Cataract induced by UVR-B 300nm : Characterization and genetic modulation of the lens sensitivity to oxidative stress

Sammanfattning: Cataract is defined as an opacification of the lens resulting in visual impairment. Worldwide, it is the number one cause of blindness and there are currently no strategies to prevent the onset of the disease. Cataract surgery is the most commonly performed elective intervention in industrialized countries. The condition has thus major impact on national and international health care systems. Exposure to ultraviolet radiation (UVR) induces cataract in humans and animals. Both epidemiological and experimental evidence indicates maximum lens sensitivity to UVR-B with wavelengths around 300 nm. Until today, little is known how the genome modulates the lens sensitivity to oxidative stress from UVR. Although chromosomal linkage is observed among several mammals, the human and the laboratory mouse genomes are by far the most extensively characterized and compared. This study characterizes the C57BL/6 mouse as an in vivo cataract model for UVR-B induced oxidative damage. Presently, we characterized light scattering in the healthy C57BL/6 mouse and defined a tolerance limit for non-pathological light scattering in the mouse lens. In the second study, cataract evolution in the C57BL/6 mouse lens after in vivo exposure to UVR-B was investigated. We demonstrated that a dose of 5 kJ/m2 UVR-B is above cataract threshold and light scattering transiently peaks 2 days after UVR-B exposure. The third part of this study estimated the dose-dependent cataractogenesis and cataract threshold dose, expressed as Maximum Tolerable Dose (MTD2,3:16) for UVR-B induced cataract. In the fourth study, we were for the first time able to demonstrate that the absence of an anti-oxidative enzyme, Glutaredoxin 1, sensitizes the lens to oxidative damage from UVR-B exposure. Furthermore we derived the relative protection the Grx1 gene provides to UVR-B exposure to 45%. The last study, investigates if an inflammatory response could be involved in UVR-B induced cataractogenesis that affects also the non-exposed eye in a sympathetic reaction. We found indications that a systemic inflammation associated with raised serum levels of IL-1? and possibly IL-6 can be triggered by UVR-B exposure that induces cataract and an inflammatory infiltration also in the non-exposed eye. We conclude, the C57BL/6 mouse is a suitable model to study UVR-B induced cataract. Efficient study design is possible based on reasonable sample sizes. Similar to other species, the C57BL/6 mouse lens is sensitive to UVR-B-300nm. The type of cataract induced is mainly anterior subcapsular, but in individual cases also cortical and/or nuclear. Cataract threshold dose (MTD2,3:16) was estimated to 2.9kJ/m2. Importantly, deficiency of the Grx1 gene increases the lenticular sensitivity to in vivo UVR-B exposure. Thus Grx1 polymorphisms may cause a varying degree of lens sensitivity to oxidative stress in age-related cataract. Furthermore, inflammation is involved in UVR-B induced cataractogenesis. Age related cataract is almost exclusively a bilateral event. Since an inflammatory response might be an important factor in the pathogenesis of the disease this study could initiate new preventive and therapeutic strategies in cataract research.