Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway

Charkoftaki, Georgia; Jester, James V.; Thompson, David C.; Vasiliou, Vasilis

doi:10.1016/j.jtos.2017.11.004

Cited by 20 publications

(13 citation statements)

References 34 publications

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“…DSBs, in particular, cause cell cycle arrest, genome stability, and chromosomal damage [ 7 ]. NM exposure in ex vivo and in vivo rabbit corneal injury models promoted apoptosis, epithelial–stromal separation, corneal collagen degradation, and neovascularization [ 3 , 5 , 8 , 9 , 10 ]. Earlier studies using the murine skin injury model and rabbit corneal culture model demonstrated that exposure to the vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM) exposure led to increases in apoptotic cell death and epidermal thickness and biomarkers, such as COX2 (cyclooxygenase 2, mediation of inflammation), MMP-9 (matrix metalloproteinase-9, inflammatory marker), and VEGF (vascular endothelial growth factor, angiogenic factor) [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Mesenchymal Stem Cell-Secreted Factors on Delay in Corneal Wound Healing by Nitrogen Mustard

Shen

Anwar

et al. 2022

IJMS

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Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is currently available. The research was conducted to investigate the therapeutic potential of mesenchymal stem cell-conditioned media (MSC-CM) in NM-induced corneal wounds. NM was added to different types of corneal cells, the ocular surface of porcine, and the ocular surface of mice, followed by MSC-CM treatment. NM significantly induced apoptotic cell death, cellular ROS (Reactive oxygen species), and reduced cell viability, metabolic gene expression, and mitochondrial function, and, in turn, delayed wound healing. The application of MSC-CM post NM exposure partially restored mitochondrial function and decreased intracellular ROS generation which promoted cell survival. MSC-CM therapy enhanced wound healing process. MSC-CM inhibited NM-induced apoptotic cell death in murine and porcine corneal tissue. The application of MSC-CM following a chemical insult led to significant improvements in the preservation of corneal structure and wound healing. In vitro, ex vivo, and in vivo results suggest that MSC-CM can potentially provide targeted therapy for the treatment of chemical eye injuries, including mustard gas keratopathy (MGK) which presents with significant loss of vision alongside numerous corneal pathologies.

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Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Mesenchymal Stem Cell-Secreted Factors on Delay in Corneal Wound Healing by Nitrogen Mustard

Shen

Anwar

et al. 2022

IJMS

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“…While one ocular corrosive (tetraethylene glycol diacrylate) showed almost no measurable response at 3 h, there was almost complete loss of stromal cell viability as measured by the ability to maintain actin, an ATP-dependent process, at 24 h. This material is a DNA cross-linker and may act as a fixative (Mabilleau et al, 2006). Previous studies of nitrogen mustards have identified a similar delay in cellular damage associated with DNA cross-linking (Charkoftaki et al, 2018). Similar delayed injury was noted in live animal studies for other cross-linking materials such as aldehydes (Maurer et al, 2001b) as well as bleaches (Maurer et al, 2001a).…”

Section: Discussionmentioning

confidence: 86%

An in vitro depth of injury prediction model for a histopathologic classification of EPA and GHS eye irritants

Lebrun¹,

Xie

Chavez³

et al. 2019

Toxicology in Vitro

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The purpose of this study was to develop Globally Harmonized System (GHS) and U.S. Environmental Protection Agency (EPA) prediction models for classifying irritant materials based on histopathologic in vitro depth of injury (DoI) measurements. Sixteen different materials were selected, representing all classes of toxicity, according to the GHS and EPA classification systems. Food-source rabbit eyes, similar to eyes used for the widely accepted Bovine Corneal Opacity and Permeability and Isolated Chicken Eye ocular irritation tests, were used. Tissues were exposed to test material for 1 min, and corneas were collected at 3-and 24-hours post-exposure. Tissues were then fixed and processed for live/dead biomarker fluorescent staining using phalloidin. DoI was then measured, and the percent DoI values for the epithelium and stroma were compared to the EPA and GHS classifications. Excluding surfactants, EPA nonclassified (category IV) materials showed no stromal and very slight epithelial damage (≤10%) to the cornea, whereas EPA corrosive (category I) materials showed significantly greater damage (P < 0.001), ranging from 39% to 100% of the stromal depth. Importantly, EPA reversible (categories II and III) materials showed significant damage to the epithelium (> 10%, P < 0.005) but significantly less severe damage to the corneal stroma (P < 0.001), ranging from 1% to 38% of the stromal depth. GHS nonclassified (category NC) irritants caused damage to the epithelium but not to the stroma. All GHS class 2 materials showed damage to the stroma (1–11%), whereas GHS corrosives caused significantly greater damage to the stroma (38–100%; P < 0.001). Additionally, one corrosive material, which produced a stromal DoI of 99% at 24 h, produced no apparent damage at 3-hours post-exposure. Based on these findings, histopathologic EPA and GHS prediction models are proposed that appear to separate and identify reversible irritants from other irritant classes. Furthermore, GHS classification appears to require stromal damage, whereas NC materials may or may not damage the corneal epithelium.

