Anti-VEGF Therapy (Bevacizumab) for Sulfur Mustard-Induced Corneal Neovascularization Associated with Delayed Limbal Stem Cell Deficiency in Rabbits

Kadar, Tamar; Amir, Adina; Cohen, Liron; Cohen, Maayan; Sahar, Rita; Gutman, Hila; Horwitz, Vered; Dachir, Shlomit

doi:10.3109/02713683.2013.850098

Cited by 45 publications

(43 citation statements)

References 49 publications

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“…VEGF could have a role in repair mechanisms by increasing limbal vessel permeability and attracting monocytes apart from its role in inducing angiogenesis. This could be suggestive of an early corneal would healing event since VEGF up-regulation has been reported in corneal wound healing and might increase scarring edema and inflammation even in the absence of new blood vessels 12, 31 .…”

Section: Discussionmentioning

confidence: 84%

“…This is primarily due to the lack of defined mechanisms contributing to pathological and clinical progression of ocular injuries by vesicants in relevant animal models. The rapid alkylating effects, and long-term deficiency of limbal stem cells have further added to the complication of developing effective therapies 12, 13 . A role of oxidative stress, inflammatory cytokines, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) in vesicant-induced ocular injuries has been reported 5, 14–17 .…”

Section: Introductionmentioning

confidence: 99%

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Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization

Goswami¹,

Tewari‐Singh²,

Dhar³

et al. 2016

Cornea

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Purpose To evaluate the toxic effects and associated mechanisms in corneal tissue exposed to vesicating agent, nitrogen mustard (NM), a bi-functional alkylating analog of chemical warfare agent sulfur mustard (SM). Methods Toxic effects and associated mechanisms were examined in maximal affected corneal tissue employing corneal cultures and human corneal epithelial (HCE) cells exposed to nitrogen mustard (NM). Results Analysis of ex vivo rabbit corneas showed that NM exposure increased apoptotic cell death, epithelial thickness, epithelial-stromal separation and levels of VEGF, COX-2 and MMP-9. In HCE cells, NM exposure resulted in a dose-dependent decrease in cell viability and proliferation, which was associated with DNA damage in terms of an increase in p53 ser15, total p53 and H2A.X ser139 levels. NM exposure also induced caspase-3 and PARP cleavage, suggesting their involvement in NM-induced apoptotic death in rabbit cornea and HCE cells. Similar to rabbit cornea, NM exposure caused an increase in COX-2, MMP-9 and VEGF levels in HCE cells, indicating a role of these molecules and related pathways in NM-induced corneal inflammation, epithelial-stromal separation and neovascularization. NM exposure also induced activation of AP-1 transcription factor proteins and upstream signaling pathways including MAPKs and Akt, suggesting that these could be key factors involved in NM-induced corneal injury. Conclusion Results from this study provide insight into the molecular targets and pathways that could be involved in NM-induced corneal injuries laying the background for further investigation of these pathways in vesicant–induced ocular injuries, which could be helpful in the development of targeted therapies.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization

Goswami¹,

Tewari‐Singh²,

Dhar³

et al. 2016

Cornea

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“…Different studies have been performed on the acute and delayed onsets of ocular lesion induced by SM toxicity on the rabbit eye and the treatment options [Mann and Pullinger, 1942;Williams and Bhattacherjee, 1984;Amir et al, 2000;Kadar et al, 2001Kadar et al, , 2013aKadar et al, , 2014Amir et al, 2003;Petrali et al, 2008;Nie et al, 2014]. In 1940s, Mann and Pullinger; Livingston and Walker observed ocular effects of SM in laboratory rabbits and discussed the treatment options [Mann and Pullinger, 1942;Williams and Bhattacherjee, 1984].…”

Section: Animal Studies On Sm-induced Ocular Symptoms and Treatment Omentioning

confidence: 99%

“…Various studies were performed on the rabbit eye to assess the treatment regime in SM-exposed eyes [Amir et al, 2000[Amir et al, , 2003Babin et al, 2004;Kadar et al, 2014] as mentioned above. Various studies were performed on the rabbit eye to assess the treatment regime in SM-exposed eyes [Amir et al, 2000[Amir et al, , 2003Babin et al, 2004;Kadar et al, 2014] as mentioned above.…”

