Inhibition of Monocyte Chemoattractant Protein 1 Prevents Conjunctival Fibrosis in an Experimental Model of Glaucoma Filtration Surgery

Chong, Rachel S.; Lee, Ying Shi; Chu, Stephanie; Toh, Li Zhen; Wong, Tina

doi:10.1167/iovs.17-21480

Cited by 17 publications

(10 citation statements)

References 48 publications

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“…Among these growth factors, the levels of several factors such as TGF-β, VEGF, CTGF, and MCP-1 increased in the AH in POAG, XFG, or neovascular glaucoma patients, which suggests that these factors stimulated the signaling pathway leading to myofibroblast transdifferentiation of HCFs, monocyte-derived cell infiltration, and ECM remodeling after trabeculectomy 11 , 13 – 15 , 27 . Several in vivo and in vitro studies have suggested that modulation of these factors could be used as a novel strategy to control scarring after trabeculectomy 13 , 14 , 28 .…”

Section: Discussionmentioning

confidence: 99%

Increased aqueous autotaxin and lysophosphatidic acid levels are potential prognostic factors after trabeculectomy in different types of glaucoma

Igarashi

Honjo

Kurano

et al. 2018

Sci Rep

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We explored the potential relevance of aqueous lysophosphatidic acid (LPA) and autotaxin (ATX) levels on postoperative outcomes of trabeculectomy, and the effects of ATX on fibrotic response in cultured human conjunctiva fibroblast (HCF) cells. We enrolled 70 glaucomatous eyes which underwent trabeculectomy, and quantified aqueous LPA and ATX. Those eyes were followed up for 12 months, and postoperative filtering blebs were evaluated using anterior segment optical coherence tomography. Also, the ATX-induced fibrotic changes in HCFs and the effects of an ATX inhibitor were assessed. Measured aqueous ATX and LPA levels were significantly different between glaucoma subtypes. In multivariate analyses, aqueous ATX levels were significantly correlated with the presence of needlings at 1, 3, 6 and 12 months after surgery. Exfoliative glaucoma, whose ATX level was significantly high, showed significantly increased numbers of needlings and a lower cumulative success rate without needlings. An in vitro study showed that fibrotic changes were upregulated by ATX treatment in HCFs, which was significantly suppressed by an ATX inhibitor. We presently demonstrate that aqueous ATX may be a prognostic factor affecting the fibrotic response in HCFs and bleb formation, and inhibition of ATX could be a therapeutic target after trabeculectomy.

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Section: Discussionmentioning

confidence: 99%

Increased aqueous autotaxin and lysophosphatidic acid levels are potential prognostic factors after trabeculectomy in different types of glaucoma

Igarashi

Honjo

Kurano

et al. 2018

Sci Rep

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“…Common between both in vivo and in vitro profiles is the specific modulation of CCL2 and several members of the interleukin family. Elevated CCL2 is implicated in greater risk of scarring in glaucoma surgery [ 37 , 38 ]. The capacity of VPA to suppress these cytokines, particularly CCL2 and VEGF-A, by steady-state conjunctival fibroblasts, suggests that pre-treatment with VPA may be advantageous for preempting the full cascade of the inflammatory and angiogenic responses in the aftermath of surgery.…”

