Clinical features of anterior blepharitis after cataract surgery.

We evaluated the clinical features of postoperative anterior blepharitis following cataract surgery and the efficacy of topical azithromycin retrospectively. Thirty eyes of 30 patients with a clinical diagnosis of anterior blepharitis by 6 months postoperatively among those who underwent cataract surgery at our institution between November 2020 and June 2022 were included. The diagnosis of anterior blepharitis and the assessment of objective and subjective findings were based on the American Academy of Ophthalmology Blepharitis Preferred Practice Pattern®. Azithromycin eye drops were prescribed for all patients, and findings and symptoms before and after the drops were reviewed. The time of onset ranged from 2 weeks to 6 months after cataract surgery, with the most common onset at 2 to 3 months postoperatively (mean time of onset 79.4 ± 39.6 days). The type of anterior blepharitis was staphylococcal blepharitis in 26 eyes and seborrheic blepharitis in 4 eyes, while mixed type with posterior blepharitis was noted in 6 eyes. Symptoms at the time of examination included irritation (including foreign body sensation) in 24 eyes, tearing in 4 eyes, and redness in 3 eyes. The findings and symptoms of anterior blepharitis were alleviated or resolved with azithromycin eye drops in 26 of the 30 eyes, but the blepharitis recurred in 6 of these eyes, requiring azithromycin eye drops to be re-prescribed. The onset of anterior blepharitis after cataract surgery may be related to a gradual decrease in postoperative eye drops. Patients tended to complain of irritation and foreign body sensation, and azithromycin eye drops were effective in such cases.

Long-term outcomes of transsclerally sutured intraocular lens correctly fixed in the ciliary sulcus.

OBJECTIVE: To report the long-term postoperative outcomes of transsclerally sutured intraocular lenses (IOLs), in which the haptics were correctly fixated into the ciliary sulcus using an auxiliary device and endoscope. METHODS AND ANALYSIS: Data were collected from eyes that were followed up for at least 12 months after ciliary sulcus suture fixation of an IOL using an auxiliary device for securely placing the IOL haptics to the ciliary sulcus, which was confirmed using intraoperative endoscopy in all cases. The corrected distance visual acuity (CDVA), refractive error, anterior chamber depth (ACD), IOL decentration and tilt, corneal endothelial cell density (CECD) and postoperative complications were recorded. ACD and IOL deviations were compared with those of normal controls after standard cataract surgery. RESULTS: A total of 146 eyes of 142 patients were included, with a mean follow-up period of 56.0±35.3 (range 12-174) months. Postoperative CDVA from 1 month to 8 years and final CDVA were significantly better, and the mean refraction error, ACD and CECD decline rate were -0.71±0.75 dioptre, 4.01±0.37 mm and -7.4%±16.0%, respectively. Compared with normal controls, ACD was not significantly different but the tilt and decentration were significantly different. The main postoperative complications included vitreous haemorrhage (24.0％), suture thread exposure (19.2%) and corectopia (18.5%). There were no cases of IOL dislocation due to suture breakage or postoperative endophthalmitis CONCLUSION: Long-term postoperative outcomes were favorable with good CDVA and without IOL dislocation and endophthalmitis. The significance and value of fixing haptics to the ciliary sulcus should be re-evaluated.

A rare case of corneal keloid occurred 30 years after pterygium surgery and 3 years after cataract surgery.

PURPOSE: We report a case of corneal keloid occurring 30 years after pterygium surgery and 3 years after cataract surgery. OBSERVATIONS: The case of a 72-year-old man was referred because of blurred vision and corneal opacity in the right eye. Pterygium surgery had been performed on the right eye 30 years earlier, and bilateral cataract surgery had been done uneventfully via a temporal corneal incision 3 years ago. Deterioration of vision occurred in the right eye from 2 years ago. At the initial visit, his best corrected visual acuity (BCVA) was 20/2000 on the right. A white nodule that was well demarcated from the underlying stroma was seen on the right cornea. The nodule was excised by superficial keratectomy, with BCVA being 180/200 at 1 week after surgery. Pathological examination of the resected specimen revealed proliferation of fibroblasts and haphazard arrangement of collagen bundles, leading to a diagnosis of corneal keloid. Keloid-like lesion was also later noted in temporal corneal incision site of cataract surgery. CONCLUSIONS AND IMPORTANCE: This rare case of corneal keloid occurred as a late complication of pterygium surgery.

