Elevated Cytokine Levels in the Aqueous Humor of Eyes With Bullous Keratopathy and Low Endothelial Cell Density

Yamaguchi, Takefumi; Higa, Kazunari; Suzuki, Terumasa; Nakayama, Naohiko; Yagi-Yaguchi, Yukari; Doğru, Murat; Satake, Yoshiyuki; Shimazaki, Jun

doi:10.1167/iovs.16-20187

Cited by 52 publications

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“…38,39 We reported an elevation of inflammatory cytokines in eyes with bullous keratopathy. 20 Moreover, the iris damage was associated with the elevation of aqueous cytokine levels. 21 However, these recent reports were cross-sectional studies and the elevated cytokine levels might just be the results, not the cause, of endothelial cell loss.…”

Section: Discussionmentioning

confidence: 99%

“…ICAM-1 mediates the recruitment of immune cells to sites of inflammation, 44 and its soluble form, sICAM-1 has been shown to be increased in the AqH of patients with bullous keratopathy. 20,45 Richer et al 44 reported strong correlations between sICAM-1 and soluble apoptotic factors, such as soluble Fas and Fas ligand in rhegmatogenous retinal detachment. Recently, Dohlman et al 46 found that blockade of Eselectin suppressed graft rejection in murine corneal transplantation model, whereas both levels of E-selectin and Pselectin were upregulated in the rejected graft.…”

Section: Discussionmentioning

confidence: 99%

“…This may be attributable to the limited number of subjects with glaucoma in the present study, because the aqueous levels of IL-1a, IL-4, IL-8, IL-10, IFN-c, and MCP-1 elevate in eyes after trabeculectomy. 20,36 Further studies are necessary to elucidate the exact mechanism of endothelial cell loss after corneal transplantation, using proteomics analysis of the aqueous humor to specify the alteration of the aqueous environment.…”

Section: Discussionmentioning

confidence: 99%

“…20 In brief, bovine serum albumin (BSA) was used as a standard in the range of 0.23 to 1.37 mg/mL. Samples (5 lL) of BSA and AqH were added to 96-well microplates, followed by immediate addition of a mixture containing 25 lL reagent A and 200 lL reagent C. After 15 minutes of incubation at room temperature in the dark, the microplates were read at 690 and 405 nm using a microplate reader (Model 550; Bio-Rad).…”

Section: Protein and Cytokine Level Measurementsmentioning

confidence: 99%

“…[15][16][17][18] In an in vitro study, a combination of proinflammatory cytokines synergistically induced the apoptosis of corneal endothelial cells. 19 We recently showed that inflammatory cytokine levels were elevated in the AqH of eyes with bullous keratopathy and reduced ECDs, 20 and that iris damage was associated with an elevation in aqueous cytokine levels. 21 Collectively, these results suggest that inflammatory factors in the AqH directly influence endothelial cell loss.…”

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Preoperative Aqueous Cytokine Levels are Associated With Endothelial Cell Loss After Descemet's Stripping Automated Endothelial Keratoplasty

Yazu

Yamaguchi

Aketa

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Citation: Yazu H, Yamaguchi T, Aketa N, et al. Preoperative aqueous cytokine levels are associated with endothelial cell loss after Descemet's stripping automated endothelial keratoplasty. Invest Ophthalmol Vis Sci. 2018;59:612-620. https://doi.org/ 10.1167/iovs.17-23049 PURPOSE. To evaluate the association between endothelial cell density (ECD) after Descemet's stripping automated endothelial keratoplasty (DSAEK) and preoperative cytokine levels in the aqueous humor (AqH).METHODS. This prospective consecutive case series included 97 consecutive patients who underwent DSAEK (64 eyes) or cataract surgery (33 eyes). AqH samples were collected at the beginning of each surgery. The levels of cytokines (IL-1a, IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFN-a, IFN-c, monocyte chemotactic protein [MCP]-1, E-selectin, P-selectin, and soluble intercellular adhesion molecule [sICAM]-1) in the AqH were measured by multiplex beads immunoassay. The correlations between preoperative aqueous cytokine levels and the ECD at 12 months after DSAEK were analyzed.RESULTS. The ECD decreased from 2747 6 259 cells/mm 2 in the donor graft to 1235 6 607 cells/mm 2 at 12 months after DSAEK. In all subjects undergoing DSAEK, the postoperative ECD at 12 months was significantly correlated with the preoperative levels of MCP-1 (r ¼ À0.467, 95% confidence interval [CI]: À0.650 to À0.222, P ¼ 0.0003). In an analysis excluding Fuchs endothelial corneal dystrophy (11 eyes), the ECD at 12 months after DSAEK was significantly correlated with preoperative levels of IL-17A (r ¼ À0.635, 95% CI: À0.819 to À0.319, P ¼ 0.0004), MCP-1 (r ¼ À0.605, 95% CI: À0.779 to À0.345, P < 0.0001), IFN-c (r ¼ À0.633, 95% CI: À0.796 to À0.385, P < 0.0001), E-selectin (r ¼ À0.516, 95% CI: À0.756 to À0.276, P ¼ 0.0004), and sICAM-1 (r ¼ À0.537, 95% CI: À0.735 to À0.253, P ¼ 0.0005).CONCLUSIONS. Higher preoperative levels of IL-17A, MCP-1, IFN-c, E-selectin, and sICAM-1 in the AqH were associated with lower ECD after DSAEK for bullous keratopathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Protein and Cytokine Level Measurementsmentioning

