The PI3K/Akt pathway mediates the expression of type I collagen induced by TGF-ß2 in human retinal pigment epithelial cells.

PURPOSE: Transforming growth factor (TGF)-ß is a key mediator of proliferative vitreoretinopathy, but the cellular mechanisms by which TGF-ß induces extracellular matrix protein (ECM) synthesis are not fully understood. This study examined whether the PI3K/Akt pathway is involved in TGF-ß2-induced collagen expression in human retinal pigment epithelial cells. METHODS: Human retinal pigment epithelial cells ARPE-19 were cultured and stimulated with TGF-ß2. The role of the PI3K/Akt pathway was evaluated using the biochemical inhibitor, wortmannin. The effect of wortmannin on the expression of type I collagen mRNA (COL1A1, COL1A2) induced by TGF-ß2 was evaluated by real-time RT-PCR. The effect of wortmannin on the synthesis of type I collagen induced by TGF-ß2 was assessed by an immunocytochemical analysis with anti-type I collagen antibody. Luciferase reporter assays were performed to examine the effect of wortmannin on the transcriptional activities of COL1A2. A luciferase assay using a mutation construct of the Smad binding site in COL1A2 promoter (Smad-mut/Luc) was also performed to examine the crosstalk between the Smad pathway and the PI3K/Akt pathway. The effects of wortmannin on the transcriptional activity of Smad3 were also examined using CAGA12-Luc. Moreover, the effect of wortmannin on TGF-ß2-induced Smad7 mRNA expression was evaluated. RESULTS: The biochemical blockade of PI3K/Akt activation inhibited TGF-ß2-induced type I collagen mRNA expression and type I collagen synthesis. The blockade of PI3K/Akt pathway inhibited the increase in COL1A2 promoter activities when induced by TGF-ß2 and reduced TGF-ß2 induction of Smad-mut/Luc promoter activity and CAGA12-Luc activity. Moreover, wortmannin increased the TGF-ß2-induced Smad7 mRNA expression levels. CONCLUSIONS: The PI3K/Akt pathway plays a role in relaying the TGF-ß2 signal to induce type I collagen synthesis in the retinal pigment epithelium through Smad-dependent and Smad-independent pathways.

Stiles-Crawford effect in focal macular ERGs from macaque monkey.

BACKGROUND: To determine whether the focal macular electroretinograms (FMERGs) are affected by the angle of incidence of the stimulating light on the retina, i.e., the Stiles-Crawford effect (SCE). METHODS: FMERGs were elicited by focal stimulation of the macula in three light-adapted macaque monkeys. The incidence of the light on the retina was varied from 0 to ±11.7°. The effects of the incidence and wavelengths of the stimulus on the SCE were determined. RESULTS: The amplitudes of the FMERG components were largest when the stimulus beam entered the eye on the visual axis and passed through the center of the pupil. The amplitudes gradually decreased as the stimulus beam passed through the pupil more eccentrically and fell on the retina more obliquely. All components of the FMERGs were decreased with the decrease least for the amplitude of the d-wave. CONCLUSIONS: The decrease in the amplitudes of the FMERGs as the angle of incidence of the stimulus beam on the retina increases demonstrates that the SCE can be detected in adult macaque monkeys. This objective method of assessing the SCE suggests that this technique can be used to assess the alignment of cones in humans with different types of macular diseases.

Optical coherence tomographic assessment of dynamic macular changes in patients with Vogt-Koyanagi-Harada disease.

To determine the relationship between visual acuity and three-dimensional optical coherence tomographic (3D-OCT) findings of the macula in eyes with Vogt-Koyanagi-Harada (VKH) disease. Twelve eyes of six patients (three men and three woman, average age 53.2 years) in the acute phase of VKH disease were examined with a 3D-OCT instrument. All of the eyes had a serous macular detachment. The height of the sensory retinal detachment (SRD) and the sensory retinal thickness (SRT) were measured by OCT before treatment (acute stage) and at the convalescent stage. The correlation between the retinal morphology and visual acuity was evaluated. The height of the SRD and the SRT were 612.5 ± 371.2 and 136. 7 ± 22.0 µm, respectively. The initial visual acuity was significantly worse in eyes with a higher SRD (P = 0.014, r = 0.68) but the correlation between initial visual acuity and SRT was not significant. The recovery of visual acuity was attained in 50.7 ± 44.1 days and the complete resolution of the SRD was attained in 30.5 ± 23.2 days. The final visual acuity was attained several days after the complete resolution of the SRD in all four eyes of patients over 60 years of age, but the recovery of visual acuity often preceded the complete resolution of the SRD. The OCT images provided a noninvasive indicator of the severity of the disease and dynamic changes in the macular morphology, reflecting the effect of treatment in association with the improvement in visual acuity. Monitoring the SRD by 3D-OCT may guide the tapering of systemic corticosteroid treatment.

