Research progress on the mechanism of epithelial mesenchymal transformation in RPE cells and the treatment of PVR / 国际眼科杂志(Guoji Yanke Zazhi)

@#Proliferative vitreoretinopathy(PVR)is a serious complication arisen from ocular trauma, diabetic retinopathy, vascular retinopathy, inflammatory retinopathy and other ocular diseases. It is also the most important reason for the failure of rhegmatogenous retinal detachment surgery, which is a great threat of visual function. A large number of studies have proved that the main risk factor for PVR is the damage of blood-retinal barrier, in which retinal pigment epithelial(RPE)cells are stimulated by cytokines in the vitreous cavity. RPE cells underwent epithelial-mesenchymal transition(EMT), which transformed into fibroblasts. The cell morphology changed, the tight junctions between cells disappeared, the cell polarity lost, and the proliferation, migration, and invasion abilities were enhanced. A contractile fibrous proliferative membrane is formed on the anterior surface or under the retina. The fibrous proliferative membrane will lead to the retina folds, pull the retina and lead to retinal detachment, which will eventually lead to vision loss or even blindness. Nowadays, plenty of studies investigating the prevention and treatment of PVR have been carried out at home and abroad. In this review, we briefly illustrated the signaling pathways related to epithelial-mesenchymal transformation in RPE cells and the treatment of PVR.

The Effect of Retinoic Acid on Experimentally-Induced Proliferative Vitreoretinopathy in the Rabbit

The proliferative vitreoretinopathy was a complication followed by operation of rhegmatogenous retinal detachment. It was the mot, comon cause of a failure of retinal detachment surgery. It was characterized by the growth of cellular fibrous membrance in detached both retinal side and vitreous and also developed by giant retinal dialysis, posterior segmental trauma, excessive cryotherapy, endophthalmitis, retianl vascular disease. In order to prevent and treat of proliferative vitreoretinopathy, various methods of operation and drugs have been researched. We executed the experiment using the rabbit to observe the effect of retinoic acid that is known by inhibition of migration and proliferation of retinal pigment epithelial cell and fibroblast in vitro. With 121 eyes of rabbit, we induced the proliferative vitreoretinopathy by injecting of human retinal pigment epithelial cell, human fibroblast, and rabbit fibroblast into eyeball of rabbits. The extent of proliferative vitreoretinopathy was compaired by injecting those cells with the group that was injected by retinoic acid and control. The result was that in those cell groups, the extent of proliferative vitreoretinopathy was significantly higher in the rabbit fibroblast group than the other two groups(P<0.05). And in the groups that were injected retinoic acid, when subconjuctivaly injected(0.3mg/0.3ml), proliferative vitreoretinopathy was effectively suppressed and when intravitrealy injected (0.05mg/0.1ml), vitreoretinopathy was more increased than the control group. This result was probably caused by high concentration of retinoic acid in vitreous and further evaluation with various concentration of retinoic acid is needed. In conclusion, we recommend a rabbit fibroblast and subconjunctival injection of retinoic acid for the study on the suppressive effect of proliferative vitreoretinopathy.

The Experimental study of Injections of Cultured Fibroblasts into the Rabbit Vitreous

The major cause of failure of retinal detachment surgery is proliferative vitreoretinopathy(PVR). This disorder is characterized by the formation of the contractile cellular membrane on both surfaces of retina and within the vitreous cavity. These cellular membranes contract and thereby cause traction retinal detachment. The pathogenesis of this disorder is not fully understood. The authors developed a consistent model of proliferative vitreoretinopathy in the rabbit by partially digesting the post. Vitreous with repeated injection and aspiration of 1 IU of hyaluronidase before injection of 250,000 homologous dermal fibroblasts. All experimental rabbit eyes had vitreous opacity and hyperemia of the optic disc head. The progression of PVR was rapid and moderately severe. On day 1, 13 of 15 eyes(87%) had vitreous strand formation alone(Grade 1 PVR). One day 3, all 15 eyes(100%) had vitreous strand formation. We have developed a model of proliferative vitreoretinopathy in the rabbit. After intravitreal autotransplantation of tissue cultured homologous skin fibroblasts, we observed high rate of vitreous strand formation in the vitreous cavity. This experimental model will be useful for studying the pathogenesis of proliferative vitreoretinopathy and evaluating potential treatment for its prevention.

The Effect of Daunorubicin on Experimental Proliferative Vitreoretinopathy

Proliferative vitreoretinopathy (PVR) is a main cause of failure in retinal reattachment surgery. There have been many studies about the inhibition of proliferative vitreoretinophthy with several drugs. Authors investigated the inhibitory effect of proliferative vitreoretinopathy and retinal toxicity with various concentration of daunorubicin after intravitreal injection into the eyes of the pigmented rabbit. 7 pigment rabbit (11eyes) were used as subjects. After lensectomy and vitrectomy, control group was injected dermal fibroblast and F-BSS, and treatment group was injected dermal fibroblast and 5, 10, 15, 30 nmol Daunorubicin. At two weeks after intravitreal injection, both group were enucleated and examined with gross finding, light--microscopy, and electronmicroscopy. In all control group, proliferative vitreoretinopathy was found, but only preretinal membrane formation was found in 5, 10 nmol Daunorubicin injected group. In 15 nmol Daunorubicin injected group, the retina structure was preserved normally. In 30 nmol Daunorubicin injected group, the retinal outer segment was degenerated in microscopic finding. These results show that Daunorubicin has a potent effect on proliferative vitreoretinopathy, especially in 15 nmol, but retinal toxicity is suspected in marethan 30 nmol.

