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| Keratoconus: The Cascade Hypothesis http://www.associazionecheratocono.it/forum/viewtopic.php?f=18&t=78 |
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| Autore: | scaistar [ mercoledì 23 febbraio 2005, 12:07 ] |
| Oggetto del messaggio: | Keratoconus: The Cascade Hypothesis |
by M. Cristina Kenney, M.D., Ph.D. During the past 10 years the scientific knowledge of keratoconus has increased greatly. We now have a much better understanding of the cellular and molecular changes that occur in keratoconus corneas. Research has provided evidence that keratoconus corneas have increased enzyme activities and decreased levels of enzyme inhibitors. The increased enzyme activity can account for the thinning of the cornea that occurs. Other studies show that keratoconus corneas have areas of fibrosis (scarring) and increased numbers of cells that undergo apoptosis, cell death (Figure1). Another line of research into the cause of keratoconus is related to the possible role of oxidative stress. The scientific approach is to first propose a hypothesis and then perform experiments to either prove or disprove the hypothesis. In the area of keratoconus, our laboratory has proposed a "Cascade Hypothesis" and we are now in the process of testing it. In our "Cascade Hypothesis" we suggest that keratoconus corneas have abnormal enzymes in various pathways that ultimately lead to increased oxidative damage of the corneas. There is an accumulation of oxidative, cell toxic by-products that can damage corneal proteins and this triggers a cascade of events, including altered enzyme activities, scarring and apoptosis (cell death). Many laboratories are now testing our cascade hypothesis with biochemical, immunohistochemical and molecular experiments. In this way we will gain more knowledge of the causes of keratoconus. In addition, if this hypothesis is accurate, then we will have some idea about which pathways might be amenable to therapy to prevent or cure keratoconus. It is most likely that keratoconus develops because of a combination of both an environmental and genetic causes. The following is a review of what is known about the genetics and some of the environmental factors involved in keratoconus. Evidence for a genetic component of keratoconus: It is reported that approximately 1 in 2,000 individuals develops keratoconus. One of the strongest arguments for the genetic component for keratoconus is that it can run in families. The likelihood that keratoconus will be found in more than one member of the immediate family is 3.34%, which is 15-70 times higher than the general population. In addition, keratoconus has been reported in identical twins and in two or more generations of many families. Studies to identify the association of keratoconus with various chromosomes have been performed. Reports for a relatively small number of keratoconus families show some connection between keratoconus and defects on chromosome 21, chromosome 17 or chromosome 13. At this time, we do not understand exactly what specific part of the chromosome is defective or how it might cause keratoconus, but these studies have pointed a direction for the researchers to follow. Future experimental studies to identify genetic abnormalities will include "candidate gene" approach and linkage studies using scans of all chromosomes with genetic markers. The BIGH3 gene (beta transforming growth factor-induced gene) on chromosome 5, once high in the list of suspects for causing keratoconus, has been eliminated. The mutations in this gene are associated with many other corneal disorders such as granular corneal dystrophy, lattice corneal dystrophy and Avellino corneal dystrophy. In a recent study to be submitted for publication, 15 keratoconus families were screened for the BIGH3 gene defects and no associations were found. These screening experiments are still underway with new "candidate genes", those genes that have increased possibilities to be related to keratoconus. One category of genes that are highly suspect are those oxidative stress-related enzymes that might account for the defect found in keratoconus. Even when one individual gene defect is found associated with keratoconus, we will continue to screen for other genes. Since there is considerable variation among keratoconus patients, it is most likely that not just a single gene but multiple genes would be involved. For example, keratoconus comes in many forms. It can be unilateral (just in 1 eye) or bilateral (in both eyes), affect the central part of the cornea or the inferior cornea, it may be mild or severe, it may start in childhood or later in life, it may occur in more than one family member or in an individual only. In future investigations, we suspect that defects in more than one gene will be associated with different forms