Lipoxin A4 (LXA4) Reduces Alkali-Induced Corneal Inflammation and Neovascularization and Upregulates a Repair Transcriptome.

Purpose: To investigate the anti-inflammatory and anti-angiogenic effects of the bioactive lipid mediator LXA4 on a rat model of severe corneal alkali injury.

Methods: To induce a corneal alkali injury in the right eyes of anesthetized Sprague Dawley rats. They were injured with a Φ 4 mm filter paper disc soaked in 1 N NaOH placed on the center of the cornea.

Neuroanatomy of Adult and Aging Chicken Cornea.

Purpose: To provide a complete nerve architecture and main sensory neuropeptide distribution in the chicken cornea.

Methods: Adult chickens aged 6 months and 4 years were used. The whole cornea was stained with protein gene product (PGP) 9.

Elucidating the structure and functions of Resolvin D6 isomers on nerve regeneration with a distinctive trigeminal transcriptome.

Innervation sustains cornea integrity. Pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) regenerated damaged nerves by stimulating the synthesis of a new stereoisomer of Resolvin D6 (RvD6si). Here, we resolved the structure of this lipid isolated from mouse tears after injured corneas were treated with PEDF + DHA.

ELV-N32 and RvD6 isomer decrease pro-inflammatory cytokines, senescence programming, ACE2 and SARS-CoV-2-spike protein RBD binding in injured cornea.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) has resulted in a pandemic affecting the most vulnerable in society, triggering a public health crisis and economic collapse around the world. Effective treatments to mitigate this viral infection are needed. Since the eye is a route of virus entrance, we use an in vivo rat model of corneal inflammation as well as human corneal epithelial cells (HCEC) in culture challenged with IFNγ as models of the eye surface to study this issue.

Neuroanatomy and neurochemistry of rat cornea: Changes with age.

Purpose: To characterize the entire rat corneal nerve architecture, the changes that occur with aging, and its sensory, sympathetic, and parasympathetic fiber distribution.

Methods: Sprague-Dawley rats (aged 1 day to 2 years old) of both sexes were euthanized, and the whole corneas were immunostained with protein gene product 9.5 (PGP9.

Elovanoid-N32 or RvD6-isomer decrease ACE2 and binding of S protein RBD after injury or INFγ in the eye.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) has resulted in a pandemic affecting the most vulnerable in society, triggering a public health crisis and economic tall around the world. Effective treatments to mitigate this virus infection are needed. Since the eye is a route of virus entrance, we use an rat model of corneal inflammation as well as human corneal epithelial cells in culture challenged with IFNγ to study this issue.

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature.

The high-density corneal innervation plays a pivotal role in sustaining the integrity of the ocular surface. We have previously demonstrated that pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) promotes corneal nerve regeneration; here, we report the mechanism involved and the discovery of a stereospecific Resolvin D6-isomer (RvD6si) that drives the process. RvD6si promotes corneal wound healing and functional recovery by restoring corneal innervation after injury.

Remodeling of Substance P Sensory Nerves and Transient Receptor Potential Melastatin 8 (TRPM8) Cold Receptors After Corneal Experimental Surgery.

Purpose: To investigate changes in corneal nerves positive to substance P (SP) and transient receptor potential melastatin 8 (TRPM8) and gene expression in the trigeminal ganglia (TG) following corneal surgery to unveil peripheral nerve mechanism of induced dry eye-like pain (DELP).

Methods: Surgery was performed on mice by removing the central epithelial and anterior stromal nerves. Mice were euthanized at different times up to 15 weeks.

Mapping the entire nerve architecture of the cat cornea.

Objective: To provide a complete nerve architecture and neuropeptide distribution in the cat cornea.

Animals Studied: Two adult domestic cats.

Procedure: The cat corneas were stained with protein gene product (PGP) 9.

Mouse strains and sexual divergence in corneal innervation and nerve regeneration.

A variety of mouse strains and sexes are used in studies of corneal wound healing and nerve regeneration. However, there is a gap of knowledge about corneal nerve density and its function in different mouse strains and sexes. In this study, we report a strain divergence of total and substance P (SP) sensory corneal nerves in uninjured mice.

Defining a mechanistic link between pigment epithelium-derived factor, docosahexaenoic acid, and corneal nerve regeneration.

The cornea is densely innervated to sustain the integrity of the ocular surface. Corneal nerve damage produced by aging, diabetes, refractive surgeries, and viral or bacterial infections impairs tear production, the blinking reflex, and epithelial wound healing, resulting in loss of transparency and vision. A combination of the known neuroprotective molecule, pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA), has been shown to stimulate corneal nerve regeneration, but the mechanisms involved are unclear.

PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection.

Herpes simplex virus type-1 (HSV-1) infection leads to impaired corneal sensation and, in severe cases, to corneal ulceration, melting and perforation. Here, we explore the potential therapeutic action of pigment epithelial-derived factor (PEDF) plus docosahexaenoic acid (DHA) on corneal inflammation and nerve regeneration following HSV-1 infection. Rabbits inoculated with 100,000 PFU/eye of HSV-1 strain 17Syn+ were treated with PEDF + DHA or vehicle.

Recovery of Corneal Sensitivity and Increase in Nerve Density and Wound Healing in Diabetic Mice After PEDF Plus DHA Treatment.

Diabetic keratopathy decreases corneal sensation and tear secretion and delays wound healing after injury. In the current study, we tested the effect of treatment with pigment epithelium-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) on corneal nerve regeneration in a mouse model of diabetes with or without corneal injury. The study was performed in streptozotocin-induced diabetic mice (C57BL/6).

Changes in Corneal Innervation after HSV-1 Latency Established with Different Reactivation Phenotypes.