Autologous transplantation of conjunctiva by modifying simple limbal epithelial transplantation for limbal stem cell deficiency.

PURPOSE: As a treatment to replace regenerative medicine to treat limbal stem cell deficiency (LSCD), we performed 4 consecutive cases of autologous transplantation of conjunctival explants by modifying simple limbal epithelial transplantation (SLET). STUDY DESIGN: Single-center case series. METHODS: Four patients with LSCD were enrolled in this study. After resection of scar tissue with neovascularization from the ocular surface, human amniotic membrane (AM) was placed over the bare ocular surface. The bulbar conjunctiva of the operated eye was dissected at the temporal superior fornix, divided into small pieces, and transplanted onto AM with fibrin glue. Keratoplasty was performed simultaneously or few months after surgery. RESULTS: Epithelialization was achieved in all patients. Best-corrected visual acuity was improved in all patients. CONCLUSION: This is the first report of ocular surface reconstruction using autologous conjunctival epithelial transplants from the affected eye. Transplantation by modifying SLET effectively restored a clear corneal surface with minimal neovascularization in 4 patients with LSCD. Autologous conjunctival transplants combined with AM transplantation could be a practical option for treating bilateral LSCD in patients without symblepharon or severe keratinization.

Pro-inflammatory role of NLRP3 inflammasome in experimental sterile corneal inflammation.

We evaluated the role of NLR family pyrin domain containing 3 (NLRP3) inflammasome in sterile corneal inflammation caused by lipopolysaccharide (LPS) or alkali burns in C57BL6 mice or NLRP3 KO (Nlrp3-/-) mice. Various molecules related to the NLRP3 inflammasome were upregulated in C57BL6 mice after both alkali burn injury and LPS treatment. After alkali burn injury, the corneal opacity grade was significantly reduced in Nlrp3-/- mice compared with C57BL6 mice. In Nlrp3-/- mice, Gr-1 immunoreactivity and MMP-9 mRNA expression in the corneal stroma were significantly reduced by both LPS treatment and alkali burn injury. Quantitative PCR and immunohistochemistry revealed that IL-1ß and MMP-9 expression in the corneal stroma were down-regulated in Nlrp3-/- mice with both alkali burn injury and LPS treatment. These findings suggest that the NLRP3 inflammasome has a pro-inflammatory effect in the cornea by recruiting neutrophils to sites of inflammation.

Implications of Inflammasomes in Human Diseases: NLRP3 Inflammasome and Animal Models.

Danger-associated molecular patterns, such as nuclear or cytosolic proteins released outside the cell or exposed on the cell surface after tissue injury, and pathogen-associated molecular patterns, such as lipopolysaccharide, peptidoglycan, and nucleic acid, stimulate the formation of a large protein complex called the inflammasome. The inflammasome is a cytosolic complex of 3 proteins that cleaves and releases interleukin-1ß. Recent studies have characterized a multitude of inflammasome ligands of both endogenous and exogenous origins. Moreover, using various animal models, the implications of inflammasomes in human diseases have been elucidated for multifaceted diseases such as metabolic syndrome, inflammatory bowel disease, Alzheimer disease, and certain inflammatory skin diseases. This article reviews several of these conditions and discusses the different models proposed for inflammasome involvement, including animal models of the cornea.

Ocular Surface Reconstruction with the Autologous Conjunctival Epithelium and Establishment of a Feeder-Free and Serum-Free Culture System.

Transplantation of the autologous cultured corneal limbal epithelium and oral mucosal epithelium is a standard technique for ocular surface reconstruction under corneal limbal stem cell deficiency. As an option for bilateral cases, we recommend utilization of autologous conjunctivae for ocular surface reconstruction. Autologous conjunctival epithelium sheet transplantation was effective for bilateral corneal limbal stem cell deficiency without symblepharon or severe keratinization. Moreover, we established a feeder-free and serum-free culture system of the limbal epithelium. This system can be applied for culturing conjunctival epithelia. Autologous cultured conjunctival epithelium transplantation is a practical option for treating bilateral corneal limbal stem cell deficiency.