of keratoconus. Evidence for oxidative damage as a possible cause of keratoconus: While it is generally believed that keratoconus probably has a genetic component, there is also data that suggest that the environment plays a role. In our laboratory, the working hypothesis is that keratoconus corneas have increased oxidative damage because of defects in the normal protective mechanisms to inactivate reactive oxygen species (free radicals, superoxides, reactive aldehydes, etc.). This oxidative damage could lead to alterations in the structure and function of proteins, triggering a series of "downstream" events and ultimately thinning of the keratoconus cornea. The supporting evidence for increased oxidative damage in keratoconus corneas comes from two different types of studies. The first are investigations of the antioxidant enzymes that normally protect human corneas. In the early 1990s scientists reported that keratoconus corneas had decreased levels of aldehyde dehydrogenase Class 3 (ALDH3), a corneal enzyme that is important for elimination from the cornea of toxic "reactive aldehydes" in the lipid peroxidation pathway. In the past three years, other scientists showed that keratoconus corneas also had lower levels of another enzyme, superoxide dismutase. This is an important antioxidant enzyme that eliminates the reactive oxygen species such as free radicals or superoxides (Figure 2). Keratoconus corneas are deficient in at least two and possibly more critical enzymes (ALDH3 and superoxide dismutase) whose functions are to remove reactive oxygen species and reactive aldehydes. In support of these findings are the second types of investigations by our laboratory demonstrating that keratoconus corneas possess large amounts of the abnormal, cell toxic by-products called malondialdehyde (MDA). This is a cell toxic aldehyde from the lipid peroxidation pathways and nitrotyrosine (NT), representing peroxynitrite, a cell toxic by-product of the nitric oxide pathway. The consequences of either MDA and/or NT accumulation is that both are toxic to corneal cells and can alter the structure and function of surrounding proteins. Once the normal functions of proteins are altered a cascade of abnormal events occurs, including apoptosis, increased enzyme activities, scarring, etc. In summary, the environmental component in the development of keratoconus may be related to the keratoconus cornea's inability to process the reactive oxygen species (free radicals, superoxides, etc.). Because the keratoconus corneas seem to lack the necessary protective enzymes (ALDH3, superoxide dismutase), there is a resultant accumulation of toxic by-products (MDA and peroxynitrites) that can damage the cornea. Therefore for keratoconus patients, it may be prudent to minimize the insults that cause reactive oxygen species. This includes reducing exposure to ultraviolet light (UV) (by wearing sunglasses outdoors), mechanical trauma (avoid vigorous eye rubbing, poorly fit contact lenses) and atopy/allergies (keep allergies under control). As scientists test the "Cascade Hypothesis" we will learn more new information about the susceptibility of keratoconus corneas to oxidative stress. In the meantime, in terms of practical information for keratoconus patients, it seems reasonable to take some steps to protect the corneas. How can we do this? Based on our findings published in the upcoming review article (Kenney, Brown) in the International Contact Lens Clinic (in press), I recommend the following: 4 UV protection in the contact lenses and/or sunglasses used by our keratoconus patients. 4 Efforts should be made to improve patient comfort in order to minimize eye rubbing. 4 Frequent use of preservative-free artificial tears and/or allergy medications as appropriate. Even if these measures are found not to be effective in halting the progression of keratoconus, they may help to make the keratoconus patient more comfortable. We are now at a point in our knowledge about keratoconus that it is reasonable to start looking for oral or topical treatments. This therapy would be aimed at restoring normal biochemical functions in keratoconus or preventing oxidative damage. Dr. Kenney is the Director of Laboratory Research in the Department of Ophthalmology at University of California, Irvine. This research is supported in part by the National Keratoconus Foundation. |
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| Autore: | F1cund14n [ mercoledì 23 febbraio 2005, 14:33 ] |
| Oggetto del messaggio: | |
Per chi vuole approfondire: Anomalie cromosomiche ( e trisomia 21): http://www.telethon.it/informagene/dett ... .asp?id=77 Problemi nel cromosoma 13: http://www.telethon.it/informagene/dett ... .asp?id=79 Psoriasi e cromosoma 17: http://www.bioagency.it/?sezione=news&s ... a=&page=22 |
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