Background and Objectives: Ocular alkaline
burn is a clinical emergency that can cause permanent vision loss due to
limbal stem cell deficiency and
corneal neovascularization (CNV). Although the basic pathogenetic mechanisms are considered to be acute oxidative stress and
corneal neovascularization triggered by
inflammation, the underlying intracellular mechanisms have not been clearly elucidated. The aim of this study was to investigate the role of endoplasmic reticulum (ER) stress on
inflammation and neovascularization, and the effect of the ER stress inhibitor
salubrinal (SLB), as a novel treatment in a corneal alkaline
burn model in rats. Methods:
Chemical burns were created by
cautery for 4 s using a rod coated with 75%
silver nitrate and 25%
potassium nitrate in the corneal center for the
corneal neovascularization (CNV) model. Twenty-eight Wistar albino rats were divided into four groups:
SHAM, CNV, CNV + SLB, and CNV +
bevacizumab (BVC). After the CNV model was applied to the right eye, a single subconjunctival dose (0.05 mL) of 1 mg/kg
salubrinal was injected into both eyes in the CNV + SLB group. A total of 1.25 mg/mL of subconjunctival BVC was administered to the CNV + BVC group. Fourteen days after experimental modeling and
drug administration, half of the globes were placed in liquid
nitrogen and stored at -20 °C until biochemical analysis. The remaining tissues were collected and fixed in 10% buffered
formalin for histopathological and immunohistochemical analysis. Three qualitative agents from three different pathways were chosen: TNFR for
inflammation,
endothelial nitric oxide synthase (e-NOS) for
vascular endothelial growth factor (
VEGF)-mediated vascular permeability, and
caspase-3 for cellular apoptosis. Results: Significantly lower
caspase-3 and eNOS levels were detected in the CNV + SLB and CNV + BVC groups than in the CNV group. Additionally, histopathological evaluation revealed a significant decrease in neovascularization, inflammatory cell infiltration, and fibroblast activity in the CNV + SLB and CNV + BVC groups. The endoplasmic reticulum stress inhibitor,
salubrinal, administered to the treatment group, attenuated apoptosis (caspase-3) and
inflammation (e-NOS). In the control group (left eyes of the SLB group),
salubrinal did not have a toxic effect on the healthy corneas. Conclusion: The ER stress pathway plays an important role in angiogenesis after alkaline corneal
burns, and treatment with SLB modulates this pathway, reducing
caspase-3 and eNOS levels. Further studies are needed to understand the molecular mechanisms altered by SLB-mediated
therapy. The fact that more than one mechanism plays a role in the pathogenesis of CNV may require the use of more than one molecule in treatment. SLB has the potential to affect multiple steps in CNV pathogenesis, both in terms of reducing ER stress and regulating cellular homeostasis by inhibiting the core event of integrated stress response (ISR). Therefore, it can be used as a new treatment option and as a strengthening agent for existing treatments. Although blockade of intracellular organelle stress pathways has shown promising results in experimental studies, more in-depth research is needed before it can be used in routine practice. To the best of our knowledge, this study is the first to report the role of ER stress in
corneal injury.