A case of apolipoprotein A-I deficiency due to carboxyl-terminal truncation.

Apolipoprotein A-I deficiency is a rare metabolic disease characterized by an impaired reverse cholesterol transport system resulting in excessive cholesterol accumulation. Here, we discuss a case of apolipoprotein A-I deficiency caused by a carboxyl-terminal truncation mutation p.His186ProfsX46 in APOA1, which might result in increased catabolism of the mutant protein.

The Japan Cornea Society Survey of the Current Status of Corneal and Conjunctival Disorders Due to Systemic Antitumor Drugs.

Purpose: To investigate the current status of corneal and conjunctival disorders due to antitumor drugs in Japan. Methods: Questionnaires on corneal and conjunctival disorders due to antitumor drugs were sent to members of the Japan Cornea Society, and data on patients' background, clinical findings, treatment and prognosis of cases between January 2009 and December 2011 were collected and analyzed. Results: Out of all 221 cases from 66 facilities, TS-1Ⓡ had been administered in 210 cases (95.0%). Corneal findings were noted in 192 cases (86.9%), including 161cases (72.9%) of superficial punctate keratopathy, 55 cases (24.9%) of epithelial crack line, 38 cases (17.2%) of sheet-like epithelial abnormality, and 15 cases (6.8%) of corneal erosion. Conjunctival and ciliary findings were observed in 49 cases (22.2%). Lacrimal obstruction and constriction were found in 81cases (36.7%). Logistic regression analyses revealed the discontinuation and switching of antitumor drugs as the significant factor of good prognosis of clinical signs and visual acuity in cases with TS-1Ⓡ administration. Conclusions: Although corneal and conjunctival disorders due to antitumor drugs, especially TS-1Ⓡ, are important adverse effects, the only effective treatment at this time is the discontinuation and switching of antitumor drugs. Future prospective studies are needed to elucidate pathogenesis, aiming to the prediction and prevention of the occurrence.

Morphological changes in the meibomian glands of patients with phlyctenular keratitis: a multicenter cross-sectional study.

BACKGROUND: Phlyctenular keratitis is a hypersensitivity reaction of the cornea, and a complication of eyelid margin disease in children and young adults. In this study, we compared the morphology of the meibomian glands in eyelids between phlyctenular keratitis patients and healthy young adults, using noncontact meibography. METHODS: The study included 16 eyes of 13 patients diagnosed with phlyctenular keratitis and 17 eyes of 17 healthy volunteers. Slit-lamp observations of the cornea and eyelid were performed on all subjects. The morphology of the meibomian glands was scored using non-contact meibography (meiboscore). The meiboscore in worse eye was used in bilateral phlyctenular keratitis. RESULTS: All eyes with phlyctenular keratitis, but not normal controls, showed corneal nodules, neovascularization, and superficial punctate keratopathy. The mean meiboscore in phlyctenular keratitis patients (upper lid: 2.9 ± 0.3, lower lid: 2.7 ± 0.5) was significantly higher than in controls (upper lid: 0.4 ± 0.6, lower lid: 0.1 ± 0.3). CONCLUSIONS: Noncontact meibography enabled visualization of meibomian gland loss in phlyctenular keratitis patients, suggesting a relationship between abnormalities of the meibomian glands in young individuals and the pathogenesis of phlyctenular keratitis.

A diagnostic method for herpes simplex keratitis by simultaneous measurement of viral DNA and virus-specific secretory IgA in tears: an evaluation.

