[The pathogenesis of vitreoretinal diseases from the standpoint of molecular biology]

It is important to study the pathogenesis in vitreoretinal diseases to develop new medical therapy. We investigated the molecular mechanisms underlying the genesis of idiopathic macular hole, exudative age-related macular degeneration (AMD), and diabetic retinopathy. We observed high levels of chymase and tryptase activity in the vitreous humor of patients with idiopathic macular hole. This activity was significantly higher than in other vitreoretinal diseases. Immunohistochemical study using monkey eyes showed the possibility that Müller cells in foveal lesions have properties similar to retinal stem cells. Intravitreal injection of chymase induced apoptosis of foveal retinal cells and fibrous change of vitreoretinal interface in the macular area. Biochemical study using cultured human Müller cells revealed that chymase caused the inhibition of growth and the induction of apoptosis in dedifferentiated Müller cells treated with basic fibroblast growth factor (bFGF). These findings show that increased production of chymase and tryptase in mast cells could be related to the pathogenesis of idiopathic macular hole. Oxidative stress and arterosclerosis may be the major causes of exudative AMD. Paraoxonase (PON) is a polymorphic protein known to prevent oxidation of low-density lipoprotein (LDL). We analyzed PON genotypes and found that two types of polymorphism were significantly different between patients with AMD and control subjects. We also investigated serum oxidized low-density lipoprotein(oxLDL) levels, PON activity, and extracellular superoxide dismutase(EC-SOD) levels. All these factors were significantly higher in patients with AMD than in controls. Titers of IgA and IgG antibodies against chlamydia pneumoniae in the serum of AMD patients were also significantly higher than in controls. These results indicate that genetic factors related to PON polymorphisms, vascular damage caused by increment of serum oxLDL and malfunction of EC-SOD, and chronic inflammation provoked by clamydia pneumoniae infection may be involved in the pathogenesis of AMD. Excess accumulation of advanced glycation end products(AGEs) has a causative role in the development of diabetic complications. We determined the concentrations of three AGEs (pentosidine, carboxy-methyllysine, and crossline) and two cytokines (VEGF, IL-6) using ELISA. The levels of the three AGEs and two cytokines in the vitreous of patients with proliferative diabetic retinopathy(PDR) were significantly higher than in controls. The concentrations of VEGF and IL-6 were strongly correlated with the level of these AGEs. Cultured human Müller cells expressed both VEGF and IL-6 mRNA and these expressions were augmented after the treatment of AGEs, while also acting as photosensitizers and accelerating the degradation of hyaluronic acid in vitro. AGEs may consequently play an important role in the pathogenesis of diabetic retinopathy by inducing the production of VEGF and IL-6 in retinal Müller cells and the acceleration of vitreous liquefaction.