Prolonged Inflammation and Infectious Changes in the Corneal Epithelium Are Associated with Persistent Epithelial Defect (PED)
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Published on: November 22, 2024
Tanmoy Dutta1,2, Jyoti Sangwan1, Moumita Mondal1
1Dr Shroff's Charity Eye Hospital, Cornea and Stem Cells Department, Delhi 110002, India.
Insights
Persistent corneal epithelial defects (PED) involve delayed healing. This study found that while tears induce inflammation, PED tissues show chronic inflammation and reduced healing factors, suggesting new therapeutic targets for corneal re-epithelialization.
Area of Science:
- Ophthalmology
- Molecular Biology
- Wound Healing Research
Background:
- Persistent corneal epithelial (CE) defects (PED) are characterized by a failure in rapid re-epithelialization post-injury.
- The underlying genetic mechanisms governing CE re-epithelialization in PED remain incompletely understood.
- Identifying key genes and pathways is crucial for developing effective treatments for corneal wound healing.
Purpose of the Study:
- To elucidate the gene network driving corneal re-epithelialization in persistent corneal epithelial defects (PED).
- To compare gene expression profiles in PED patients' corneal tissue and in response to tear treatments.
- To investigate the roles of specific genes in CE homeostasis, inflammation, and cell-cell communication during healing.
Main Methods:
- Collected epithelial scrapes and tear samples from PED patients and healthy controls (PRK group).
- Utilized quantitative real-time PCR (qRT-PCR) to analyze the expression of key genes (e.g., KLF4, GPX4, IL6, TNFα, IL8, desmoglein, E-cadherin).
- Assessed KLF4 localization via immunofluorescence and matrix metalloproteinase (MMP) activity using zymography.
Main Results:
- Kruppel-like factor 4 (KLF4) was downregulated in PED tissues but upregulated in tear-treated cells.
- Cell-cell communication genes showed decreased expression in PED tissues but increased expression with tear treatment.
- Pro-inflammatory genes (IL6, TNFα, IL8) were significantly upregulated in both conditions, with increased MMP9 activity observed upon tear treatment.
Conclusions:
- Tears may induce an acute pro-inflammatory state contributing to PED pathology, while PED tissues reflect a chronic inflammatory stage.
- Interferons and pro-inflammatory pathways are implicated in PED pathogenesis.
- These findings suggest potential therapeutic targets for enhancing corneal epithelialization in PED.
Abstract:
Purpose: Failure of rapid re-epithelialization within 10-14 days after corneal injury, even with standard supportive treatment, is referred to as persistent corneal epithelial (CE) defect (PED). Though an array of genes regulates reepithelization, their mechanisms are poorly understood. We sought to understand the network of genes driving the re-epithelialization in PED. Method: After obtaining informed consent, patients underwent an ophthalmic examination. Epithelial scrapes and tears samples of six PED patients and six individuals (control) undergoing photorefractive keratectomy (PRK) were collected. RNA isolation and quantification were performed using either the epithelial scrape taken from PED patients or from HCLE cells treated with control tears or tears of PED patients. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of a few important genes in CE homeostasis, inflammation, and cell-cell communication, viz., Kruppel-like factor 4 (KLF4), GPX4, IL6, TNFα, STING, IL8, desmoglein, and E-cadherin, among others. Their expressions were normalized with their respective housekeeping genes and fold changes were recorded. KLF4 localization and MMPs activity was carried out via immunofluorescence and zymography, respectively. Results: KLF4, a transcription factor important for CE homeostasis, was upregulated in tears-treated HCLE cells and downregulated in PED patients compared to the healthy PRK group. Cell-cell communication genes were also upregulated in tears-treated cells, whereas they were downregulated in the PED tissue group. Genes involved in proinflammation (IL6, 282-fold; TNFα, 43-fold; IL8, 4.2-fold) were highly upregulated in both conditions. MMP9 activity increased upon tears treatment. Conclusions: This study suggests that tears create an acute proinflammatory milieu driving the PED disease pathology, whereas the PED patients scrapes are an indicator of the chronic stage of the disease. Interferons, pro-inflammatory genes, and their pathways are involved in PED, which can be a potential target for inducing epithelialization of the cornea.
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