Elevated Neutrophil Elastase in Tears of Ocular Graft-Versus-Host Disease Patients

Arafat, Samer N.; Robert, Marie-Claude; Abud, Tulio Batista; Spurr-Michaud, Sandra; Amparo, Francisco; Dohlman, Claes H.; Dana, Reza; Gipson, Ilene K.

doi:10.1016/j.ajo.2016.12.026

Cited by 43 publications

(21 citation statements)

References 44 publications

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“…This confirms that neutrophils and NETs are not the source of TNF-α found on the ocular surface. While the presence of some cytokines (neutrophil elastase, myeloperoxidase, IL-8 and TNFα) in the tears has been previously reported, 36,37,105,106 the presence of Oncostatin M, NGAL, BDNF and LIGHT/ TNFSF14 is a novel finding and may be clinically relevant as one or more of these NETassociated proteins may serve as a potential biomarker in oGVHD, therefore these will be discussed in more details.…”

Section: Discussionmentioning

confidence: 96%

“…In a pre-clinical murine model of chronic oGVHD, neutrophils form a significant component of the intracorneal infiltrate. 35 Marked abundance of neutrophil elastase has been reported in tears of chronic oGVHD patients, 36 which is indirect evidence of neutrophilic activity. Neutrophils have been found in impression cytology specimens from the ocular surfaces of patients with chronic oGVHD.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies

Ilangovan

Surenkhuu

et al. 2019

The Ocular Surface

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Purpose: To investigate the role of neutrophil extracellular traps (NETs) and NET-associated proteins in the pathogenesis of oGVHD and whether dismantling of NETs with heparin reduces those changes. Methods: Ocular surface washings from oGVHD patients and healthy subjects were analyzed. Isolated peripheral blood human neutrophils were stimulated to generate NETs and heparinized NETs. We performed in vitro experiments using cell lines (corneal epithelial, conjunctival fibroblast, meibomian gland (MG) epithelial and T cells), and in vivo experiments using murine models, and compared the effects of NETs, heparinized NETs, NET-associated proteins and neutralizing antibodies to NET-associated proteins. Results: Neutrophils, exfoliated epithelial cells, NETs and NET-associated proteins (extracellular DNA, Neutrophil Elastase, Myeloperoxidase, Oncostatin M (OSM), Neutrophil gelatinaseassociated lipocalin (NGAL) and LIGHT/TNFSF14) are present in ocular surface washings (OSW) and mucocellular aggregates (MCA). Eyes with high number of neutrophils in OSW have more severe signs and symptoms of oGVHD. NETs (and OSM) cause epitheliopathy in murine corneas. NETs (and LIGHT/TNFSF14) increase proliferation of T cells. NETs (and NGAL) inhibit proliferation and differentiation of MG epithelial cells. NETs enhance proliferation and myofibroblast transformation of conjunctival fibroblasts. Sub-anticoagulant dose Heparin (100 IU/mL) dismantles NETs and reduces epithelial, fibroblast, T cell and MG cell changes induced by NETs.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies

Ilangovan

Surenkhuu

et al. 2019

The Ocular Surface

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“…This cannot not be attributed to polymer irritation caused by placement at the inferior bulbar surface because our studies have demonstrated that even superior bulbar placement of the DDS still results in severe inferior corneal NV. We postulate that this is due to the presence of inflammatory cytokine in the tears 40 – 42 that pool inferiorly due to gravity. In addition, vessel maturation leads to loss of dependency on VEGF signaling, and therefore anti-VEGF therapy gradually becomes less effective.…”

Section: Discussionmentioning

confidence: 97%

Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye

Zhou

Singh

Qian

et al. 2020

Trans. Vis. Sci. Tech.

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To describe a novel microporous drug delivery system (DDS) for sustained antivascular endothelial growth factor (VEGF) delivery to the eye and to evaluate its efficacy in a corneal injury model. Methods: A macro-porous DDS (1.5 × 1.5 × 4 mm) loaded with 2 mg of bevacizumab was implanted subconjunctivally in three Dutch-belted pigmented rabbits after corneal alkali injury (2N NaOH). Three rabbits received sham DDS. Animals were followed for three months and assessed in vivo and ex vivo for corneal neovascularization (NV), epithelial defect, stromal scarring, endothelial cell loss, and expression of angiogenic and inflammatory markers in the cornea and retina. Results: Anti-VEGF DDS treatment led to complete inhibition of superior cornea NV and complete corneal re-epithelialization by day 58 whereas sham DDS resulted in severe cornea NV and persistent epithelial defect (9%∼12% of total cornea area) through the end of the study. Histologically, anti-VEGF DDS significantly reduced CD45 + and F4/80 CD11b + cell accumulation (79%, P < 0.05) in the cornea, ameliorated tumor necrosis factor-α expression (90%, P < 0.05), reduced corneal stromal scarring and prevented corneal endothelial cell loss, as compared to sham DDS. Moreover, anti-VEGF DDS achieved retinal penetration and reduction in retinal VEGF levels at 3 months. Conclusions: Use of subconjunctival anti-VEGF DDS suppresses cornea NV, inflammation, stromal scarring, prevents endothelial cell loss, and abrogates retinal VEGF upregulation in a rabbit corneal alkali burn model. Moreover, it delivers anti-VEGF antibodies to the retina for three months. This delivery platform could enable antibody therapy of other corneal and retinal vascular pathologies. Translational Relevance: We describe a method for sustained anti-VEGF delivery to the eye for the treatment of ocular injuries.

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“…Neutrophil elastase is a potent sheddase of mucins. 57,58 Further, data from these studies indicate that galectin-3 could potentially be used as a biomarker for the evaluation and management of patients with ocular surface pathology.…”

Section: New Evaluation For Decreased Wettability and Glycocalyx Barrmentioning

confidence: 95%

The Ocular Surface Glycocalyx and its Alteration in Dry Eye Disease: A Review

Uchino

2018

Invest. Ophthalmol. Vis. Sci.

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Many studies have revealed that transmembrane mucins, large glycoproteins with heavily glycosylated glycans, are essential for maintaining ocular surface epithelium lubrication and wettability. Recent reports indicate that transmembrane mucins and galectin-3, a chimera type of galectin that binds b-galactoside in the glycan, play a crucial role in maintaining the epithelial glycocalyx barrier. This review summarizes current evidence regarding the role of galectin-3, the role of the three major transmembrane mucins (i.e., MUC1, MUC4, and MUC16), in the maintenance of ocular surface wettability and transcellular barrier. Pathological mechanisms of glycocalyx barrier disruption and epithelial surface wettability decreases in dry eye disease are also summarized. Lastly, new ophthalmic drugs that target transmembrane mucin are described.

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Elevated Neutrophil Elastase in Tears of Ocular Graft-Versus-Host Disease Patients

Cited by 43 publications

References 44 publications

Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies

Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies

Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye

The Ocular Surface Glycocalyx and its Alteration in Dry Eye Disease: A Review

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