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AbstractPurposeMethodsResultsConclusionsGlaucoma filtration surgery (GFS) stands as a paramount clinical intervention for glaucoma. Nonetheless, the prevalent cause of GFS failure is filtration bleb scarring, and the role of inflammation and immune response in contributing to fibrosis remains elusive.The study employed 30 female Sprague-Dawley rats (8 weeks old, 200-250 g) to assess the anti-scarring impact of the Chemokine (C-C motif) receptor 5 (CCR5)-Chemokine (C-C motif) ligand 5 (CCL5) antibody after GFS. Additionally, anti-fibrotic effects on HConFs were examined, creating an intra-operative inflammatory response using damaged-HConFs supernatant medium (DHSM). In vitro and in vivo validation aimed to elucidate the potential anti-fibrotic molecular mechanism of the CCR5-CCL5 antibody.The CCR5-CCL5 antibody effectively prolonged filtration bleb duration and enhanced the functionality of the filtered bleb. Improved postoperative intraocular pressure values (IOP) and morphological images were observed in the CCR5-CCL5 antibody-treated group. Histochemical staining and cellular experiments confirmed the antifibrotic function of the CCR5-CCL5 antibody. Notably, M2-type macrophage polarization was reduced in the CCR5-CCL5 antibody-treated model. CCL5-induced fibrosis in HConFs was mediated through the PI3K/Akt signaling pathway. Consistently, inhibition of PI3K/Akt significantly attenuated the profibrotic effects of CCR5-CCL5. Mechanistically, the CCL5 antibody exerts its antifibrotic effect by targeting CCR5 on HConFs, leading to the inhibition of the PI3K/Akt mechanism.This study unveils that CCR5-CCL5 promotes fibrosis in GFS through inflammatory stimulation of HConFs and enhanced activation of the PI3K/Akt signaling pathway. The findings suggest that intraoperative CCR5-CCL5 antibody treatment could serve as a cost-effective therapeutic agent or a useful adjuvant in preventing ocular bleb scar formation. [ABSTRACT FROM AUTHOR]

Metformin has effective therapeutic effects in anti-tumor and anti-fibrotic diseases. However, how the antifibrotic effect of metformin in the eye and how it is transferred are still unclear. Here, the eye drop of metformin treatment was studied in Sprague–Dawley (SD) rats of glaucoma filtrating surgery (GFS). Rats were administered randomly bilateral drops: control group (without surgery), GFS group, metformin group or mitomycin C (MMC) group (sponge application intraoperatively, 0.02%). Bleb features and intraocular pressure (IOP) were assessed for postoperative week 4. Metformin effectively inhibited fibrosis and improved the surgical outcomes of GFS. In vitro, we found that the degree of oxidative stress and fibrosis in metformin pretreated-Human Conjunctival Fibroblasts (HConFs) were reduced; the pro-fibrotic response of HConFs were decreased by inducing macrophagic polarity changes. Besides, the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2)/AMP-activated protein kinase (AMPK) and the competition of organic cation transporters (OCTs) effectively reduced the anti-fibrotic capability of metformin. Together, this experiment indicates that metformin enters into HConFs cell with OCTs, which can protect against filtrating blebs scar formation in SD rats of GFS via activating AMPK/Nrf2 axis and the downregulation of profibrogenic and inflammatory biomarkers.

Metformin has effective therapeutic effects in anti-tumor and anti-fibrotic diseases. However, how the antifibrotic effect of metformin in the eye and how it is transferred are still unclear. Here, the eye drop of metformin treatment was studied in Sprague–Dawley (SD) rats of glaucoma filtrating surgery (GFS). Rats were administered randomly bilateral drops: control group (without surgery), GFS group, metformin group or mitomycin C (MMC) group (sponge application intraoperatively, 0.02%). Bleb features and intraocular pressure (IOP) were assessed for postoperative week 4. Metformin effectively inhibited fibrosis and improved the surgical outcomes of GFS. In vitro , we found that the degree of oxidative stress and fibrosis in metformin pretreated-Human Conjunctival Fibroblasts (HConFs) were reduced; the pro-fibrotic response of HConFs were decreased by inducing macrophagic polarity changes. Besides, the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2)/AMP-activated protein kinase (AMPK) and the competition of organic cation transporters (OCTs) effectively reduced the anti-fibrotic capability of metformin. Together, this experiment indicates that metformin enters into HConFs cell with OCTs, which can protect against filtrating blebs scar formation in SD rats of GFS via activating AMPK/Nrf2 axis and the downregulation of profibrogenic and inflammatory biomarkers. [ABSTRACT FROM AUTHOR]

Glaucoma filtration surgery (GFS) is an effective clinical treatment for glaucoma when intraocular pressure (IOP) control is poor. However, the occurrence of conjunctival scarring at the surgical site is the main reason for failure of the surgery. In a previous study, we isolated and developed S58, a novel nucleic acid aptamer targeting TβR II, by systematic evolution of ligands by exponential enrichment (SELEX). Here, we show how S58 sterically inhibits the TβR II interaction with TGF-β. The effects of topical S58 treatment were studied in a rabbit model of GFS. At 6 postoperative weeks, S58 reduced fibrosis and prolonged bleb survival in rabbits after GFS. Further in vitro tests showed that the levels of fibrosis in S58 treated-Human Conjunctival Fibroblasts (HConFs) were decreased and that antioxidant defense was increased. In addition, the loss of nuclear factor erythroid 2-related factor 2 (Nrf2) or the inhibition of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) reversed the anti-fibrotic effects of S58. The present work suggests that S58 could effectively improve GFS surgical outcomes by activating the intracellular antioxidant defense PI3K/Akt/Nrf2 signaling pathway.

Anti-fibrotic therapeutic methods with safety and efficiency after glaucoma filtration surgery (GFS) are desirable. In our previous study, by using Human Tenon's Fibroblasts (HTFs) as a model, we proved the expression of peroxisome proliferator activates receptor-γ (PPAR-γ) in HTFs; in addition, rosiglitazone (RSG), an agonist of PPAR-γ, can inhibit transforming growth factorsβ1 (TGF-β1)-induced reactivation of HTFs, thus to inhibit specifically scarring after GFS through intervening TGF-β/Smads signal pathway. However, a better drug delivery way of RSG, to prolong the duration of its function, and to reduce the toxicity of RSG to ocular tissue still remains challenges. Low density lipoprotein receptor (LDLr) is strongly expressed in hyper-proliferation HTFs after GFS. Therefore, we structured targeting LDL-RSG complexes and channel them into HTFs through LDL-LDLr pathway in order to promote anti-proliferation of HTFs and reduce the toxicity to ocular tissue. Meanwhile, in order to improve the release properties of LDL-RSG complexes, we structured slow release system of LDL-RSG/chitosan-calcium alginate - nanoparticles (CSNP), which effectively inhibited TGF-β1-induced HTFs proliferation, synthesis of extracellular matrix and activation of TGF-β1/SMAD pathway. These data suggested that LDL-RSG/CSNP can be a new anti-fibrotic therapeutic method on scarring after GFS and also a novelty administration of RSG., Competing Interests: CONFLICTS OF INTEREST None for all authors.