Retinal injury mouse model and pathophysiological assessment of the effect of arsenical vesicants

Zhylkibayev, Assylbek; Srivastavá, R. C.; Anantharam, Poojya; Crotch, Claire; Athar, Mohammad; Gorbatyuk, Marina S.

doi:10.1016/j.exer.2022.109354

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…The UPR is a cellular adaptive response that launches prosurvival programs in cells to restore cellular homeostasis by activating PERK, activating transcription factor 6 (ATF6), and inositol-requiring enzyme type 1 α (IRE1 α ). Under sustained cellular stress, such as that induced by vesicant exposure, we observed that persistent UPR activation shifted the cellular survival program toward death ( Zhylkibayev et al, 2023 ). Although all three UPR arms may play significant roles in ocular tissue damage, chronically activated PERK signaling is well accepted to mostly contribute to apoptotic cell death.…”

Section: Resultsmentioning

confidence: 96%

“…Moreover, in treated HCK cells, the observed increase in VEGF secretion was concomitant with UPR activation, suggesting that VEGF may serve as a prodeath signaling molecule transmitted to the retina. In a previous study of lewisite, significant upregulation of the cytokines Il-1 β , Il-6, and Cox2 was found in the retina of treated mice 24 hours after exposure ( Zhylkibayev et al, 2023 ), suggesting that acute cellular stress was transmitted from the cornea. Moreover, secreted VEGF may trigger corneal neovascularization, which was observed in NM-exposed animals ( Goswami et al, 2019 ), suggesting that strategies aimed at targeting UPR→VEGF may slow down the magnitude of corneal neovascularization in exposed individuals.…”

Section: Discussionmentioning

confidence: 93%

“…ImageJ software was employed to calculate the ratios of integrated density of VEGF signal over the area of interest, yielding the mean value from three samples and normalized the VEGF level (n = 6). TUNEL assay was described in our previous study (Zhylkibayev et al, 2023). TUNEL-positive nuclei were counted manually by masked investigators (n = 7).…”

Section: Histology and Immunochemistrymentioning

confidence: 99%

“…(Zhylkibayev et al, 2023) Moreover, significant cytokine upregulation associated with chronically activated UPR was detected in both PAO-and LEW-exposed ocular tissues, suggesting the presence of cross-talk between these pathways. (Zhylkibayev et al, 2023) In SM-exposed rabbit ocular tissue, VEGF expression reached its highest point at 28 days postexposure and led to corneal neovascularization.…”

Section: Introductionmentioning

confidence: 97%

“…Our recent studies of the vesicants phenylarsine oxide and lewisite (LEW) revealed chronic unfolded protein response (UPR) activation in the exposed corneal cells and retinal tissues ( Zhylkibayev et al, 2023 ). Moreover, significant cytokine upregulation associated with chronically activated UPR was detected in both phenylarsine oxide- and LEW-exposed ocular tissues, suggesting the presence of crosstalk between these pathways ( Zhylkibayev et al, 2023 ). In SM-exposed rabbit ocular tissue, VEGF expression reached its highest point at 28 days postexposure and led to corneal neovascularization.…”

Section: Introductionmentioning

confidence: 99%

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The Involvement of Unfolded Protein Response in the Mechanism of Nitrogen Mustard–Induced Ocular Toxicity

Zhylkibayev,

Ung,

Mobley

et al. 2023

J Pharmacol Exp Ther

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Nitrogen mustard (NM) is a known surrogate of sulfur mustard, a chemical-warfare agent that causes a wide range of ocular symptoms, from a permanent reduction in visual acuity to blindness upon exposure. Although it has been proposed that the two blistering agents have a similar mechanism of toxicity, the mode of NM-induced cell death in ocular tissue has not been fully explored. Therefore, we hypothesized that direct ocular exposure to NM in mice leads to retinal tissue injury through chronic activation of the unfolded protein response (UPR) PERK arm in corneal cells and VEGF secretion, eventually causing cell death. We topically applied NM directly to mice to analyze ocular and retinal tissues at 2 weeks postexposure. A dramatic decline in retinal function, measured by scotopic and photopic electroretinogram responses, was detected in the mice. This decline was associated with enhanced TUNEL staining in both corneal and retinal tissues. In addition, exposure of corneal cells to NM revealed 228 differentially and exclusively expressed proteins primarily associated with the UPR, ferroptosis, and necroptosis. Moreover, these cells exhibited activation of the UPR PERK arm and an increase in VEGF secretion. Enhancement of VEGF staining was later observed in the corneas of the exposed mice. Therefore, our data indicated that the mechanism of NM-induced ocular toxicity should be carefully examined and that future research should identify a signaling molecule transmitted via a prodeath pathway from the cornea to the retina. SIGNIFICANCE STATEMENT This study demonstrated that NM topical exposure in mice results in dramatic decline in retinal function associated with enhanced TUNEL staining in both corneal and retinal tissues. We also found that the NM treatment of corneal cells resulted in 228 differentially and exclusively expressed proteins primarily associated with ferroptosis. Moreover, these cells manifest the UPR PERK activation and an increase in VEGF secretion. The latter was also found in the corneas of the cexposed mice.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 93%

Section: Histology and Immunochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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