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Protective Role of Glutathione and Role of Nitric Oxide Production in the Pathogenesis of Pterygium

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Protective Role of Glutathione and Role of Nitric Oxide Production in the Pathogenesis of Pterygium Protective Role Of Glutathione And Role Of Nitric Oxide Production In The Pathogenesis Of Pterygium Fidelina Parra Instituto Politecnico Nacional Escuela Superior de Medicina Alexandre Kormanovski ( [email protected] ) Instituto Politecnico Nacional Escuela Superior de Medicina https://orcid.org/0000-0001-8731-0527 Gustavo Guevara-Balcazar Instituto Politecnico Nacional Escuela Superior de Medicina Maria del Carmen Castillo-Hernández Instituto Politecnico Nacional Escuela Superior de Medicina Antonio Franco-Vadillo Instituto Politecnico Nacional Escuela Superior de Medicina Mireille Toledo-Blas Instituto Politecnico Nacional Escuela Superior de Medicina Rosa Adriana Jarillo-Luna Instituto Politecnico Nacional Escuela Superior de Medicina Eleazar Lara-Padilla Instituto Politecnico Nacional Escuela Superior de Medicina Research article Keywords: pterygium, glutathione, nitric oxide, endothelial nitric oxide synthase, gender differences Posted Date: May 13th, 2020 DOI: https://doi.org/10.21203/rs.2.17704/v2 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/15 Abstract Background: In the pathogenesis of pterygium, the protective role of glutathione and nitric oxide production is unclear. These are important factors for homeostasis in the redox state of cells. The aim of this study was to determine the levels of these and related parameters in pterygium tissue. Methods: Five groups of tissue samples were examined: control, primary pterygium, recurrent pterygium and two groups of primary pterygium given a one-month NAC pre-surgery treatment (topical or systemic). The levels of endothelial nitric oxide synthase (e-NOS), nitric oxide (NO), 3-nitrotyrosine (3NT), reduced and oxidized glutathione (GSH and GSSG), and catalase (CAT) were evaluated in tissue homogenates. Results: Compared to the control, decreased levels of eNOS, NO and 3-nitrotyrosine as well as the degree of oxidation of GSH (GSSG%) were observed in primary and recurrent pterygium. 3-Nitrotyrosine and GSSG% were also reduced in the other pterygium groups. GSH and CAT were enhanced in recurrent pterygium and systemic-treated, but were unchanged for topical-treated primary pterygium. There was a strong positive correlation of eNOS with NO and 3NT, GSSG% with NO and 3NT, and GSH with GSSG and CAT. Conclusions: The results are congruent with the following proposed sequence of events leading to a protective response of the organism during the pathogenesis of primary pterygium: a decreased level of eNOS provokes a decline in the level of NO in pterygium tissue, which then leads to the modulation of the intracellular level of GSH through synthesis and/or mobilization from other tissues. Background Pterygium is triggered by a degenerative lesion in the conjunctiva and cornea of the eye and proceeds to brous tissue growth on the surface of the cornea. Surgery is the principal treatment, leading in some cases to recurrence. The mechanisms of pathogenesis have been discussed in several reviews [1-3]. The key factor in the etiology of pterygium is considered to be chronic exposure to UV radiation [4, 5], resulting in oxidative stress. In the long run, this condition can cause damage to DNA, other critical biological molecules, and the structure of the cell membrane. Indeed, this type of cell damage can contribute to the pathogenesis of different ocular diseases. The mechanisms of the protective response of the organism during the development of pterygium are not clear. Various molecules contribute to oxidative stress, including nitric oxide (NO) at an elevated concentration and derivatives of the same (e.g., peroxynitrite). Peroxynitrite is very potent oxidant that reacts with tyrosine residues of proteins to form 3-nitrotyrosine (3NT). 