Investigating the Association between Angiogenic Cytokines and Corneal Neovascularization in Sulfur Mustard Intoxicated Subjects 26 Years after Exposure

Authors

  • Department of Ophthalmology, Medical University of Urmia, Urmia
  • Department of Ophthalmology, Medical University of Urmia, Urmia
  • Department of Ophthalmology, Aja University of Medical Sciences, Tehran
  • Department of Ophthalmology, Medical University of Urmia, Urmia

Keywords:

Basic fibroblast growth factor, corneal neovascularization, platelet-derived growth factor-BB, sulfur mustard, vascular endothelial growth factor

Abstract

Objectives: This study aimed to evaluate the associations between the concentrations of three major angiogenic cytokines–vascular endothelial growth factor"‘A165 (VEGF"‘A165), basic fibroblast growth factor (bFGF), and platelet"‘derived growth factor"‘BB (PDGF"‘BB)–in the tear of sulfur mustard (SM)"‘exposed subjects and corneal neovascularization (CNV) 26 years after exposure. Materials and Methods: The concentrations of VEGF"‘A, bFGF, and PDGF"‘BB were measured by enzyme"‘linked immunosorbent assay (ELISA) in reflex tears of (i) SM"‘injured patients with CNV (positive case group including 18 individuals) and (ii) SM"‘injured patients without CNV (negative case group including 22 individuals). Then results were compared to corresponding values obtained from tears of 40 healthy control subjects. Results: The mean concentrations of all investigated growth factors, VEGF"‘A165, bFGF, and PDGF"‘BB, were significantly higher in positive cases than controls (P ≤ 0.001, P = 0.028, and P = 0.041, respectively). Whereas, VEGF"‘A165 was the only growth factor which displayed significantly elevated concentrations in negative case group compared to the healthy individuals (P = 0.030). Additionally, the mean level of VEGF"‘A165 was also higher in positive patient group than negative patients (P = 0.022). Subjects with increased concentrations of tear VEGF"‘A165 were more than 10 times more likely to suffer from CNV than normal individuals (odds ratio (OR) = 10.43, confidence interval (CI): 2.14–38.46, P = 0.001), while elevated levels of bFGF and PDGF"‘BB increased the risk of CNV by about twofold. Conclusion: Although all investigated cytokines had increased in tears of positive patients, VEGF"‘A was the only one which showed a significant correlation with the severity of CNV, and thus played a crucial role in corneal angiogenesis.

Downloads

Download data is not yet available.

References

Graham JS, Schoneboom BA. Historical perspective on effects and treatment of sulfur mustard injuries. Chem Biol Interact 2013;206:512"‘22.

Khateri S, Ghanei M, Keshavarz S, Soroush M, Haines D. Incidence of lung, eye, and skin lesions as late complications in 34,000 Iranians with wartime exposure to mustard agent. J Occup Environ Med 2003;45:1136"‘43.

Wattana M, Bey T. Mustard gas or sulfur mustard: An old chemical agent as a new terrorist threat. Prehosp Disaster Med 2009;24:19"‘29.

Javadi MA, Yazdani S, Sajjadi H, Jadidi K, Karimian F, Einollahi B, et al. Chronic and delayed"‘onset mustard gas keratitis: Report of 48 patients and review of literature. Ophthalmology 2005;112:617"‘25.

Ghasemi H, Ghazanfari T, Babaei M, Soroush MR, Yaraee R, Ghassemi"‘Broumand M, et al. Long"‘term ocular complications of sulfur mustard in the civilian victims of Sardasht, Iran. Cutan Ocul Toxicol 2008;27:317"‘26.

Panahi Y, Eftekhari Milani A, Sahebkar A, Naderi M, Babaei M, Beiraghdar F, et al. Tear total protein analysis in patients with late sulfur mustard"‘induced ocular complications: A cross"‘sectional study. Cutan Ocul Toxicol 2012;31:104"‘10.

Pickard H. Ocular action of dichlorethylsulphid (mustard gas). Am J Ophthalmol 1919;2:136"‘7.

Solberg Y, Alcalay M, Belkin M. Ocular injury by mustard gas. Surv Ophthalmol 1997;41:461"‘6.

McNutt P, Hamilton T, Nelson M, Adkins A, Swartz A, Lawrence R, et al. Pathogenesis of acute and delayed corneal lesions after ocular exposure to sulfur mustard vapor. Cornea 2012;31:280"‘90.

Lim P, Fuchsluger TA, Jurkunas UV. Limbal stem cell deficiency and corneal neovascularization. Semin Ophthalmol 2009;24:139"‘48.

Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9"‘22.

Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695.e1"‘15.

Shinkaruk S, Bayle M, Lain G, Deleris G. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr Med Chem Anticancer Agents 2003;3:95"‘117.

Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 1992;267:26031"‘7.

Kim WJ, Mohan RR, Mohan RR, Wilson SE. Effect of PDGF, IL"‘1alpha, and BMP2/4 on corneal fibroblast chemotaxis: Expression of the platelet"‘derived growth factor system in the cornea. Invest Ophthalmol Vis Sci 1999;40:1364"‘72.

Jo N, Mailhos C, Ju M, Cheung E, Bradley J, Nishijima K, et al. Inhibition of platelet"‘derived growth factor B signaling enhances the efficacy of anti"‘vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006;168:2036"‘53.

Montesano R, Vassalli JD, Baird A, Guillemin R, Orci L. Basic fibroblast growth factor induces angiogenesis in vitro. Proc Natl Acad Sci U S A 1986;83:7297"‘301.

Kadar T, Amir A, Cohen L, Cohen M, Sahar R, Gutman H, et al. Anti"‘VEGF therapy (bevacizumab) for sulfur mustard"‘induced corneal neovascularization associated with delayed limbal stem cell deficiency in rabbits. Curr Eye Res 2014;39:439"‘50.

Chang JH, Garg NK, Lunde E, Han KY, Jain S, Azar DT. Corneal neovascularization: An anti"‘VEGF therapy review. Surv Ophthalmol 2012;57:415"‘29.

Zakaria N, Van Grasdorff S, Wouters K, Rozema J, Koppen C, Lion E, et al. Human tears reveal insights into corneal neovascularization. PLoS One 2012;7:e36451.

Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 2013;120:106"‘14.

Enriquez"‘de"‘Salamanca A, Castellanos E, Stern ME, Fernandez I, Carreno E, Garcia"‘Vazquez C, et al. Tear cytokine and chemokine analysis and clinical correlations in evaporative"‘type dry eye disease. Mol Vis 2010;16:862"‘73.

Onguchi T, Han KY, Chang JH, Azar DT. Membrane type"‘1 matrix metalloproteinase potentiates basic fibroblast growth factor"‘induced corneal neovascularization. Am J Pathol 2009;174:1564"‘71.

Stavri GT, Zachary IC, Baskerville PA, Martin JF, Erusalimsky JD. Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells. Synergistic interaction with hypoxia. Circulation 1995;92:11"‘4.

Mandriota SJ, Pepper MS. Vascular endothelial growth factor"‘induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor. J Cell Sci 1997;110:2293"‘302.

Chheda LV, Ferketich AK, Carroll CP, Moyer PD, Kurz DE, Kurz PA. Smoking as a risk factor for choroidal neovascularization secondary to presumed ocular histoplasmosis syndrome. Ophthalmology 2012;119:333"‘8.

Zhong ZL, Han M, Chen S. Risk factors associated with retinal neovascularization of diabetic retinopathy in type 2 diabetes mellitus. Int J Ophthalmol 2011;4:182"‘5.

Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP. Smoking and age"‘related macular degeneration: A review of association. Eye (Lond) 2005;19:935"‘44.

Klein R, Lee KE, Gangnon RE, Klein BE. The 25"‘year incidence of visual impairment in type 1 diabetes mellitus the wisconsin epidemiologic study of diabetic retinopathy. Ophthalmology 2010;117:63"‘70.

Rolfsen ML, Frisard NE, Stern EM, Foster TP, Bhattacharjee PS, McFerrin HE Jr, et al. Corneal neovascularization: A review of the molecular biology and current therapies; 2013.

Chaoran Z, Zhirong L, Gezhi X. Combination of vascular endothelial growth factor receptor/platelet"‘derived growth factor receptor inhibition markedly improves the antiangiogenic efficacy for advanced stage mouse corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2011;249:1493"‘501.

Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, et al. Angiogenic synergism, vascular stability and improvement of hind"‘limb ischemia by a combination of PDGF"‘BB and FGF"‘2. Nat Med 2003;9:604"‘13.

Li J, Wei Y, Liu K, Yuan C, Tang Y, Quan Q, et al. Synergistic effects of FGF"‘2 and PDGF"‘BB on angiogenesis and muscle regeneration in rabbit hindlimb ischemia model. Microvasc Res 2010;80:10"‘7.

Published

2018-06-04

How to Cite

Abbaszadeh, M., Aidenloo, N. S., Nematollahi, M. K., & Motarjemizadeh, Q. (2018). Investigating the Association between Angiogenic Cytokines and Corneal Neovascularization in Sulfur Mustard Intoxicated Subjects 26 Years after Exposure. Toxicology International, 21(3), 300–306. Retrieved from https://www.informaticsjournals.com/index.php/toxi/article/view/21415

Issue

Section

Original Research