Abstract
Corneal scarring is characterized by the improper deposition of extracellular matrix components and myofibroblast differentiation from keratocytes. The bromodomain-containing protein 4 (BRD4) inhibitor JQ1 has been shown to attenuate pathological fibrosis. The present study aimed to explore the potential therapeutic effect of JQ1 on mechanical injury-induced mouse corneal scarring and TGFβ-induced human corneal myofibroblast differentiation and the related mechanism. The corneal scarring and myofibroblast differentiation were evaluated with clinical observation and fibrosis-related gene expression analysis. In mice, subconjunctivally injected JQ1 suppressed the initial development and reversed the established progression of corneal scarring, while having no impairment on the epithelial regenerative capacity. BRD4 inhibition with either JQ1 or small-interfering RNA inhibited the differentiation and promoted the dedifferentiation of human corneal myofibroblasts. Moreover, JQ1 attenuated the accumulation of intracellular reactive oxygen species induced by TGFβ treatment, induced Nrf2 nuclear translocation and activated the expression of Nrf2-ARE downstream antioxidant genes. In conclusion, this study implicates that JQ1 suppresses and reverses corneal scarring through the regulation of BRD4 inhibition and Nrf2-dependant antioxidant induction.
Highlights
Corneal transparency is important for the light transmission to the retina for optimal vision
The JQ1 supplement suppressed the differentiation of corneal myofibroblasts induced by transforming growth factor β (TGFβ), which is shown as the weaker staining of α-smooth muscle actin (α-SMA), F-actin and Collagen I (Fig. 1a)
JQ1 attenuates mechanical injury-induced corneal scarring To investigate the effect of JQ1 during the progression of corneal scarring, a mechanical injury-induced mouse corneal scarring model was established by removing the corneal epithelium and anterior stroma
Summary
Corneal transparency is important for the light transmission to the retina for optimal vision. Corneal scarring is the most common result after trauma, infection, or refractive surgery and causes visual impairment[1]. Keratocytes, the major cellular elements in the corneal stroma, remain quiescent and synthesize extracellular matrix (ECM) components to maintain corneal stromal turnover. Inflammation-induced transforming growth factor β (TGFβ) activates the transition of corneal keratocytes into fibroblasts and myofibroblasts with the expression of α-smooth muscle actin (α-SMA) as key marker[2,3,4,5]. Myofibroblasts rapidly synthesize and secrete redundant ECM proteins, including Collagen I and fibronetin during wound healing, leading. Targeting therapies primarily depend on corneal transplantation. Pharmacologic interventions with corticosteroids and mitomycin C are limited because of the side effects such as ulceration and reduced keratocyte density of the anterior stroma[7,8,9]
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