PURPOSE: We performed simultaneous measurement of herpes simplex virus (HSV) DNA by real-time polymerase chain reaction (real-time PCR) and of HSV-specific secretory IgA antibody (HSV-sIgA) by enzyme-linked immunosorbent assay (ELISA) in tears obtained using Schirmer strips in order to investigate its diagnostic efficacy for herpes simplex keratitis (HSK). METHODS: A total of 59 affected eyes from 59 patients with clinically suspected HSK (HSK group) and 23 eyes from 23 healthy volunteers (control group) were enrolled in this study. The HSK group was divided into five subgroups: dendritic/geographic keratitis, disciform keratitis, necrotizing keratitis, atypical keratitis, and others. The tear samples were taken using Schirmer strips to determine the HSV DNA and HSV-sIgA levels. RESULTS: The overall sensitivity and specificity were 55.8 and 100 % for HSV DNA and 49.2 and 82.6 % for HSV-sIgA. The HSV DNA levels in the disciform keratitis subgroup (median, 3.1 × 10(2) copies/sample) were significantly lower than those in the dendritic/geographic keratitis subgroup (median, 2.3 × 10(4) copies/sample) (P < 0.05, Mann-Whitney test). The HSV-sIgA levels in the disciform keratitis subgroup (median, 50.0 NU/ml) were significantly higher than those in the control group (median, 18.0 NU/ml) (P < 0.05, Steel test). The positive and negative predictive values obtained by simultaneous measurement of HSV DNA and sIgA were 90.9 and 61.3 %, respectively. CONCLUSION: The combination of laboratory detection of HSV DNA by real-time PCR and of HSV-sIgA by ELISA using tear samples enables higher reliability in diagnosing the subgroups of HSK, although the HSV DNA value is relatively lower in disciform HSK than in dendritic/geographic HSK.

Anti-inflammatory effect of topical administration of tofacitinib on corneal inflammation.

We evaluated an anti-inflammatory effect of topical administration of tofacitinib, janus kinase (JAK) blocker, on corneal inflammation. Topical instillation of either tofacitinib or PBS was applied after wounding BALB/c mice corneas with alkali burn. Topical instillation was performed until day 14 after injury and injured eye was analyzed. The vascularized area in the alkali burned cornea was significantly reduced in the tofacitinib group compared with that in the PBS group. The immunoreactivity of Gr-1, F4/80, IFN-γ, and phosphorylated STAT(signal transducer and activator of transcription)1 in corneal stroma was diminished significantly in the tofacitinib group. Using laser capture microdissection system and quantitative PCR array analysis, the expression levels of CXCL9, CXCL5, CCL7, CCL2, MMP(matrix metalloproteinase)-9, and STAT1 in corneal stroma were down-regulated in the tofacitinib group. In in vitro study, human fibroblast pretreated by IFN-γ showed phosphorylation of STAT1, and this phosphorylation was down-regulated by adding tofacitinib to the culture medium. These results indicate the topical application of JAK inhibitor causes down-regulation of JAK- or IFN-γ-related molecules. Therefore, we deduce that application of JAK inhibitor for topical instillation may contribute to the treatment of corneal inflammation.

Potential Application of Biological Products for the Treatment of Ocular Surface Inflammation.

Various biological products have been introduced for the treatment of autoimmune diseases. The injection of tocilizumab [anti-interleukin (IL)-6R antibody] and a tumor necrosis factor receptor fusion protein (TNFR-Fc) has been approved for the treatment of rheumatoid arthritis. We investigated the effect of the anti-IL-6R antibody and TNFR-Fc on corneal inflammation. Topical instillation of the anti-IL-6R antibody (MR16-1, 2 µg/µL; anti-IL-6R group) or TNFR1-Fc (100 µg/mL; TNFR1 group) was performed after corneal wounds were induced in BALB/c mice by alkali burns. The injured eye was analyzed on day 14 or 28 after injury, and topical instillation was performed until day 14 or day 28. Corneal stromal sections were made using a laser capture microdissection system, and total RNA from the specimens was subjected to quantitative polymerase chain reaction array analysis. Topical instillation of phosphate-buffered saline (PBS) served as a control. The vascularized area was significantly reduced in the anti-IL-6R (day 14) and TNFR1 groups (day 28) compared with that in the PBS group. In the anti-IL-6R group, the expression levels of matrix metalloproteinase-13, monocyte chemotactic protein-1, and C-C motif ligand-22 were downregulated compared with those in the PBS group. In the TNFR1 group, expression of mitogen-activated protein kinase 8 was downregulated. These results indicate the possible application of biological products for topical instillation for the treatment of corneal inflammation.