The effect of subtenon injection of methylprednisolone acetate on the breakdown of blood retinal barrier after cryotherapy

Using computerized vitreous fluorophotometry (VFP, Fluorotron(TM)), we examined the effect of cryotherapy on the blood retinal barrier (BRB) and the effect of subtenon injection of methylprednisolone acetate (Depomedrol(R)). In experiment 1, the right eyes of the 13 pigmented rabbits were treated with heavy cryotherapy after baseline VFP readings. The freezes were applied at 6 places in each quadrant around the equator are in two rows, a total of 24 places circumferentially. The left eyes were reserved as controls. In 6 rabbits (cryo with steroid group), Depomedrol(R) 10 mg of Depomedrol was injected into subtenon space after cryotherapy. The other 7 rabbits were treated with cryotherapy only (cryo only group). The VFP readings were taken 1, 3, 5, and 7 days, 2, 3, 5, and 7 weeks after cryotherapy. Cryotherapy increased the breakdown of BRB significantly. The peak VFP readings were obtained 5 days after cryotherapy in the cryo only group and 7 days after cryotherapy in the cryo with steroid group. In the cryo only group, the severity of the breakdown of BRB was higher than in the cryo with steroid group, and the increased VFP readings could not be normalized until 7 weeks after cryotherapy. In experiment 2, both eyes of the 8 pigmented rabbits were treated with medium cryotherapy after baseline VFP readings. The freezes were applied at 3 places in the superior temporal quadrant and at 3 places in the superior nasal quadrant, a total of 6 places. Depomedrol(R) 10 mg was injected into subtenon space after cryotherapy in the right eyes only. The VFP readings were taken 1, 3, 5, 7, 10, and 14 days after cryotherapy. In this experiment, cryotherapy did not increase the breakdown of BRB. But in the right eye, the severity of the breakdown of BRB was significantly lower than in the left eye 7 and 10 days after cryotherapy. These results suggest that Depomedrol(R) can decrease the severity of the breakdown of BRB after cryotherapy, and may be useful in the prevention of proliferative vitreoretinopathy (PVR).

Effect of Intravitreal Silicone Oil and Gas Tamponade to Proliferative Vitreoretinopathy(PVR)

Silicone oil is widely used as a retinal tamponade in the treatment of PVR. But reproliferation of membrane can occur under the silicone oil. Formerly, silicone oil was believed to suppress the proliferation of membrane, but recently, there were reports that silicone oil might actually promote proliferation of membrane, and recommended to use long-lasting gas rather than silicone oil. But it is known that proliferation of membrane can also occur in the eye in which intraocular gas has been used. So a careful study to compare the effect of intraocular gas and silicone oil to proliferation of membrane is needed. Rabbits are divided into three groups. Retinal tears were made in all the groups. in control group, no further surgery was done, and in the other two group, perfluoropropane gas was injected into the vitreous cavity. The intraocular gas was left unchanged(gas group), or it was exchanged with silicone oil 3 days later(silicone oil group). The fundus was examined periodically, and the eyeball was removed at 1, 2, 4, and 8 weeks after surgery for histopathologic study with light and electron microscope. Both intravitreal gas and silicone oil were shown to increase the formation of proliferative membrane compared to control group, but there was no statistically significant difference between them.

Effect of Cryotherapy on Proliferative Vitreoretinopathy(PVR)

Cryotherapy is blamed for inducing or aggravating PVR, by releasing retinal pigment epithelial(RPE) cells. These are based on the fact that PVR rarely occurs in non-operated eye, and many of PVR patients have received cryotherapy during surgery. Nontheless, in eyes with diathermy also developed PVR, and although there have been many experiments, the effect of cryotherapy on inducing PVR was not proven experimentally in the living eye. We made retinal tears in the living rabbit eyes, and applied cryotherapy on one eye of each rabbit. The result was compared histopathologically with noncryothermized control eye. There was no statistically significant difference between the two groups concerning the migration of RPE, and the proliferation of RPE. Although the formation of epiretinal membrane was more obvious in the cryothermized group, the difference was not statistically significant.

The effect of cryotherapy on proliferative vitreoretinopathy (PVR)

Cryotherapy is implicated for inducing or aggravating proliferative vitreoretinopathy (PVR) by releasing retinal pigment epithelial (RPE) cells. These are based on the fact that PVR rarely occurs in a non-operated eye, and many of the PVR patients have received cryotherapy during surgery. Nonetheless, eyes with diathermy also developed PVR, and although there have been many experiments, the effect of cryotherapy on inducing PVR has not been proven experimentally in the living eye. We made retinal tears in living rabbit eyes, and applied cryotherapy on one eye of each rabbit. The result was compared histologically with the contralateral noncryothermized control eye. There was no statistically significant difference between the two groups concerning the migration of RPE, and the proliferation of RPE. Although the formation of an epiretinal membrane was more obvious in the cryothermized group, the difference was not statistically significant.