Celastrol-based nanoporous membranes prevent subconjunctival fibrosis by activating autophagy

Abstract

Subconjunctival fibrosis is the final manifestation of various ocular surface injuries and inflammatory diseases; however, clinical treatment is not currently available to prevent or reverse this condition. Celastrol, a triterpene derived from Tripterygium wilfordii, is a potent antifibrotic agent. However, the underlying mechanism of the effect of celastrol on subconjunctival fibrosis remains unknown. It is difficult to choose the method of administration to improve the antifibrotic effect of drugs on subconjunctival fibrosis. In this study, we developed a class of porous nanofibrous membranes loaded with celastrol for sustainable release and hyaluronic acid as a coating layer to prevent burst release. The SEM images indicated that the nanopores and coating layer were clearly observed. In addition, Western blot and confocal microscopic analysis of human pterygium fibroblasts revealed that celastrol induced autophagy. Moreover, celastrol increased the expression of LC3 II in subconjunctival tissue and inhibited the expression of FN and COLⅠ in rats. This finding suggests that autophagy induction by celastrol protects against subconjunctival fibrosis. Furthermore, we revealed that celastrol activated autophagy by inhibiting the PI3K/Akt/mTOR pathway. Moreover, the porous nanofibrous membrane exhibited excellent biocompatibility for potential application in future clinical translation. Thus, this study reveals the importance of autophagy as a possible therapeutic target and celastrol as a potential candidate drug against subconjunctival fibrosis, demonstrating an alternative to inhibit fibrosis, and extend ocular sustainable delivery of various drugs to treat eye diseases.