Photopic negative response reflects severity of ocular circulatory damage after central retinal artery occlusion.

PURPOSE: To determine the relationship of the photopic negative response (PhNR) of the photopic electroretinogram (ERG) with the degree of circulatory disturbances in eyes following central retinal artery occlusion (CRAO). METHODS: The circulatory disturbance was graded as mild (group 1) when the arm-to-retina transmission time was <30 s, moderate (group 2) when the time was >30 s and severe (group 3) when concurrent choroidal circulatory damage was found. For statistical analysis, groups 1, 2 and 3 were scored as 1, 2 and 3, respectively. Photopic ERGs were elicited by either short-flash (SF) or long-flash (LF) stimuli. RESULTS: Both the SF and LF PhNR were significantly reduced in groups 2 and 3. The PhNR amplitude was negatively correlated with the severity of the ocular circulatory disturbances (p = 0.0498, rho = -0.507 for SF PhNR; p = 0.0050, rho = -0.750 for LF PhNR). CONCLUSION: The amplitude of the PhNR became more reduced as the severity of the circulatory disturbances increased in eyes with CRAO.

[Heidelberg Retina Tomograph II topographic parameters, diagnostic capabilities of moorfields regression analysis, and their affecting factors].

PURPOSE: To investigate optic disc topographic parameters at every stage in glaucoma patients and to compare results with data from normal Japanese subjects. We used a Heidelberg Retina Tomograph II (HRT II), to evaluate the sector diagnostic capabilities of Moorfields regression analysis in early glaucoma patients, and to determine whether there is a correlation between the background factors and either the topographic parameters or the diagnostic capabilities. SUBJECTS AND METHODS: We measured topographic parameters using HRT II, and examined static visual fields in 303 normal and 130 glaucoma eyes without high refractive error. RESULTS: Mean disc area was 2.181 +/- 0.384 mm2 in the normal Japanese subjects. At the time visual field loss first appeared, disc damage was already advanced. Moorfields regression analysis of sensitivity and specificity was 81.3% and 90.1%, respectively, for early glaucoma. The best diagnostic precision was found in the temporal/inferior sector. Correlations were noted for normal subject topographic parameters and the disc area, age, sex, and conus, but not for Moorfields regression analysis and the disc area, refractive error, age, and sex, even though diagnostic capabilities declined with the presence of conus. CONCLUSIONS: HRT II is more useful in glaucoma diagnosis than in follow-up. Focus should be on the temporal/inferior sector as well as on the overall Moorfields regression analysis. Also, close attention should be paid to the presence of conus.

p38 MAPK mediates the expression of type I collagen induced by TGF-beta 2 in human retinal pigment epithelial cells ARPE-19.

PURPOSE: Transforming growth factor (TGF)-beta has been implicated as the key mediator of proliferative vitreoretinopathy, but the cellular mechanisms by which TGF-beta induces extracellular matrix protein (ECM) synthesis are not fully understood. The current study was conducted to examine whether the mitogen-activated protein kinase (MAPK) pathway is involved in TGF-beta 2-induced collagen expression in retinal pigment epithelial cells. METHODS: Human retinal pigment epithelial cells ARPE-19 were cultured and stimulated with various concentrations of TGF-beta 2. The type I collagen gene (COL1A1, COL1A2) expression induced by TGF-beta 2 was evaluated by real-time RT-PCR. Synthesis of type I collagen was evaluated by the concentration of the C-terminal propeptide of type I (PICP) in the medium. The activation of MAPK pathways by TGF-beta 2 was assessed by immunoblot with anti-phospho-p38 and anti-phospho-extracellular signal-regulated kinase (ERK)1/2 antibodies. The role of MAPK was assessed using biochemical inhibitors. To examine the transcriptional activities of COL1A1 and COL1A2, luciferase reporter assays were also performed. RESULTS: mRNA expression of COL1A1 and COL1A2 and type I collagen synthesis were activated by TGF-beta 2. Both ERK and p38 MAPK pathways were also activated by TGF-beta 2. The biochemical blockade of p38 MAPK activation, but not ERK activation, inhibited TGF-beta 2-induced type I collagen mRNA expression and type I collagen synthesis. Moreover, blockade of the p38 MAPK pathway inhibited the increase in both COL1A1 and COL1A2 promoter activities when induced by TGF-beta 2. CONCLUSIONS: TGF-beta 2 activates p38 MAPK and p38 MAPK plays a role in relaying the TGF-beta 2 signal to type I collagen production in the retinal pigment epithelium.

