P38 inhibition reverses TGFβ1 and TNFα-induced contraction in a model of proliferative vitreoretinopathy.
Lauren SchiffNathan C BolesMarie FernandesBar NachmaniRonald GentileTimothy A BlenkinsopPublished in: Communications biology (2019)
Proliferative vitreoretinopathy (PVR) is a metaplasia in the vitreous of the eye manifested by the transformation of retinal pigment epithelial (RPE) cells and the development of contracting epiretinal membranes (ERM), which lead to retinal detachment and vision loss. While TGFβ1 and TNFα have been associated with PVR, here we show that these cytokines act synergistically to induce an aggressive contraction phenotype on adult human (ah)RPE. Connected RPE detach upon contraction and form motile membranes that recruit more cells. TGFβ1 and TNFα (TNT)-induced contracting membranes uniquely express muscle and extracellular rearrangement genes. Whole transcriptome RNA sequencing of patient-dissected PVR membranes showed activation of the p38-MAPK signaling pathway. Inhibition of p38 during TNT treatment blocks ahRPE transformation and membrane contraction. Furthermore, TNT-induced membrane contractility can be reversed by p38 inhibition after induction. Therefore, targeting the p38-MAPK pathway may have therapeutic benefits for patients with PVR even after the onset of contracting ERMs.
Keyphrases
- induced apoptosis
- high glucose
- rheumatoid arthritis
- signaling pathway
- smooth muscle
- diabetic rats
- transforming growth factor
- endothelial cells
- cell cycle arrest
- epithelial mesenchymal transition
- drug induced
- gene expression
- genome wide
- oxidative stress
- cell death
- pi k akt
- case report
- dna methylation
- drug delivery
- stress induced
- induced pluripotent stem cells
- combination therapy