Involvement of Chemokines and a CD4-Positive T Cell Subset in the Development of Conjunctival Secondary Lymphoid Follicles in an Atopic Keratoconjunctivitis Mouse Model.

BACKGROUND: Massive B cell lymphoid hyperplasia and its associated factors may play a role in exacerbating inflammation in allergic disorders. We here investigated the chemokines and CD4-positive T cell subset involved in the development of secondary lymphoid follicles (iCALT) in conjunctival tissues in an atopic keratoconjunctivitis mouse model (AKC mouse). METHODS: NC/Nga mice were divided into three groups: AKC (percutaneous sensitization and instillation of crude house dust mite antigen), AD (percutaneous sensitization only) and C (untreated control). Pathological changes in the conjunctival tissues of each group were investigated using histological and immunohistochemical detection of CD4 and CD20. Furthermore, tissue sections of iCALT (AKC-iCALT subgroup) and conjunctiva without iCALT (AKC-conjunctiva subgroup) were obtained from AKC mice using laser-assisted microdissection. mRNA expression of chemokine and T cell subset-related transcription factors were compared between the AKC-iCALT and AKC-conjunctiva subgroups using polymerase chain reaction (PCR) array and real-time reverse transcription-PCR (RT-PCR) methods. RESULTS: iCALT with central aggregation of CD20-positive B cells and CD4-positive T cell infiltration surrounding B cells was observed in the palpebral conjunctival tissue of the AKC group, but not in that of the AD and C groups. Chemokine and T cell subset-related transcription factor expression was confirmed using real-time RT-PCR, with significant increases in Ccl5, Ccl17, Cxl20, Cxcl3, Ccr7, Foxp3 and T-bet mRNA expression in the AKC-iCALT subgroup compared with those in the AKC-conjunctiva subgroup. CONCLUSIONS: We concluded that CCL5, CCL17 and CCL20, as well as T-bet- and Foxp3-positive lymphocytes may be iCALT-related factors and that iCALT-related chemokines are worth evaluating as biomarkers.

Increased Tear Fluid Production as a Compensatory Response to Meibomian Gland Loss: A Multicenter Cross-sectional Study.

PURPOSE: To compare tear film parameters as well as meibomian gland morphologic features and function among patients with meibomian gland dysfunction (MGD), those with non-Sjögren syndrome aqueous-deficient dry eye (non-SS ADDE), those with non-SS ADDE and MGD, and normal subjects. DESIGN: Multicenter, cross-sectional, observational case series. PARTICIPANTS: Forty-one eyes of 41 patients (all women; mean age ± standard deviation, 62.1±9.9 years) with non-SS ADDE, 70 eyes of 70 patients (all women; 66.0±8.7 years) with MGD, 17 eyes of 17 patients (all women; 72.4±7.8 years) with non-SS ADDE and MGD, and 70 eyes of 70 normal control subjects (all women; 65.0±7.1 years). METHODS: Ocular symptoms were scored from 0 to 14 and lid margin abnormalities from 0 to 4 according to their respective number. Meibomian gland changes were scored from 0 to 6 (meiboscore) on the basis of noncontact meibography findings, and meibum was graded from 0 to 3 depending on its volume and quality. Conjunctival and corneal epithelial damage were scored from 0 to 9 (fluorescein score). Tear film break-up time (TBUT) was measured as an index of tear film stability, and tear fluid production was evaluated with Schirmer's test. MAIN OUTCOME MEASURES: Ocular symptom score, lid margin abnormality score, meiboscore, meibum grade, fluorescein score, TBUT, and Schirmer's test value. RESULTS: The ocular symptom score did not differ significantly between the MGD and non-SS ADDE groups (P = 0.762). The lid margin abnormality score, meiboscore, and meibum grade were significantly higher in the MGD group than in the non-SS ADDE group (P = 0.0012, P < 0.0001, and P < 0.0001, respectively). The fluorescein score, TBUT, and Schirmer's test value were significantly worse in the non-SS ADDE group than in the MGD group (P < 0.0001, P = 0.0061, and P < 0.0001, respectively). The meiboscore correlated significantly with Schirmer's test value only in the MGD group (ρ = 0.508, P = 8.3×10(-6)). CONCLUSIONS: An increase in tear fluid production likely compensates for loss of meibomian glands in individuals with MGD.