Pharmacokinetic and pharmacodynamic differences between ocular and nasal instillation of carteolol on intraocular pressure and heart rate in Japanese men with high CYP2D6 activity.

Sublingual administration of carteolol or instillation into one eye reduces intraocular pressure (IOP) in both eyes. This suggests that carteolol absorbed systemically can reduce IOP and that the extra-ophthalmic route (e.g., the nasal route) can be an alternative method of drug administration. The authors compared the differences between ocular and nasal instillation relating to the pharmacokinetic and pharmacodynamic effects of a carteolol-ophthalmic solution on IOP and heart rate (HR) in a randomized, double-blind, crossover, placebo-controlled design in 11 healthyyoung extensive metabolizers for CYP2D6. The tmax, Cmax, and AUC0-t of carteolol (0.8 mg) instilled into the nostril were significantly higher than those into the eye (p < 0.05): tmax (h) = 0.25 (0.17-5.0),1.0 (0.17-5.0) (median value with range in the parenthesis, ocular vs. nasal); Cmax (ng/ml) = 1.33 +/- 1.57, 2.29 +/- 2.09; and AUC0-t (ng x h/ml) = 9.36 +/- 2.04, 21.13 +/- 1.58 (geometric mean +/- SD, ocular vs. nasal). The reduction of IOP after ocular instillation persisted significantly longer than that of nasal instillation (p < 0.05). The HR was significantly reduced after both ocular and nasal instillation (p < 0.05), although there were no significant differences between them. In conclusion, ocular instillation of a carteolol-ophthalmic solution has advantages over nasal instillation in controlling IOP and the potential to decrease adverse reactions due to lower plasma concentrations.

Rod-driven focal macular electroretinogram.

PURPOSE: To determine the stimulus conditions required to elicit rod-driven, focal macular electroretinograms (rod FMERGs). METHODS: A blue (lambda(max)=470 nm) stimulus, 5 degrees in size, was imaged at a luminance of 1.5 cd/m(2) on different regions of the human retina. Electroretinograms (ERGs) elicited by this stimulus were recorded from the light- and dark-adapted retina of four subjects without any ophthalmological abnormalities. A subject with cone dystrophy was also tested by this method. RESULTS: Stimulus luminance <==1.5 cd/m(2) did not elicit a response when it was imaged on the optic disc, but higher intensities elicited a small b-wave from stray light. When this stimulus was imaged on the macular area or the 15 degrees temporal retina, an ERG was elicited that had the shape of the full-field scotopic ERG. This stimulus with a luminance of 1.5 cd/m(2) did not elicit a response from stimulation of the macular area of a light-adapted retina but elicited a slow-rising positive b-wave after 30 minutes of dark adaptation. In a subject with cone dystrophy, focal rod response was elicited from the macula, despite no response under photopic conditions. CONCLUSION: We conclude that this stimulus will elicit a response that is derived exclusively from rods and is a focal response with no contribution from stray light.

High correlation of scotopic and photopic electroretinogram components with severity of central retinal artery occlusion.

