Abstract
Purpose :
Glaucoma is a growing health concern, and 1 in 8 people will develop the condition by the age of 80. Glaucoma filtration surgery (GFS) is the most effective treatment, but it has a high failure rate due to scarring caused by activated Tenon's fibroblasts (HTFs). Transforming growth factor β (TGFβ) is a profibrotic growth factor that plays a major role in ocular fibrosis. TGFβ activated kinase-1 (TAK1) is a kinase that regulates TGFβ signaling, and is key in fibrosis pathogenesis. This study aimed to demonstrate the protective antifibrotic effects of inhibiting TAK1 activity using 5Z-7-oxozeanol in HTFs.
Methods :
HTFs cultured from GFS patients were used for cell viability, cell proliferation, gel contractility and ELISA bioassays. In all experiments, three conditions were tested to investigate the effect of 5Z-7-oxozeanol: (1) media alone, (2) TGFβ1 (10 ng/mL) + vehicle, or (3) TGFβ1 (10 ng/mL) + 5Z-7-oxozeanol (0.1 to 30 uM). Cell-TiterGlo assessed cell viability and proliferation, collagen gel contraction assessed the contractile ability of HTFs in a three-dimensional collagen matrix, and ELISA detected the protein expression of fibrotic markers.
Results :
5Z-7-oxozeanol did not show toxicity up to 10 uM (P<0.001), therefore it was tested up to 10 uM in all assays. 5Z-7-oxozeanol reduced TGFβ1-induced HTFs proliferation (P<0.05). Comparative measurement of gel area showed that 5Z-7-oxozeanol also suppressed TGFβ1-induced cell contractility (P<0.05). The expression of a-SMA, fibronectin and collagen were also significantly lower with 5Z-7-oxozeanol treatment (P<0.001).
Conclusions :
5Z-7-Oxozeaenol can inhibit the profibrotic effects of TGFβ1 on HTFs, highlighting the feasibility of targeting TAK1 activity as a strategy to reduce fibrosis resulting from GFS.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.