Injury drives inflammation then fibrosis: the response of the lens epithelium to cataract surgery
| Author(s) | Novo, Samuel G. | |
| Date Accessioned | 2023-02-27T14:33:04Z | |
| Date Available | 2023-02-27T14:33:04Z | |
| Publication Date | 2022 | |
| SWORD Update | 2022-09-21T16:08:32Z | |
| Abstract | Cataracts are the leading cause of blindness worldwide. The treatment for cataracts, cataract surgery, is high successful due to the advances in IOL (intraocular lens) technology and surgical techniques. However, the wound healing response to cataract surgery does have subsequent complications in the form of inflammation and posterior capsular opacification (PCO), which is also known as a secondary cataract. While both of these complications are treatable, with inflammation being treated through the use of steroidal and non-steroidal anti-inflammatory drugs and PCO being treated through the use of Nd-Yag laser capsulotomy, there are issues with the treatments either through low patient compliance for inflammatory drugs or complications such as IOL dislocation, retinal detachment or macular edema from laser capsulotomy. As a result, cataract surgeons agree that new treatments for inflammation and PCO are desired and that they would be prescribed if available. ☐ To create new therapeutics, understanding the mechanism of how post cataract surgery inflammation and fibrosis/PCO pathogenesis develops is imperative. There is literature in the field from our laboratory and others discussing how PCO pathogenesis initiates using an in vivo mouse cataract surgery model, however, there is the question of how well these studies mimic the process in humans. Using the unbiased global approach of RNA-sequencing, the transcriptome of human lens epithelial cells (LECs) at 0 hours and 24 hours cultured in the human capsular bag model of PCO was compared to mouse LECs from the in vivo stimulated cataract surgery model at 0 hour and 24 hours. Sequencing data showed that mouse and humans generally undergo similar inflammatory and fibrotic transcriptomic changes during the first 24 hours culture/post cataract surgery (PCS) with a subgroup of genes uniquely regulated in each species. ☐ Mouse and humans undergo similar PCS changes, which demonstrates that the mouse cataract surgery is a good model to mimic the changes in humans. However, there is still the unanswered question of what are the regulatory mechanisms and signaling pathways responsible for inducing the wound healing responses of inflammation and fibrosis/PCO pathogenesis? Therefore, an RNA-seq was conducted on wild type mice at 0 hour and 6 hour PCS to investigate what are the immediate changes being induced by the trigger of the cataract surgery (Chapter 4). By 6 hours, the LECs express the upregulation of proinflammatory cytokines and profibrotic regulators. Therefore, the LECs at 6 hours are already primed for the subsequent responses of inflammation and fibrosis. Notably, at 6 hours, various immediate early transcription factors (IETFs) were highly upregulated. IETFs are known to mediate the inflammatory and fibrotic responses in other systems, and as a result, could be mediating the post cataract surgery responses. Therefore, two IETFs, Egr1 and FosB, were investigated to identify their role in regulating the post cataract surgery response. Egr1 and FosB did mediate some of the inflammatory and fibrotic responses, however, there is the possibility of compensation from the other IETFs for the global response as they are expressed at high levels in the knockout mice. Alternatively, there could be a threshold established by the various IETF and knocking out many of the IETF are necessary to elicit a decrease in the wound healing responses. In addition, the ERK/MAPK signaling pathway was identified and validated to be upregulated acutely PCS and thus could be mediating the observed upregulation of IETFs. Biomechanical stress pathway was found to be a possible initial trigger causing the PCS response leading to the upregulation of ERK/MAPK signaling and IETF expression. ☐ The work described in this dissertation has shown that the mouse model is an appropriate model to describe the changes in humans and can continue to be used to identify new therapeutic/drug targets. In addition, these works have identified potential pathways mediating the post cataract surgery response enabling the field to get a comprehensive timeline of the changes that occur from the time of cataract surgery to changes that occur various years afterwards in the form of PCO. | |
| Advisor | Duncan, Melinda K. | |
| Degree | Ph.D. | |
| Department | University of Delaware, Department of Biological Sciences | |
| DOI | https://doi.org/10.58088/b49m-my81 | |
| Unique Identifier | 1371238136 | |
| URL | https://udspace.udel.edu/handle/19716/32362 | |
| Language | en | |
| Publisher | University of Delaware | |
| URI | https://login.udel.idm.oclc.org/login?url=https://www.proquest.com/dissertations-theses/injury-drives-inflammation-then-fibrosis-he/docview/2737175378/se-2?accountid=10457 | |
| Keywords | Cataract surgery | |
| Keywords | Inflammation | |
| Keywords | Lens | |
| Keywords | Posterior capsular opacification | |
| Title | Injury drives inflammation then fibrosis: the response of the lens epithelium to cataract surgery | |
| Type | Thesis |