Purpose Of The Study: We used a rabbit model infected with high phenotypic reactivators (HPRs) as well as recombinant HSV-1 (herpes simplex virus 1) with deletions to study their effect on corneal innervations after latency was established.

Materials And Methods: Corneas from noninfected New Zealand white rabbits were used to obtain the entire map of corneal innervation. Others were inoculated with the HSV-1 strains McKrae, 17Syn+, or recombinant mutants with glycoprotein K (gK) deletion, or with infected early protein 0 (ICP0) deletion.

Neuroanatomy and Neurochemistry of Mouse Cornea.

Purpose: To investigate the entire nerve architecture and content of the two main sensory neuropeptides in mouse cornea to determine if it is a good model with similarities to human corneal innervation.

Methods: Mice aged 1 to 24 weeks were used. The corneas were stained with neuronal-class βIII-tubulin, calcitonin gene-related peptide (CGRP), and substance P (SP) antibodies; whole-mount images were acquired to build an entire view of corneal innervation.

The PEDF Neuroprotective Domain Plus DHA Induces Corneal Nerve Regeneration After Experimental Surgery.

Purpose: To compare a 44-mer pigment epithelial-derived factor (PEDF) peptide with neurotrophic activity, and a 34-mer PEDF with antiangiogenic properties in association with docosahexaenoic acid (DHA) in corneal nerve regeneration after experimental surgery.

Methods: A corneal stromal dissection was performed in rabbits. Treatment groups received topical 44-mer, 34-mer, or full PEDF plus DHA.

Morphology and neurochemistry of rabbit iris innervation.

The aim of this study was to map the entire nerve architecture and sensory neuropeptide content of the rabbit iris. Irises from New Zealand rabbits were stained with antibodies against neuronal-class βIII-tubulin, calcitonin gene-related peptide (CGRP) and substance P (SP), and whole-mount images were acquired to build a two-dimensional view of the iridal nerve architecture. After taking images in time-lapse mode, we observed thick nerves running in the iris stroma close to the anterior epithelia, forming four to five stromal nerve rings from the iris periphery to the pupillary margin and sub-branches that connected with each other, constituting the stromal nerve plexus.

Neuroprotectin D1 restores corneal nerve integrity and function after damage from experimental surgery.

Purpose: To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy.

Methods: An 8-mm stromal dissection was performed in the left eye of each rabbit. The rabbits were treated with NPD1, pigment epithelial-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) or vehicle for 6 weeks, and corneas were obtained at 8 weeks.

Corneal nerve architecture in a donor with unilateral epithelial basement membrane dystrophy.

Background: Epithelial basement membrane dystrophy (EBMD) is by far the most common corneal dystrophy. In this study, we used a newly developed method of immunofluorescence staining and imaging to study the entire corneal nerve architecture of a donor with unilateral EBMD.

Method: Two fresh eyes from a 56-year-old male donor were obtained; the right eye of the donor was diagnosed with EBMD and the left was normal.

Lipoxin A₄ inhibits platelet-activating factor inflammatory response and stimulates corneal wound healing of injuries that compromise the stroma.

Platelet-activating factor (PAF) is a bioactive lipid mediator with strong inflammatory properties. PAF induces the expression and activation of metalloproteinase-9 (MMP-9) in corneal epithelial cells and myofibroblasts, and delays epithelial wound healing in an organ culture system. Lipoxin A(4) (LXA(4)) is a lipid mediator involved in resolution of inflammation and cornea epithelial wound healing.

Mapping the nerve architecture of diabetic human corneas.

Objective: To investigate the entire human corneal nerve architecture of donors with different durations of insulin-dependent diabetes mellitus (IDDM).

Design: Experimental study.

Participants And Controls: Sixteen fresh human eyes from 8 diabetic donors (aged 43-66 years, with IDDM for 2-17 years) and 12 eyes from 6 normal donors (aged from 44-67 years) were obtained from the National Disease Research Interchange (NDRI).

Recovery of corneal sensitivity, calcitonin gene-related peptide-positive nerves, and increased wound healing induced by pigment epithelial-derived factor plus docosahexaenoic acid after experimental surgery.

Objective: To assess function of regenerated corneal nerves in correlation with epithelial wound healing after experimental nerve damage in rabbits treated with pigment epithelial-derived factor (PEDF) plus docosahexaenoic acid (DHA).

Methods: An 8-mm stromal dissection was performed in the right eyes of adult New Zealand rabbits. Treatment with PEDF+DHA was for 6 weeks.

Aspirin-triggered lipoxin A4 (15-epi-LXA4) increases the endothelial viability of human corneas storage in Optisol-GS.

Purpose: The human corneal endothelium has a very low mitotic rate, and with aging there is a decrease in the number of cells. 15-epi-LXA4 is an anti-inflammatory, bioactive lipid formed when aspirin acetylates cyclooxygenease-2 and redirects cyclooxygenease-2 catalytic activity away from prostaglandins. The purpose of the current study was to evaluate the action of 15-epi-LXA4 in the endothelium viability of human corneas stored in Optisol-GS.

The induction of an angiogenic response in corneal myofibroblasts by platelet-activating factor (PAF).

Purpose: Although the exact mechanisms underlying corneal neovascularization remain unclear, cytokines and growth factors play an important role in their development. We have shown previously that the inflammatory mediator platelet-activating factor (PAF) is a potent inducer of corneal neovascularization in vivo. In this study, we investigate the role of stromal myofibroblasts in neovascularization and the effect of PAF on this process.

Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model.

Purpose: Dry eye (DE) is a common ocular surface disease, particularly among women and the elderly, with chronic symptoms of eye irritation and, in severe cases, blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Resolvin E1 (RvE1; RX-10001) is an endogenous mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid and is involved in inflammation resolution and tissue protection.