PURPOSE: The aim of this study was to determine whether a significant correlation exists between the scotopic and photopic components of electroretinograms (ERGs) and the degree of circulation disturbances caused by a central retinal artery occlusion (CRAO). DESIGN: Observational clinical study. PARTICIPANTS: Sixteen patients with a CRAO (16 eyes). METHODS: The circulatory disturbance in eyes with CRAO was graded as mild (group 1) when the arm-to-retina transmission time was <30 sec and severe (group 2) when the arm-to-retina transmission time was ≥30 sec. Scotopic and photopic ERG components in eyes with CRAO were compared with those in healthy fellow eyes with respect to the degree of circulation disturbance. RESULTS: The scotopic and photopic b-waves were significantly reduced only in group 2, whereas the amplitudes of the photopic negative response (PhNR) of the photopic cone ERGs were significantly reduced in both groups. The amplitudes of each ERG component, except for the a-wave of the mixed rod-cone ERG, were significantly smaller in group 2 than in group 1. CONCLUSIONS: The PhNR was reduced even in group 1 with minimal circulatory disturbance and thus may be a good functional indicator.

Unusual protrusion of conjunctiva in two neonates with harlequin ichthyosis.

BACKGROUND: We present two patients who developed severe protrusion of the conjunctiva and chemosis secondary to Harlequin ichthyosis (HI). CASE REPORTS: Case 1 was a male infant diagnosed with HI who had parchment-like appearance and conjunctival protrusion with severe chemosis. Case 2 was a female infant on whom HI had been suspected before birth through ultrasonography. She showed thickened skin over the entire body and conjunctival protrusion with severe chemosis. For both cases, a vitamin A derivative was applied and the hyperkeratotic layer was peeled off every day. Great care was taken to sterilize and moisten the ocular surface. The conjunctival protrusion gradually improved and other systemic conditions were successfully treated. HI is a rare condition, but affected infants are surviving longer than previously and hence guidelines for ocular management are now required. CONCLUSIONS: Gentle and patient debridement of the hyperkeratotic skin and moisturizing were important in treating the unusual conjunctival protrusion.

Two Cases of Endogenous Endophthalmitis Caused by Gram-Positive Bacteria with Good Visual Outcome.

BACKGROUND: Endogenous endophthalmitis is a rare disease and its visual prognosis is poor. CASE REPORTS: We present two patients, a 60-year-old man and a 53-year-old man, who developed endogenous endophthalmitis caused by Gram-positive organisms but recovered good vision after antibiotics and vitrectomy. RESULTS: The first patient complained of ocular pain and visual decrease in his right eye. Ophthalmoscopy showed inflammation in the anterior chamber and vitreous opacities. Antibiotic was administrated systemically, and blood culture detected Streptococcus anginosus. He underwent successful heart surgery for endocarditis and total dental extraction for severe gingivitis. Vitrectomy was performed 36 days after the onset and vision improved from 0.02 to 0.7. The second patient was referred for acute visual decrease in his left eye. Severe iritis and vitreous opacities were observed, and systemic examination showed acute pyelitis and prostatic abscesses. Blood cultures detected Staphylococcus sp., and systemic antibiotics were given. Vitrectomy was performed 12 days after the onset, and vision improved from 0.06 to 1.2. CONCLUSIONS: We conclude that the rapid treatment with systemic antibiotics for the organisms at the primary site, and the vitrectomy, even though delayed, can lead to a good recovery of vision.

Cystoid Macular Edema: Possible Complication of Infliximab Therapy in Behçet's Disease.

AIM: Infliximab, an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, has been reported to be effective in refractory uveoretinitis in Behçet's disease. Because it has been used clinically for a short time, information on its adverse effects is limited. We report a patient who developed cystoid macular edema (CME) following infliximab use for uveoretinitis associated with Behçet's disease. Case Report: A 27-year-old man had refractory uveoretinitis and neuro-Behçet's disease, and intravenous infliximab was administered. RESULTS: One day after infliximab infusion, the patient complained of a decrease in the vision in his left eye. The visual acuity had decreased from 1.2 to 0.5. Daily optical coherence tomographic evaluations showed a progressive worsening of the CME, and fluorescein angiography showed a typical staining with a cystic pattern. Two weeks later, the height of CME appeared to reach a maximum level and thereafter gradually resolved in spite of the continuation of infliximab administration. The visual acuity improved while the patient was treated with repeated subtenon injections of steroids in addition to continuation of infliximab and finally increased from 0.15 to 1.2. CONCLUSIONS: Although the mechanism of CME is not known, clinicians should be aware that infliximab therapy might cause a development and worsening of CME. Thus, it is crucial to rule out preexisting abnormalities in the macula prior to commencing infliximab infusion.