confidence: 99%

mentioning

confidence: 99%

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Preoperative Aqueous Cytokine Levels are Associated With Endothelial Cell Loss After Descemet's Stripping Automated Endothelial Keratoplasty

Yazu

Yamaguchi

Aketa

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Association of α-Melanocyte–Stimulating Hormone With Corneal Endothelial Cell Survival During Oxidative Stress and Inflammation-Induced Cell Loss in Donor Tissue

et al. 2020

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cell (CEnC) damage and loss are major issues in eye banking and transplantation. The underlying mechanisms for CEnC loss are incompletely understood, and cytoprotective strategies that enhance CEnC viability could have a major effect on donor tissue quality and graft survival.OBJECTIVE To investigate the cytoprotective role of neuropeptide α-melanocyte-stimulating hormone (α-MSH) in preventing CEnC loss in eye bank cold-stored corneas under oxidative and inflammatory cytokine-induced stress. DESIGN, SETTING, AND PARTICIPANTS This single-center comparative research study conducted ex vivo experiments using 16 pairs of research-grade human donor corneas (courtesy of Eversight Eye Bank). Data were collected from June 2018 to November 2019, and data were analyzed from December 2019 to January 2020.EXPOSURES Two corneas from the same donor were randomized to either control or 0.1 mmol/L of α-MSH treatment and then subjected to oxidative stress (1.4 mmol/L of hydrogen peroxide-phosphate-buffered saline for 15 minutes at 37 °C; n = 8 pairs) or cytokine-induced stress (100 ng/mL of tumor necrosis factor-α and 100 ng/mL of interferon γ for 18 hours at 37 °C; n = 8 pairs). Corneas were then stored at 4 °C. Specular images were taken at baseline and repeated twice per week using a calibrated wide-field specular microscope. CEnC viability was assessed using a fluorescent live/dead viability assay. MAIN OUTCOME AND MEASURESEndothelial morphometry analysis, central corneal thickness measurements, and percentage of dead cells at day 11. RESULTSOf 16 donors who provided corneas, 9 (56%) were male, and the mean (SD) age was 57.9 (12.4) years. Corneas were paired, and baseline parameters were comparable between all groups. At all time points, CEnC loss was lower in the α-MSH groups compared with the control groups. This difference was statistically significant after cytokine-induced stress (20.2% vs 35.2%; sample estimate of median, −14.9; 95% CI, −23.6 to −6.3; P = .008). Compared with the control group, α-MSH treatment resulted in a smaller increase in central corneal thickness (cytokine-induced stress: 89.3 μm vs 169.8 μm; sample estimate of median, −84.9; 95% CI, −131.5 to −41.6; P = .008; oxidative stress: 43.6 μm vs 111.9 μm; sample estimate of median, −68.8; 95% CI, −100.0 to −34.5; P = .008) and a smaller proportion of cell death (cytokine-induced stress: 2.7% vs 10.4%; difference, −7.7; 95% CI, −13.1 to −2.4; P = .01; oxidative stress: 2.9% vs 12.4%; difference, 9.5; 95% CI, 5.1 to 13.9; P = .006). CONCLUSIONS AND RELEVANCEIn this study, α-MSH treatment attenuated CEnC loss during cold storage after acute oxidative and cytokine-induced stress in human eye bank cold-stored corneas. These data suggest that supplementation of corneal storage solution with α-MSH may positively affect CEnC survival after transplant and protect the endothelium from proinflammatory cytokines and oxidative stress after full-thickness or endothelial keratoplasty, which is particularly valuable in patients at high risk of graft failure.

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Corneal Endothelial Cell Transfer

Kinoshita,

Ueno,

Sotozono

2023

Essentials in Ophthalmology

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Elevated Cytokine Levels in the Aqueous Humor of Eyes With Bullous Keratopathy and Low Endothelial Cell Density

Cited by 52 publications

References 54 publications

Preoperative Aqueous Cytokine Levels are Associated With Endothelial Cell Loss After Descemet's Stripping Automated Endothelial Keratoplasty

Preoperative Aqueous Cytokine Levels are Associated With Endothelial Cell Loss After Descemet's Stripping Automated Endothelial Keratoplasty

Association of α-Melanocyte–Stimulating Hormone With Corneal Endothelial Cell Survival During Oxidative Stress and Inflammation-Induced Cell Loss in Donor Tissue

Corneal Endothelial Cell Transfer

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