sirolimus and Corneal-Diseases

Corneal diseases affect 4.2 million people worldwide and are a leading cause of vision impairment and blindness. Current treatments for corneal diseases, such as antibiotics, steroids, and surgical interventions, have numerous disadvantages and challenges. Thus, there is an urgent need for more effective therapies. Although the pathogenesis of corneal diseases is not fully understood, it is known that injury caused by various stresses and postinjury healing, such as epithelial renewal, inflammation, stromal fibrosis, and neovascularization, are highly involved. Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, metabolism, and the immune response. Recent studies have revealed that activation of mTOR signalling extensively contributes to the pathogenesis of various corneal diseases, and inhibition of mTOR with rapamycin achieves promising outcomes, supporting the potential of mTOR as a therapeutic target. In this review, we detail the function of mTOR in corneal diseases and how these characteristics contribute to disease treatment using mTOR-targeted drugs.

Topics: Corneal Diseases; Humans; Inflammation; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Autophagy has been reported to be involved in many aspects of innate and adaptive immunity. Manipulating autophagy is recognized as a promising therapeutic approach for treating immunological diseases, including allograft rejection, and graft-versus-host disease. However, whether autophagy was closely associated with the pathogenesis of corneal allograft rejection remains largely unknown. Here, we showed that rapamycin (RAPA)-induced autophagy alleviated corneal allograft rejection. By contrast, blocking autophagic activity using 3-methyladeine (3-MA) aggravated corneal transplantation rejection. Mechanistically, we revealed that the enhanced autophagic turnover by RAPA inhibited NLRP3 inflammasome activity through NLRP3 degradation. While blocking the fusion of autophagosomes with lysosomes by bafilomycin A1(BafA1), the reduced NLRP3 inflammasome activity induced by RAPA was significantly restored, with increased protein levels of NLRP3 and cleaved Casp-1(p10), as well as IL-1β secretion. Moreover, we further revealed that pharmacologically blocking NLRP3 inflammasome signaling prolonged the survival of corneal allografts. Taken together, these findings underscored the critical roles of enhanced autophagy in treating corneal allograft rejection, which provided an alternative intervention strategy to control corneal transplantation rejection.

Topics: Autophagy; Corneal Diseases; Corneal Transplantation; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Sirolimus

To investigate the protective effect of rapamycin on oxidative stress-induced cell death of human corneal endothelial cells (HCECs).. HCECs were cultured according to previously published methods. With treatment of 0 mM or 5 mM of tert-butyl hydroperoxide (tBHP) with various concentrations (0, 25 and 50 nM) of rapamycin, reactive oxygen species (ROS) production was measured using an oxidation-sensitive fluorescent probe, 2'7'-dichlorofluorescin diacetate (DCFH-DA, USA) methods. Cell viability was assayed by the method of Cell Counting Kit-8 (CCK-8, Wako). The levels of cellular glutathione were also assessed enzymatically with glutathione reductase by using a commercial glutathione (GSH) assay kit (Cayman Chemical, USA).. Rapamycin reduced 2'7'-dihydrodichlorofluorescein oxidation and increased GSH in HCECs. Rapamycin significantly inhibited tBHP-induced ROS production. Cells treated with rapamycin showed higher viability compared to control at 5 mM tBHP. Rapamycin effectively protected HCECs from ROS-induced cell death through increasing intracellular GSH.. Our data suggest that rapamycin protects HCECs from oxidative injury-mediated cell death via inhibition of ROS production and enhancement of GSH.

Topics: Adult; Cell Count; Cell Death; Cells, Cultured; Corneal Diseases; Endothelium, Corneal; Humans; Immunosuppressive Agents; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Sirolimus