Functional and morphological evaluation of purtscher retinopathy.

PURPOSE: To determine the extent of retinal damage in Purtscher retinopathy (PR). METHODS: A longitudinal analysis of the retinal morphology and function was made by optical coherence tomography and electroretinography, respectively, on a patient with unilateral PR. RESULTS: Optical coherence tomography showed a marked thickening of the inner retinal layers in the acute phase and a thinning of the inner retinal layers and alteration of the outer layers in the chronic phase. The site of these changes corresponded with the cotton-wool patches. The results of electroretinography indicated reduced inner layer function in the acute phase and partial recovery in the chronic phase. CONCLUSION: The inner and outer retinal layers are altered morphologically and functionally in eyes with PR. The dynamic evaluation on retinal morphology and function may be useful in understanding the pathophysiology of PR.

Analysis of p53 mutations and the expression of p53 and p21WAF1/CIP1 protein in 15 cases of sebaceous carcinoma of the eyelid.

PURPOSE: The purpose of this study was to detect mutation of the p53 gene, to assess its relationship with p53 or p21(WAF1/CIP1) expression, and to evaluate the correlation between p53 mutation or p21(WAF1/CIP1) expression and clinicopathologic findings in sebaceous carcinoma of the eyelid. METHODS: Fifteen conventional paraffin-embedded samples of sebaceous carcinoma of the eyelid were analyzed. Using the single-strand conformation polymorphism technique, the authors sequenced coding exons 5-8 of the p53 gene. The expression of p53 and p21(WAF1/CIP1) protein was analyzed by immunohistochemistry. RESULTS: In 10 of the 15 cases (66.7%), point mutations were detected in the p53 gene. CC to TT double-base changes (tandem mutations), which are known to be induced only by UV, were not detected in any of the mutations. Correlations between p53 mutation and expression were found to be statistically significant (P = 0.007). There was no significant correlation between p53 mutation and clinicopathologic findings or p21(WAF1/CIP1) expression. However, there was a significant inverse correlation between p21(WAF1/CIP1) expression and presence of lymph node metastasis (P = 0.007). CONCLUSIONS: Among human cancers, sebaceous carcinoma of the eyelid may be one of those showing most frequent mutation of the p53 gene, which may not be caused by exposure to UV. p21(WAF1/CIP1) downregulation may be associated with lymph node metastasis.

Optical coherence tomographic evaluation of the outer retinal architecture in Oguchi disease.

BACKGROUND: To report the changes in the optical coherence tomography (OCT) images of the outer retinal layers after prolonged dark adaptation in a patient with Oguchi disease. CASE: A 75-year-old woman showed the typical golden-yellow fundus reflex of Oguchi disease, and the coloration returned to normal after prolonged dark adaptation. Fourier domain OCT (FD-OCT) was performed on the patient's left eye before and after prolonged dark adaptation. OBSERVATIONS: Before dark adaptation, the FD-OCT images at the fovea had three identifiable reflection bands, namely, the external limiting membrane (ELM), the border between the photoreceptor inner and outer segments (IS/OS line), and the retinal pigment epithelium (RPE)/Bruch band. The paramacular area had only the ELM and RPE/Bruch bands. After 4 h of dark adaptation, the IS/OS line was also detected in the paramacular area. CONCLUSIONS: The absence of the IS/OS line in the extramacular regions in the partly dark adapted condition was most likely due to a defect in the rod photoreceptors of this area. The emergence of the IS/OS line after prolonged dark adaptation suggests that microarchitectural changes occur in the photoreceptors and that the changes may be correlated with the improvement of rod function.

Changes in retinal thickness are correlated with alterations of electroretinogram in eyes with central retinal artery occlusion.

