TNF-α and NF-κB signaling play a critical role in cigarette smoke-induced epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy

Abstract

Proliferative vitreoretinopathy (PVR) is characterized by the growth and contraction of cellular membranes within the vitreous cavity and on both surfaces of the retina, resulting in recurrent retinal detachments and poor visual outcomes. Proinflammatory cytokines like tumor necrosis factor alpha (TNFα) have been associated with PVR and the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. Cigarette smoke is the only known modifiable risk factor for PVR, but the mechanisms are unclear. The purpose of this study was to examine the impact of cigarette smoke on the proinflammatory TNFα/NF-κB/Snail pathway in RPE cells to better understand the mechanisms through which cigarette smoke increases the risk of PVR. Human ARPE-19 cells were exposed to cigarette smoke extract (CSE), for 4 to 24-hours and TNFα, Snail, IL-6, IL-8, and α-SMA levels were analyzed by qPCR and/or Western blot. The severity of PVR formation was assessed in a murine model of PVR after intravitreal injection of ARPE-19 cells pre-treated with CSE or not. Fundus imaging, OCT imaging, and histologic analysis 4 weeks after injection were used to examine PVR severity. ARPE-19 cells exposed to CSE expressed higher levels of TNFα, SNAIL, IL6 and IL8 mRNA as well as SNAIL, Vimentin and α-SMA protein. Inhibition of TNFα and NF-κB pathways blocked the effect of CSE. In vivo, intravitreal injection of ARPE-19 cells treated with CSE resulted in more severe PVR compared to mice injected with untreated RPE cells. These studies suggest that the TNFα pathway is involved in the mechanism whereby cigarette smoke increases PVR. Further investigation into the role of TNFα/NF-κB/Snail in driving PVR and pharmacological targeting of these pathways in disease are warranted.

Risk factors for proliferative vitreoretinopathy after retinal detachment surgery: A systematic review and meta-analysis

“…Additionally, smoking was correlated with the development of uveitis and retinal neovascularization [ 34 , 35 ]. Wang et al [ 36 ] indicated that the increase of pro-inflammatory cytokine signaling could play an essential role in the development of PVR in smokers. More investigations are needed to clarify the role of smoking in the risk of PVR after RD surgery.…”

Surgical Failures After Primary Scleral Buckling for Rhegmatogenous Retinal Detachment

“…8,25,26 A recent study has suggested that increased signaling of proinflammatory cytokines may contribute a crucial role of PVR development in cigarette smokers, a feature that may be relevant whether undergoing SBP, PPV, or both. 27 Two features that may influence the decision to pursue SB for RD repair include the absence of posterior vitreous detachment (PVD) preoperatively and the chronicity/duration of visual symptoms. Evolution of PVD after SB has been cited as a cause for surgical failure, as new retinal tears may result.…”

“…8,25,26 A recent study has suggested that increased signaling of proinflammatory cytokines may contribute a crucial role of PVR development in cigarette smokers, a feature that may be relevant whether undergoing SBP, PPV, or both. 27…”

Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma

“…CSE was prepared by bubbling smoke from two 1R6F research cigarettes into 20 mL of serum-free culture RPMI medium at one cigarette/min. 57 After adjusting pH to 7.4, the medium was considered 100% CSE. Serum-free culture RPMI medium was used as a control for CSE treatment in vitro .…”