Section: Management Of Acute Ocular Lesionsmentioning

confidence: 99%

Ocular Effects of Sulfur Mustard and Therapeutic Approaches

Panahi

Rajaee

Sahebkar

2017

J of Cellular Biochemistry

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Sulfur mustard (SM) is a strong blistering, highly reactive, lipophilic chemical war agent that causes injury in different organs including the skin, eyes, and respiratory tract. The Eyes are especially susceptible to the consequences of SM poisoning because of the aqueous and mucosal nature of conjunctiva and cornea. DNA alkylation and depletion of glutathione, are the most important mechanisms of SM action in the eye injuries. Acute clinical symptoms are including decrease in visual acuity, dryness, photophobia, blepharospasm, conjunctivitis, and complaints of foreign body sensation and soreness that gradually progress to severe ocular pain. Corneal abrasions, ulcerations, vesication, and perforations are common corneal consequences in SM injured victims. Appearance of chronic symptoms has been reported as chronic inflammation of the corneal and conjunctival vasculature, ischemia, lipid and cholesterol deposition, scarring in cornea, corneal thinning, opacification and perforation of the cornea, limbal stem cell deficiency (LSCD), and neovascularization. Different medical and surgical protocols have been documented in the management of SM-induced ocular injuries, including preservative-free artificial tears, topical steroids and antibiotic, mydriatic, antiglaucoma drops, therapeutic contact lenses, dark glasses and punctal plugs/cauterization, N-acetylcysteine, tarsorrhaphy, amniotic membrane transplantation, stem cell transplantation, and corneal transplantation. New drugs such as resolvin E1, topical form of essential fatty acids, thymosin β4, 43 amino-acid polypeptides, topical form of curcumin, newly formulated artificial tears, diquafosol, rebamipide, tretinoin, and oral uridineseems to be beneficial in the management of ocular lesion associated with sulfur mustard poisoning. Further studies are needed to approve these drugs in SM victims. J. Cell. Biochem. 118: 3549-3560, 2017. © 2017 Wiley Periodicals, Inc.

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“…Current in vivo models of corneal fibrosis used to investigate anti-fibrotic agents utilize various methodologies such as sulfur mustard exposure, laceration and suture, and alkali burn (Berdahl et al 2009, Kadar et al 2013, Okada et al 2014). The alkali burn is easy to perform, does not require specialized equipment and presents minimal risk to those performing the procedure.…”

Section: Introductionmentioning

confidence: 99%

Development of a novel in vivo corneal fibrosis model in the dog

Gronkiewicz

Giuliano

Kuroki

et al. 2016

Experimental Eye Research

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The aim of this study was to develop a novel in vivo corneal model of fibrosis in dogs utilizing alkali burn and determine the ability of suberanilohydroxamic acid (SAHA) to inhibit corneal fibrosis using this large animal model. To accomplish this, we used seven research Beagle dogs. An axial corneal alkali burn in dogs was created using 1 N NaOH topically. Six dogs were randomly and equally assigned into 2 groups: A) vehicle (DMSO, 2 μL/mL); B) anti-fibrotic treatment (50 μM SAHA). The degree of corneal opacity, ocular health, and anti-fibrotic effects of SAHA were determined utilizing the Fantes grading scale, modified McDonald-Shadduck (mMS) scoring system, optical coherence tomography (OCT), corneal histopathology, immunohistochemistry (IHC), and transmission electron microscopy (TEM). The used alkali burn dose to produce corneal fibrosis was well tolerated as no significant difference in mMS scores between control and treatment groups (p=0.89) were detected. The corneas of alkali burned dogs showed significantly greater levels of α-smooth muscle actin, the fibrotic marker, than the controls (p=0.018). Total corneal thickness of all dogs post-burn was significantly greater than baseline OCT images irrespective of treatment (p=0.004); TEM showed that alkali burned corneas had significantly greater minimum and maximum interfibrillar distances than the controls (p=0.026, p=0.018). The tested topical corneal alkali burn dose generated significant opacity and fibrosis in dog corneas without damaging the limbus as evidenced by histopathology, IHC, TEM, and OCT findings, and represents a viable large animal corneal fibrosis in vivo model. Additional in vivo SAHA dosing studies with larger sample size are warranted.

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Anti-VEGF Therapy (Bevacizumab) for Sulfur Mustard-Induced Corneal Neovascularization Associated with Delayed Limbal Stem Cell Deficiency in Rabbits

Cited by 45 publications

References 49 publications

Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization

Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization

Ocular Effects of Sulfur Mustard and Therapeutic Approaches

Development of a novel in vivo corneal fibrosis model in the dog

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