Genotype-Phenotype Associations of IL6 and PRG4 With Conjunctival Fibrosis After Glaucoma Surgery

Abstract

IMPORTANCE Postsurgical fibrosis is a critical determinant of the long-term success of glaucoma surgery, but no reliable biomarkers are currently available to stratify the risk of scarring. OBJECTIVE To compare the clinical phenotype of patients with conjunctival fibrosis after glaucoma surgery with candidate gene expression tissue biomarkers of fibrosis. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, 42 patients were recruited at the time of glaucoma surgery at the Moorfields Eye Hospital from September 1, 2014, to September 1, 2016. The participants were divided into those with fibrosis and those without fibrosis. MAIN OUTCOMES AND MEASURES Genotype-phenotype correlations of the IL6 or PRG4 gene and detailed clinical phenotype. The IL6 and PRG4 protein expression in conjunctival tissues was also assessed using in situ immunohistochemical analysis. Central bleb area, maximal bleb area, and bleb height were graded on a scale of 1 to 5 (1 indicating 0%; 2, 25%; 3, 50%; 4, 75%; and 5, 100%). Bleb vascularity was graded on a scale of 1 to 5 (1 indicating avascularity; 2, normal; 3, mild; 4, moderate; and 5, severe hyperemia). RESULTS A total of 42 patients were recruited during the study period; 28 participants (67%) had previously undergone glaucoma surgery (fibrotic group) (mean [SD] age, 43.8 [3.6 years]; 16 [57%] female; 22 [79%] white), and 14 participants (33%) had not previously undergone glaucoma surgery (nonfibrotic group) (mean [SD] age, 47.7 [6.9] years; 4 [29%] female; 9 [64%] white). The fibrotic group had marked bleb scarring and vascularization and worse logMAR visual acuity. The mean (SD) grades were 1.4 (0.1) for central bleb area, 1.4 (0.1) for bleb height, and 3.4 (0.2) for bleb vascularity. The IL6 gene was upregulated in fibrotic cell lines (mean, 0.040) compared with nonfibrotic cell lines (mean, 0.011) (difference, 0.029; 95% CI, 0.015-0.043; P = .003). The PRG4 gene was also downregulated in fibrotic cell lines (0.002) compared with nonfibrotic cell lines (mean, 0.109; difference, 0.107; 95% CI, 0.104-0.110; P = .03). The study found a strong correlation between the IL6 gene and the number of glaucoma operations (r = 0.94, P < .001) and logMAR visual acuity (r = 0.64, P = .03). A moderate correlation was found between the PRG4 gene and the number of glaucoma operations (r = −0.72, P = .005) and logMAR visual acuity (r = −0.62, P = .03). CONCLUSIONS AND RELEVANCE IL6 and PRG4 represent potential novel tissue biomarkers of disease severity and prognosis in conjunctival fibrosis after glaucoma surgery. Future longitudinal studies with multiple postoperative measures are needed to validate the effect of these potential biomarkers of fibrosis.

Cytokine profile in tear and aqueous humor of primary open-angle patients as a prognostic factor for trabeculectomy outcome

“…21,22 Studies regarding increased fibrosis in patients with trabeculectomy failure reveal an up-regulation of the IL-6 and PRG4 gene as well as increases in VEGF and MCP-1 aqueous humor levels, although samples as small and not many inflammatory markers have simultaneously been evaluated. [23][24][25][26] Therefore, given that inflammation markers are elevated in glaucoma and have been associated with increased scarring after trabeculectomy, it is possible that higher preoperative ocular pro-inflammatory cytokine levels may determine the success of surgery. In this regard, valuable prognostic biomarkers for trabeculectomy success could be obtained.…”

Gasotransmitters: Potential Therapeutic Molecules of Fibrotic Diseases

“…Translocation of activated NF-κB into the nucleus can promote the expression of related genes, such as TNF-α, IL-6, IL1β, and NLRP3 [49]. These substances are reported to play an important role in the occurrence and development of fibrosis [50][51][52][53][54][55]. Research showed that Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, can ameliorate chronic kidney disease through mitigating TNF-mediated tissue injury and fibrosis [50].…”

Expression of Lubricin in the Human Amniotic Membrane

“…2 Lubricin is produced by numerous tissues, including the cornea, conjunctiva, trabecular meshwork, heart, lung, liver, cartilage, bone, kidney, brain, testis, placenta and small intestine. 1,[10][11][12][13][14] At these locations lubricin may act to regulate a number of processes, such as homeostasis, tissue development, shear stress, innate immunity, inflammation and wound healing. 1,[11][12][13] We hypothesize that lubricin is also synthesized and expressed by the amniotic membrane (AM).…”

“…1,[10][11][12][13][14] At these locations lubricin may act to regulate a number of processes, such as homeostasis, tissue development, shear stress, innate immunity, inflammation and wound healing. 1,[11][12][13] We hypothesize that lubricin is also synthesized and expressed by the amniotic membrane (AM). Our rationale is that this tissue possesses anti-adhesive, anti-fibrotic and antiinflammatory properties, and promotes ocular surface redevelopment and wound healing.…”