RNA sequencing analysis reveals Diclofenac-induced changes in gene expression in a dry eye biomimetic model

抄録

Assuring the safety of ophthalmic drugs is crucial for their successful development. However, the existing preclinical models of the ocular surface lack the necessary complexity of biological cellular components and biomechanical conditions, which makes it challenging to accurately assess drug toxicity. For example, the safety of the nonsteroidal anti-inflammatory drug Diclofenac (DCF) in clinical practices for post-cataract surgery or dry eye diseases is controversial. To address these issues, we utilized our previously developed corneal epithelium-on-a-chip (CEpOC) model that mimics the eye's blinking stimulus, allowing for spatiotemporal analysis of metabolite secretion and transportation in the barrier^{1, 2}. This study used the CEpOC model to investigate the effects of DCF on the corneal barrier under dry eye-like conditions (DE). RNA sequencing of human corneal epithelial cells (HCE-T) revealed significant changes in the expression of key DE-related genes, such as overexpression of collagen and inflammatory cytokines and downregulation of adherence junctions, lubricant mucins, and cytokeratin filaments. Although DCF did not affect cell viability, it led to an overexpression of the pro-inflammatory cytokine IL-6 and a down-regulation of growth factor TGF-β1, occludin tight junction, and the antioxidant glutathione synthetase. These findings suggest that DCF may compromise the integrity of the corneal barrier under DE conditions, raising safety concerns.

¹Abdalkader, R. & Kamei, K.-I. Lab Chip 20, 1410–1417 (2020).

²Abdalkader, R., Chaleckis, R., Wheelock, C. E. & Kamei, K. Exp. Eye Res. 209, 108646 (2021).