Mechanisms of Retinal Damage after Ocular Alkali Burns

Abstract

Alkali burns to the eye constitute a leading cause of worldwide blindness. In recent case series, corneal transplantation revealed unexpected damage to the retina and optic nerve in chemically burned eyes. We investigated the physical, biochemical, and immunological components of retinal injury after alkali burn and explored a novel neuroprotective regimen suitable for prompt administration in emergency departments. Thus, in vivo pH, oxygen, and oxidation reduction measurements were performed in the anterior and posterior segment of mouse and rabbit eyes using implantable microsensors. Tissue inflammation was assessed by immunohistochemistry and flow cytometry. The experiments confirmed that the retinal damage is not mediated by direct effect of the alkali, which is effectively buffered by the anterior segment. Rather, pH, oxygen, and oxidation reduction changes were restricted to the cornea and the anterior chamber, where they caused profound uveal inflammation and release of proinflammatory cytokines. The latter rapidly diffuse to the posterior segment, triggering retinal damage. Tumor necrosis factor-α was identified as a key proinflammatory mediator of retinal ganglion cell death. Blockade, by either monoclonal antibody or tumor necrosis factor receptor gene knockout, reduced inflammation and retinal ganglion cell loss. Intraocular pressure elevation was not observed in experimental alkali burns. These findings illuminate the mechanism by which alkali burns cause retinal damage and may have importance in designing therapies for retinal protection.

Permanent neuroglial remodeling of the retina following infiltration of CSF1R-inhibition resistant peripheral monocytes

“…In addition, we used a small molecule inhibitor of colony stimulating factor 1 receptor (CSF1R) to perform a set of microglia depletion experiments to study the roles of microglia and peripheral monocytes in retinal repopulation. This study shows that peripheral monocytes are not only responsible for acute retinal inflammation after ocular injury (1,14), but that they contribute to the permanent remodeling of the neuroglia system by establishing a pro-inflammatory phenotype that may promote or contribute to neurodegeneration. These findings may be clinically important and can help us better understand the mechanisms by which patients with acute ocular injuries (chemical, surgical, or traumas) become susceptible to progressive neurodegeneration processes, such as progressive retina ganglion cell loss (glaucoma) (15) long after the injury has taken place.…”

“…Prolonged residency of activated monocytes in the retina can lead to progressive gradual neuronal damage and irreversible visions loss, which recapitulates the clinical picture of glaucomatous damage after anterior segment injury, and may appear clinically as loss of retina ganglion cells. Under normal intraocular pressure this can resemble glaucoma seen in patients with chemical injuries (39)(40)(41), and could explain the increased glaucoma susceptibility in patients that have suffered acute ocular injuries (2,3,14,15). In the setting of ocular injury, ramified CX3CR1 + cells from the bone marrow may occupy and engraft into the three distinct microglia strata, thereby co-existing with embryonically derived microglia, yet as we have shown in this study they have distinct pro-inflammatory phenotype.…”

“…In conclusion, we have demonstrated that a surface injury to the eye can cause not only peripheral monocyte infiltration into the retina, but also permanent engraftment and integration into the neuroretinal tissue; morphologically resembling yolk sac-derive microglia. However, despite this resemblance, peripherally derived microglia are functionally distinct from yolk sac Alkali chemical burns were performed according to our previous study (14). In brief, mice were anesthetized using ketamine (60 mg/kg) and xylazine (6 mg/kg) and deep anesthesia was confirmed by toe pinch.…”

lncRNA MIAT suppression alleviates corneal angiogenesis through regulating miR-1246/ACE

“…The alkali-burn injured rat model of corneal neovascularization was used to identify the inflammatory and oxidative mechanism [18]. Additionally, the alkali-burn injured rat model of corneal injury was also taken to explore the retinal damage [19], the therapeutic effects of antagomir-21 [20] and the inflammatory fibrosis [21]. In the present study, the corneal neovascularization rat model was established using the alkali-burn, our results obtained that the in vivo model was highly reproducible, which provided meaningful instruction for further corneal neovascularization study.…”

Glaucoma after ocular chemical burns: Incidence, risk factors, and outcome

“…Despite the IOP control in 80% of glaucoma eyes by intensive management, the final BCVA was <20/200 in 73.3% of eyes with glaucoma, which presents the possibility of irreversible damage to the optic nerve and retinal ganglion cell layer after ocular surface burn. In this regard, several animal studies investigated the mechanism by which anterior burn could inflict harm on the posterior segment of an eye 17,18 . These studies revealed that the posterior segment damage was not mediated by direct detrimental effect of chemical agent or altered pH which was effectively buffered by the anterior segment.…”