encompass in vitro capsular bag models and the lens implant. The in vitro capsular bag models make use of a sham cataract operation in producing a capsular bag. The system mentioned above are characterized by similar cellular organization since both the cells and in vivo do grow on their natural bag. Additionally, lens cells found in these tissue culture systems can easily be maintained in a medium of serum-free for an extended period of culture. In this regard, the culture conditions, are controlled so that data interpretation becomes easier as compared to a more complex system. Moreover, other than the in vivo methods, scientists have worked to come up with in vivo animal models which make it possible to study transgenic animals in order to further find out the PCO progression. There are various features that are similar in both PCO and ASC with TGF? being strongly implicated. The historical analysis of the post-mortem specimens shows that there is an increase in the matrix deposition, matrix contraction, and transdifferentiation. Additionally, there are also molecules of activated TGF?, as well as Smads present. Research shows that applying TGF? to the in vitro capsular bags, cells lines or lens epithelia explants induces, increase in matrix production, myofibroblast expression, as well as matrix contraction. Thus, end up mimicking those clinically observed features. In this respect, TGF? again does serve as the key focus of research in so far as the PCO formation is concerned. However, there are various other mechanisms that likely do govern fibrosis. It is thus, essential establishing a full, true picture in so far as the assessment of the formation of fibrosis tissue is concerned. Regulation of fibrosis There are various biological, as well as cellular processes contributing to fibrotic conditions (Radisky & Przybylo, 2008). In justifying appropriateness of the lens model in studying fibrosis, it is important to look at the mechanism that underpins their involvement. They are the various biological and cellular processes that contribute to fibrotic conditions. The notable mechanisms underpinning their involvement include how inflammation drives the processes of fibrosis along with factors leading to the increase in matrix production or deposition, as well as the modification, which define the conditions of fibrosis in the lens and also throughout the body. Inflammation Inflammation sets the stage for the development of fibrosis (McAnulty, 2007). This is because inflammation angiogenic factors and response components are commonly found in many of the fibrotic disorders. But, one thing to note is that the important mechanistic controls that are often involved are not well understood. The tissue injury or damage which includes the surgical results in any inflammation aiming at repairing, as well as protecting the tissue that found around (McAnulty, 2007). It is a well known fact that the tissues that are damaged often release chemicals which are responsible for attracting the white blood cells like the lymphocytes T helper cells. These cells help in coordinating the ensuing immune responses through releasing of cytokines such as the interukins. They also work to secrete proteins activate resident macrophages, which then enhances the production of chemokines, cytokines, as well as other inflammatory mediators. They also recruit the monocytes that would ultimately help in returning the injured tissues back to their normal status. Studies indicate that TGF?can independently signal the Smad function. For example, the TGF? type I receptor is capable of phoshorylating serine and tyrosine residues within the SHCA adaptor, recruits the adaptor protein GRB2, as well as Ras guanine exchange factor son of sevenless in order to activate the Ras-Raf-MEK-ERK mitogen-activating protein kinase within the cells of mammals. The tyrosine kinase Sr is capable of phosphorylating the cytoplasmic domain of TGF?RII, thereby causing SHC and GRB2 recruitment. This enables activation of p38 MAP kinase pathway. Additionally, the Rho kinase signaling along with the JNK MAP kinase pathways can easily be activated by TGF?. Within the context, the lens of fibrosis, p38 MAP kinase, and the Smad-independent signalling pathways are often activated by the TGF? within the human lens’ epithelial cells. The idea that TGF?-induces matrix contraction is because of the Smad-independent signaling and is fully supported by non-ocular system investigation in which case, p38 MAPK Rho or and Rho kinase promote matrix contraction. By and large, ERK signalling pathways do promote the matrix contraction through activating myosin light chain kinase, which is the main enzymatic regulator for the contractile force (Lovicu, et al, 2002). Thus, with the use of lens fibrosis models, roles of Smad-independent signalling pathways on TGF?-induced matrix contraction requires investigation in order to work best with the regulatory TGF? mechanism that controls the detrimenta fibrotic characteristics. Research, as well show that TGF? Smad-independent pathways (Lovcu et al, 2002) might mediate the events of fibrosis throughout the human body. Conclusion The lens fibrotic disorders affect millions of people. A number of unique biological properties attributable to the lens make it to serve best as an exquisite biological tool especially in investigating the processes underpinning fibrosis. This, thus, clearly implies that through employing the lens as the study system, we shall be able to observe hyperproliferation following matrix contraction, injury, trasdifferantiation to myofibroblasts, and matrix production or deposition. With the use of various strategies employing tissue culture models, cell lines, and transgenic animals, there are various pathways driving lens fibrosis that are emerging. Clearly, the lens is the most excellent experimental model system for investigating tissue fibrosis per se. References Dawes L. J., Eldred J. A., Anderson I. K., Sleeman M., Reddan J. R., Duncan G., Wormstone I. 2008. TGF beta-induced contraction is not promoted by fibronectin–fibronectin receptor interaction, or alpha SMA expression. Invest. Ophthalmol. Vis. Sci. 49, 650–661. Dawes L. 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