Granular corneal dystrophy type 2 is associated with morphological abnormalities of meibomian glands.

AIMS: To investigate morphological changes in meibomian glands in patients with granular corneal dystrophy type 2 (GCD2) using non-invasive meibography. METHODS: Eleven patients (3 men and 8 women) with GCD2, and sex-matched and age-matched healthy volunteers as a controls were enrolled in this study. The diagnosis of GCD2 was confirmed by transforming growth factor ß-induced (TGFBI) gene analysis using direct sequencing in exon 4 of TGFBI gene. Meibography was performed in the right eye of the studied cases. Meiboscore was determined according to the morphology of meibomian gland and classified into four grades; grade 0 (no meibomian gland loss), grade 1 (loss less than one-third the total area of meibomian glands), grade 2 (area loss between one-third and two-thirds of the total area), and grade 3 (area loss greater than two-thirds of the total). RESULTS: R124H mutation was detected in all patients with GCD2. Extinguishing or shortening of the meibomian glands was observed in patients with GCD2. The meiboscore was 3.8±1.3 in patients with GCD2 and 1.3±1.1 in the control group, showing significant difference between two groups (Mann-Whitney U-test, p=0.042). CONCLUSIONS: In GCD2, corneal deposits, and also morphological abnormalities of meibomian glands, such as obstruction or shortening, were found. Since abnormal phospholipid deposition is noted in GCD2, these results are interesting because phospholipid is possibly secreted from the meibomian gland.

Simultaneous study of matrix metalloproteinases, proinflammatory cytokines, and soluble cytokine receptors in the tears of noninfectious corneal ulcer patients.

BACKGROUND: We investigated the presence of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), proinflammatory cytokines, and soluble cytokine receptors in the tear fluid of patients with noninfectious corneal ulcers in the peripheral cornea. METHODS: The subjects were 20 eyes of 17 patients with peripheral noninfectious corneal ulcers and 20 eyes of 20 volunteers. Tear samples were taken by the Schirmer test I method and the presence of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, and MMP-13) and TIMPs (TIMP-1, TIMP-2, and TIMP-4) were investigated using an MMP antibody array system. The concentrations of proinflammatory cytokines {IL-1ß, IL-6, and TNF-α (tumor necrosis factor-alpha)} and soluble cytokine receptors {soluble (s) IL-1R1, sIL-1R2, sIL-2Rα, sIL-4R, sIL-6R, sTNFR1, sTNFR2, s-vascular endothelial growth factor receptor (VEGFR) 1, sVEGFR2, sVEGFR3, and sgp130} were determined using the multiplex bead immunoassay system. RESULTS: The concentrations of MMP-8 and MMP-9 were significantly up-regulated in the tear fluid of the ulcer patients, whereas TIMPs concentrations did not change. The concentrations of IL-1ß, IL-6, sIL-1R2, sIL-6R, sTNFR1, and sTNFR2 were up-regulated in the ulcer patients, whereas sgp130 and sVEGFR1 concentrations significantly decreased. CONCLUSIONS: The presence of some MMPs increased significantly in the patients with peripheral noninfectious corneal ulcers, whereas the presence of TIMPs remained unchanged. Although some proinflammatory cytokines were up-regulated, their antagonists, soluble cytokine receptors, were also up-regulated. It is thus possible that the up-regulation of MMPs disrupts the balance between the MMPs and TIMPs and that this balance may play a pivotal role in the pathophysiology of corneal ulceration.

Significance of ectodomain shedding of TNF receptor 1 in ocular surface.