BACKGROUND: We investigated the relationship between the retinal thickness and electroretinogram (ERG) components in patients with central retinal artery occlusion (CRAO). METHODS: The optical coherence tomographic (OCT) images and ERGs of the nine patients (six men and three women; mean age, 61.8 years) were retrospectively analyzed. The thickness of the inner and outer retinal layers at 1 and 2 mm nasal and temporal to the fovea was measured in the horizontally scanned OCT images. The ratio of the inner layer thickness/sensory retinal thickness (IT/ST ratio) was calculated. The amplitudes of the a- and b-waves of the mixed rod-cone ERGs and the photopic negative response (PhNR) of the photopic ERGs were analyzed. The ratio of the amplitude of each component in the affected eye to that of the healthy fellow eye (a/f ratio) was calculated. RESULTS: In the chronic phase (1 to 8 months after onset, eight eyes), the inner layer was significantly thinner than that in the acute phase (P = 0.0147, 0.0076, 0.002, and 0.0003 for 2 mm nasal, 1 mm nasal, 1 mm temporal, and 2 mm temporal respectively, within 5 days of onset, six eyes), while the thickness of outer layer was not significantly changed. The ERGs were recorded 6.4 +/- 1.5 days after the onset of CRAO. The median of the a/f ratio was 0.84 in the a-wave, 0.56 in the b-wave, and 0.27 in the PhNR. The IT/ST in the chronic phase was positively correlated with the a/f ratio of the amplitude of the PhNR. CONCLUSIONS: Measurement of retinal thickness by OCT can be useful for monitoring the changes following CRAO. The correlation between the retinal thickness, especially inner layer thickness, and the ERG components was determined, suggesting that the PhNR in the acute phase might be a good indicator for predicting the thinning of the damaged retina in the chronic phase.

Severe acute ocular ischemia associated with spontaneous internal carotid artery dissection.

A healthy 40-year-old man developed unilateral ocular ischemic syndrome as the only manifestation of a spontaneous internal carotid artery dissection.

Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGF-beta2 in human retinal pigment epithelial cells.

Proliferative vitreoretinopathy (PVR) is a major cause of the failure of rhegmatogenous retinal detachment surgery. The pathogenesis of PVR includes a fibrotic reaction of retinal pigment epithelial (RPE) cells caused by transforming growth factor (TGF)-beta. The cellular mechanisms by which TGF-beta induces extracellular matrix protein synthesis are not fully understood. In this study, we examined whether the RhoA/Rho-kinase pathway was involved in TGF-beta2-induced collagen expression in a human RPE cell line, ARPE-19. The roles of RhoA and Rho-kinase were evaluated using biochemical inhibitors, RhoA inhibitor, simvastatin and Rho-kinase inhibitor, Y27632. The effects of simvastatin or Y27632 on the type I collagen mRNA (COL1A1 and COL1A2) expression induced by TGF-beta2 were evaluated by real-time RT-PCR. The effects of simvastatin or Y27632 on type I collagen synthesis induced by TGF-beta2 were assessed by immunocytochemical analysis with anti-type I collagen antibody. To examine the effects of simvastatin or Y27632 on COL1A2 promoter activity induced by TGF-beta2, luciferase reporter assays were also performed. Moreover, the role of RhoA itself on COL1A2 promoter activity was assessed using the constructs of constitutively active RhoA and dominant-negative RhoA. RhoA was activated within 5 min after stimulation with TGF-beta2, and its activation persisted for as long as 1 h in a dose-dependent fashion. Preincubation of ARPE-19 with simvastatin (5 microM) or Y27632 (10 microM) significantly prevented TGF-beta2-induced COL1A1 and COL1A2 gene expression. Inhibition of RhoA/Rho-kinase markedly suppressed TGF-beta2-induced type I collagen synthesis in ARPE-19. Moreover, the blockage of RhoA/Rho-kinase inhibited the increase in COL1A2 promoter activity when induced by TGF-beta2. Constitutively active RhoA increased COL1A2 promoter activity in the presence or absence of TGF-beta2. Simvastatin and Y27632 reduced active RhoA-induced COL1A2 promoter activity. The dominant-negative RhoA inhibited COL1A2 promoter activity augmentation induced by TGF-beta2. In the luciferase assay using a mutation construct of the Smad binding site in COL1A2 promoter (Smad-mut/Luc), the treatment with simvastatin and Y27632 significantly reduced TGF-beta2 induction of Smad-mut/Luc promoter activity. On the other hand, both simvastatin and Y27632 significantly reduced CAGA12-Luc activity induced by TGF-beta2. These results indicate that the RhoA/Rho-kinase pathway plays a role in relaying TGF-beta2 signal transduction to type I collagen synthesis in RPE cells in a Smad-dependent and Smad-independent fashion. The RhoA/Rho-kinase pathway may be a therapeutic target for treating PVR.