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Differential Gene Transcription of Extracellular Matrix Components in Response to In Vivo Corneal Crosslinking (CXL) in Rabbit Corneas.

ABSTRACT: Purpose:We studied changes in gene transcription after corneal crosslinking (CXL) in the rabbit cornea in vivo and identified potential molecular signaling pathways. Methods:A total of 15 corneas of eight male New-Zealand-White rabbits were de-epithelialized and equally divided into five groups. Group 1 served as an untreated control. Groups 2 to 5 were soaked with 0.1% riboflavin for 20 minutes, which in Groups 3 to 5 was followed by UV-A irradiation at a fluence of 5.4 J/cm2. Ultraviolet A (UVA) irradiation was delivered at 3 mW/cm2 for 30 minutes (Group 3, standard CXL protocol), 9 mW/cm2 for 10 minutes (Group 4, accelerated), and 18 mW/cm2 for 5 minutes (Group 5, accelerated). At 1 week after treatment, corneal buttons were obtained; mRNA was extracted and subjected to cDNA sequencing (RNA-seq). Results:A total of 297 differentially transcribed genes were identified after CXL treatment. CXL downregulated extracellular matrix components (collagen types 1A1, 1A2, 6A2, 11A1, keratocan, fibromodulin) and upregulated glycan biosynthesis and proteoglycan glycosylation (GALNT 3, 7, and 8, B3GALT2). Also, CXL activated pathways related to protein crosslinking (transglutaminase 2 and 6). In 9.1% of the significantly different genes, CXL at 3 mW/cm2 (Group 1) induced a more distinct change in gene transcription than the accelerated CXL protocols, which induced a lower biomechanical stiffening effect. Conclusions:Several target genes have been identified that might be related to the biomechanical stability and shape of the cornea. Stiffening-dependent differential gene transcription suggests the activation of mechano-sensitive pathways. Translational Relevance:A better understanding of the molecular mechanisms behind CXL will permit an optimization and individualization of the clinical treatment protocol.

SUBMITTER: Kling S

PROVIDER: S-EPMC5727938 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIndividuals who have failed one or more full thickness penetrating keratoplasties may be offered repeat corneal surgery using an artificial or donor cornea. An artificial or prosthetic cornea is known as a keratoprosthesis. Both donor and artificial corneal transplantations involve removal of the diseased and opaque recipient cornea (or the previously failed cornea) and replacement with another donor or prosthetic cornea.ObjectivesTo assess the effectiveness of artificial versus donor corneas in individuals who have had one or more failed donor corneal transplantations.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 11); Ovid MEDLINE; Ovid Embase; LILACS (Latin American and Caribbean Health Sciences Literature database); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 4 November 2019.Selection criteriaTwo review authors independently assessed reports from the electronic searches to identify randomized controlled trials or controlled clinical trials. Any discrepancies were resolved by discussion or consultation.Data collection and analysisWe used standard methodological procedures expected by Cochrane. For discussion purposes, we summarized findings from relevant comparative case series. We performed no data synthesis.Main resultsWe did not identify any randomized controlled trials or controlled clinical trials comparing artificial corneas with donor corneas for repeat corneal transplantations.Authors' conclusionsThe optimal management for those individuals who have failed a conventional corneal transplantation is unknown. Currently, in some centers, artificial corneal devices are routinely recommended after just one graft failure, while in other centers, they are not recommended until after multiple graft failures, or not at all. To date, there have been no controlled trials comparing the visual outcomes and complications of artificial corneal devices (particularly the Boston type 1 keratoprosthesis, which is the most commonly implanted artificial corneal device) with repeat donor corneal transplantation, in order to guide surgeons and their patients. Such a trial is needed and would offer significant benefit to an ever-increasing pool of people with visual disability due to corneal opacification, most of whom are still in productive stages of their lives.

Project description:PurposeTo assess the reliability of successive Corvis ST® measurements (CST, Oculus, Wetzlar, Germany) in keratoconus (KC) ≥ 2 years after accelerated corneal crosslinking (9 mW/cm2, 10 min, 5.4 J/cm2) compared to untreated KC corneas.MethodsThree successive CST measurements per eye were performed in ≥ 2 years after CXL (CXLG, n = 20 corneas of 16 patients) and a control group consisting of non-operated, ABC-stage-matched KC corneas according to Belin's ABCD KC grading (controls, n = 20 corneas, 20 patients). Main outcome measures included maximal keratometry (Kmax), the Belin/Ambrósio-Enhanced-Ectasia-Deviation-Index BAD-D; the biomechanical parameters A1 velocity, deformation amplitude (DA) ratio 2 mm, Ambrósio relational thickness to the horizontal profile (ARTh), integrated radius, stiffness parameter A1 (SP-A1), and the Corvis Biomechanical Factor (CBiF, the linearized term of the Corvis Biomechanical Index). Mean values, standard deviations, and Cronbach's alpha (CA) were calculated.ResultsBoth groups were tomographically comparable (BAD: 11.5 ± 4.7|11.2 ± 3.6, p = 0.682, Kmax: 60.5 ± 7.2|60.7 ± 7.7, p = 0.868 for controls|CXLG, paired t-test). A1 velocity (mean ± SD: 0.176 ± 0.02|0.183 ± 0.02, p = 0.090, CA: 0.960|0.960), DA ratio 2 mm (6.04 ± 1.13|6.14 ± 1.03, p = 0.490, CA: 0.967|0.967), integrated radius (12.08 ± 2.5|12.42 ± 1.9, p = 0.450, CA: 0.976|0.976), and CBiF (4.62 ± 0.6|4.62 ± 0.4, p = 0.830, CA: 0.965|0.965) were also comparable (controls|CXLG). ARTh was significantly higher in controls (177.1 ± 59, CA: 0.993) than after CXL (155.21 ± 65, p = 0.0062, CA: 0.993) and SP-A1 was significantly higher after CXL (59.2 ± 13, CA: 0.912) than in controls (52.2 ± 16, p = 0.0018, CA: 0.912).ConclusionARTh and SP-A1 differed significantly between controls and CXLG. Biomechanical measurements were generally of excellent reliability in both groups. CXL seems to affect biomechanical measurements of human corneas over more than 2 years.

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Differential Gene Transcription of Extracellular Matrix Components in Response to In Vivo Corneal Crosslinking (CXL) in Rabbit Corneas.

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