PURPOSE: We evaluated an anti-inflammatory effect of TNF receptor 1 (TNFR1) ectodomain shedding in ocular surface. METHODS: Human corneal epithelial cell (HCEC) was first pretreated by TNF-α. Ectodomain shedding was stimulated by uridine triphosphate (UTP) or peptidoglycan (PGN), with or without shedding inhibition using TNF-α processing inhibitor (TAPI). The phosphorylation of the NF-κB inhibitory protein, IκB, was assessed by Western blotting and concentrations of soluble TNFR1 (sTNFR1) in culture medium were analyzed by ELISA. Tear fluid from patients with Sjögren syndrome and graft-versus-host disease (GVHD) was collected and analyzed by ELISA for sTNFR1 concentration. Five dry eye patients underwent topical treatment using diquafosol sodium eye drops, a purinergic P2Y2 receptor agonist, and the tear fluid of the patients was sampled before and 4 weeks after the treatment for sTNFR1 ELISA. RESULTS: Phosphorylation of IκB was diminished by adding UTP or PGN, and this down-regulation of IκB phosphorylation was reversed by adding TAPI. In HCEC medium, sTNFR1 release was increased significantly by adding UTP or PGN, and inhibited significantly by adding TAPI. In the tears of the patients with Sjögren syndrome and GVHD, sTNFR1 expression was upregulated. In the tears of the patients with short breakup time (BUT) dry eye, sTNFR1 concentrations (ng/mL) in the tears were 1.30 ± 0.58 ng/mL for the pretreatment baseline, and 1.64 ± 0.70 after treatment, statistically significantly higher than those for the pretreatment (P < 0.01). CONCLUSIONS: Ectodomain shedding of sTNFR1 blocked TNF-α-induced intracellular signaling in corneal epithelium. The upregulation of sTNFR1 in inflamed ocular surfaces suggests an anti-inflammatory role of sTNFR1 ectodomain shedding at the ocular surface.

Metalloproteinases in corneal diseases: degradation and processing.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with the potential to degrade all types of extracellular matrix. The ADAM (a disintegrin and metalloproteinase) family of peptidases was recently identified as cleaving the extracellular domain of transmembrane proteins. This was termed ectodomain shedding. We investigated the MMP expression in patients with corneal diseases and the potential role of ADAMs in corneal pathophysiology. We detected upregulation of the active form of MMP-2 and MMP-9 in the tear fluid from patients with corneal melting or recurrent corneal erosion. Using human corneal epithelial cells, we observed ADAM17-dependent ectodomain shedding of soluble tumor necrosis factor receptor 1 and soluble interleukin-6 (IL-6) receptor (sIL-6R). The production of sIL-6R was also induced by messenger RNA splicing in the human corneal epithelial cells. IL-6/sIL-6R-induced signal transducer and activator of transcription 3 phosphorylation was observed in cultured human corneal fibroblasts, suggesting that IL-6 trans-signaling induced inflammatory cellular signaling in the human corneal fibroblasts. We demonstrated that MMPs are significantly upregulated in collagen-destructive disorders of the cornea. Additionally, we observed that ectodomain shedding by ADAMs in corneal epithelial cells mediated the production of soluble cytokine receptors. Trans-signaling of IL-6 can induce an inflammatory response in corneal stroma, indicating the significance of IL-6 trans-signaling in ocular surface inflammation. Thus, MMPs and ADAMs play an important role in the pathophysiology of corneal diseases.

Anti-inflammatory effect of IL-6 receptor blockade in corneal alkali burn.

We investigated the effect of soluble IL-6R (sIL-6R) blockade on corneal inflammation. Topical instillation of either anti-IL-6R antibody (MR16-1) or phosphate buffered saline (PBS) was applied after wounding BALB/c mice corneas with alkali burn. The vascularized area was significantly reduced in the MR16-1 group. The immunoreactivity of phosphorylated STAT3, Gr-1, and F4/80 diminished significantly in the MR16-1 group. Laser capture microdissection resulted in a significant down-regulation of the mRNA expressions of ICAM-1, MCP-1, and VEGF-A in the corneal stroma of the MR16-1 group. Adding a combination of recombinant IL-6 and sIL-6R resulted in a significant increase in the release of VEGF from human corneal fibroblasts. As the infiltration of inflammatory cells, the expression of phosphorylated STAT3, and the expressions of inflammatory-related molecules in the experimental model of corneal inflammation were significantly inhibited by topical instillation of MR16-1, we deduce that IL-6 trans-signaling plays a significant role in ocular surface inflammation and that the blockade of IL-6R contributes to the reduction in corneal inflammation.