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“…cause several corneal abnormalities [ 31 , 33 , 116 , 117 ]. Various ocular pathologies such as ocular edema, redness, tearing, itching, abrasion, corrosions, corneal injury, neovascularization, blurred vision, and loss of vision in humans and animals have been observed following exposure to industrial chemicals (alkali, acids, anhydrous ammonia, phosphine), warfare agents (mustard gas, chlorine, acrolein, phosgene oxime, lewisite) and pesticides (carbofuran, ethylene oxide) [ 32 , 33 , 35 , 118 , 119 , 120 , 121 , 122 , 123 , 124 ]. Our recent studies and research reported in the literature have led us to postulate that irregular autophagosomal and lysosomal biogenesis leads to improper clearance of injurious factors and the accumulation of unwanted and harmful molecules/proteins in keratocytes, ultimately resulting in corneal pathologies.…”

Section: Dysregulated or Delayed Autophagy And Its Late Effectsmentioning

confidence: 99%

Autophagy in Extracellular Matrix and Wound Healing Modulation in the Cornea

Kempuraj

Mohan

2022

Biomedicines

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Autophagy is a robust cellular mechanism for disposing of harmful molecules or recycling them to cells, which also regulates physiopathological processes in cornea. Dysregulated autophagy causes inefficient clearance of unwanted proteins and cellular debris, mitochondrial disorganization, defective inflammation, organ dysfunctions, cell death, and diseases. The cornea accounts for two-thirds of the refraction of light that occurs in the eyes, but is prone to trauma/injury and infection. The extracellular matrix (ECM) is a noncellular dynamic macromolecular network in corneal tissues comprised of collagens, proteoglycans, elastin, fibronectin, laminins, hyaluronan, and glycoproteins. The ECM undergoes remodeling by matrix-degrading enzymes and maintains corneal transparency. Autophagy plays an important role in the ECM and wound healing maintenance. Delayed/dysregulated autophagy impacts the ECM and wound healing, and can lead to corneal dysfunction. Stromal wound healing involves responses from the corneal epithelium, basement membrane, keratocytes, the ECM, and many cytokines and chemokines, including transforming growth factor beta-1 and platelet-derived growth factor. Mild corneal injuries self-repair, but greater injuries lead to corneal haze/scars/fibrosis and vision loss due to disruptions in the ECM, autophagy, and normal wound healing processes. Presently, the precise role of autophagy and ECM remodeling in corneal wound healing is elusive. This review discusses recent trends in autophagy and ECM modulation in the context of corneal wound healing and homeostasis.

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Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway

Abstract: NM induces concentration- and exposure time-dependent damage to the cornea that increases in severity over time. Alterations in the sphingomyelin-ceramide pathway may contribute to the damaging effects of NM exposure.

Cited by 20 publications

References 34 publications

Therapeutic Potential of Mesenchymal Stem Cell-Secreted Factors on Delay in Corneal Wound Healing by Nitrogen Mustard

Therapeutic Potential of Mesenchymal Stem Cell-Secreted Factors on Delay in Corneal Wound Healing by Nitrogen Mustard

An in vitro depth of injury prediction model for a histopathologic classification of EPA and GHS eye irritants

Autophagy in Extracellular Matrix and Wound Healing Modulation in the Cornea

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