Section: Discussionmentioning

confidence: 99%

Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva

et al. 2018

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Valproic acid (VPA) is a histone deacetylase inhibitor used clinically for neurological disorders. It is also potentially useful as anti-fibrotic therapy as it reduced collagen deposition in the post-operative conjunctiva. In this study, we further evaluated the effects of VPA on post-operative inflammation using the mouse model of conjunctival scarring. VPA, injected into the subconjunctiva immediately after surgery, did not cause any adverse tissue response when examined by live microscopy and produced an apparent reduction of proinflammatory and proangiogenic markers in immunohistological examinations. In-depth analyses of the treated operated tissues revealed that VPA selectively inhibited the CD45highF4/80low macrophage subset as well as the production of specific proinflammatory cytokines/ chemokines, including CXCL1, IL-5, IL-6, and IL-10 which were reduced by ≥ 2.0-fold. VPA also specifically reduced tissue NF-кB2 p100 protein by mean 3.87-fold. On conjunctival fibroblasts, VPA treatment resulted in decreased secretion of specific cytokines, including CCL2, VEGF-A, and IL-15. In the presence of TNF-α, VPA inhibited the induction of specific cytokines/chemokines, notably CCL5 and VEGF-A, as well as NF-кB2 p100. In corroboration, VPA suppressed TNF-α stimulation of NF-кB reporter transcription by 1.51-fold. These data indicate that VPA can modulate both proinflammatory cellular and molecular targets in a selective manner and may therefore attenuate surgery-induced conjunctival inflammation. These and previous findings suggest that, by suppressing key mediators of both inflammation and fibrosis, VPA is a useful therapeutic for improving surgical outcome involving the conjunctiva.Key messages VPA inhibited recruitment of a CD45highF4/80low macrophage subset. VPA reduced chemokine and cytokine levels in treated tissues.VPA selectively suppressed tissue NF-кB2 p100 levels.VPA suppressed TNF-α induction of chemokines, cytokines and NF-кB2 p100 expression.VPA suppressed TNF-α stimulation of NF-кB reporter.

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“…Experimental animal models provide the major advantage of producing readily available biological samples to perform multiple assays on. This has enabled the development of studies that make use of objective quantitative methods such as real‐time polymerase chain reactions to study genetic alterations in experimental glaucoma filtration surgery, as well as histological research that evaluates differences in inflammatory cell populations in terms of cell proliferation/density, cell toxicity and changes in the extracellular matrix (Seet et al; 2010; Chong et al 2017). Changes in the inflammatory cell profile mediate scarring predisposition due to the increased secretion of profibrotic cytokines, together with the deposition of extracellular matrix proteins such as collagen and fibronectin that are important modulators of wound healing.…”

Section: Considerations When Evaluating Animal Models Of Glaucoma Filmentioning

confidence: 99%

“…An example of these imaging methods is shown in Fig. 1 (Chong et al 2017). Capsular porosity has also been postulated to be a major determinant of fluid outflow (Gardiner et al 2010) and has been studied in rabbits following the implantation of intracameral drainage devices (Nguyen et al 2012; Pandav et al 2016) where the authors found that infusions of balanced salt solution at physiological pressures in the absence of inflammatory cytokines were sufficient to alter the porosity of the fibrous capsule at the surgical site.…”

Section: Considerations When Evaluating Animal Models Of Glaucoma Filmentioning

confidence: 99%

Experimental models of glaucoma filtration surgery

Chong

Crowston

Wong

2020

Acta Ophthalmologica

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Glaucoma filtration surgery plays an important role in achieving intraocular pressure (IOP) reduction in patients who have high IOP despite maximum medical therapy. Preclinical experimental models of glaucoma filtration surgery contribute a great deal to our knowledge of the wound healing processes that predispose to scarring and may lead to poor outcomes. However, this research needs to be interpreted in the light of the specific study design, animal model and methods used. We review the existing literature addressing various models of experimental glaucoma filtration surgery, discuss the considerations in assessing these models and describe future steps in evaluating potential therapeutics and bleb characteristics that could impact translational research in this field.

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Inhibition of Monocyte Chemoattractant Protein 1 Prevents Conjunctival Fibrosis in an Experimental Model of Glaucoma Filtration Surgery

Abstract: Targeting MCP-1 results in prolonged bleb survival following experimental GFS with less cellular toxicity as compared to MMC. MCP inhibition could provide a safer alternative to conventional antifibrotic adjunctive treatments in GFS.

Cited by 17 publications

References 48 publications

Increased aqueous autotaxin and lysophosphatidic acid levels are potential prognostic factors after trabeculectomy in different types of glaucoma

Increased aqueous autotaxin and lysophosphatidic acid levels are potential prognostic factors after trabeculectomy in different types of glaucoma

Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva

Experimental models of glaucoma filtration surgery

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