3NT serves as an indicator of nitrosative stress. However, these molecules are also important for cell signaling, involved in mechanisms for modulating and adapting to oxidative stress in a multitude of tissues. The synthesis and/or redistribution of glutathione (GSH) is one such possible mechanism. Reports on NO in pterygium tissue are contradictory, as both low [6] and high levels [7] have been found, the latter reecting probably the quantity of women in the study (by higher levels of NO in women, compared to men). The overall effect of Page 2/15 NO and related molecules revolves around the balance between the positive physiological ramications of their signaling and the negative consequences of oxidative stress. There is no published data, to our knowledge, on the level of GSH in pterygium tissue. This antioxidant is synthesized in all tissues but in notably larger quantities in the liver. Although three constitutive amino acids (cysteine, glutamate and glycine) participate in the synthesis of GSH, the limiting factor is cysteine. Under healthy conditions, the concentration of GSH reaches millimolar levels in the cornea and micromolar levels in other ocular tissues (as well as in uids) [8, 9]. Micromolar concentrations of reduced GSH and oxidized GSH (GSSG) have been described in retinoblastoma [10]. NO reportedly affects the level of GSH in the liver of mice with induced endotoxemia: a reduction in NO stimulates GSH synthesis and on the contrary [11]. The relation NO-GSH was observed in primary cultured conjunctival epithelial cell layers from rabbits [12] and in retinal pigment epithelial cells [13]. GSH has a strong anity for NO, and S-nitrosoglutathione is the primary intermediary in the production of other nitrosothiols regulators metabolism [14, 15]. This suggests that the most relevant effect of NO in the pathogenesis of pterygium may be on the synthesis and/or redistribution of GSH in ocular tissues. N-acetylcysteine (NAC) is derived from the amino acid L-cysteine and is used as a precursor of GSH synthesis in respiratory tract diseases [16]. By modulating oxidative stress, L-cysteine indirectly exerts an antiviral and anti-inammatory effect, inhibits angiogenesis, and inhibits cancer cell growth in different diseases, including ocular tissues [17, 18]. The aim of the present study was to evaluate the levels of GSH, GSSG, NO, 3-nitrotyrosine (3NT), catalase (CAT) and endothelial nitric oxide synthase (eNOS) in tissues samples of pterygium representing four conditions: untreated primary pterygium, recurrent pterygium, and primary pterygium treated with NAC, either systemic or topic. Methods Study population This study conducted in the Hospital “Nuestra Señora de la Luz” specialized in ophthalmology and High Medical School of National Polytechnic Institute (Mexico). This study was performed in accordance with the Helsinki Declaration. 120 patients (54 men and 66 women) took part in the study, selected from individuals who went to the “Nuestra Señora de la Luz” Hospital for pterygium resection surgery from 2015 to 2019 and had been given a clinical diagnosis of primary or recurrent pterygium. The tissue samples evaluated represent ve conditions: the control (healthy conjunctiva) and four patient groups, including untreated primary pterygium, recurrent pterygium, and primary pterygium treated topically or systemically with NAC. The following were criteria for non-inclusion: 1) history of disease or trauma to the ocular surface involving the sampling area; 2) ocular surgery during the three months prior to the pending pterygium surgery; 3) oral or topical immunosuppressive treatment during four weeks before the pending pterygium surgery; 4) systemic diseases such as diabetes, rheumatoid arthritis, another autoimmune disease or neoplasia; 5) chronic addictions to substances (e.g., tobacco or alcohol). Finally, Page 3/15 during the four years of the study, 28 patients with primary pterygium (12 women and 16 men) were excluded. The number of patients by group and their age was presented in Table 1. Table 1. Age (mean ± SD) of the study population by group and gender. Groups C P R Ps Pt all patients age 61.3 ± 6.0 56.9 ± 10.5 46.1 ± 6.3** 53.0 ± 10.3 55.4 ± 9.3* N 19 36 19 17 29 men age 61.9 ± 5.9 53.8 ± 8.7* 45.6 ± 7.1**& 50.1 ± 8.0** 56.5 ± 13.4& N 7 18 10 8 11 women age 60.8 ± 5.4 62.1 ± 13.0 46.8 ± 4.9** 55.5 ± 8.9 52.5 ± 10.3*& N 12 18 9 9 18 C, control group; P, untreated primary pterygium group; R, recurrent pterygium group; Ps, systemic-treated primary pterygium group; and Pt, topic-treated primary pterygium group. Treatments were with NAC. * P < 0.05 versus the control; & P < 0.05 comparing the primary pterygium group to other pathological groups. The average age of individuals in the recurrent pterygium group was lower than in the control group. Upon comparing the primary pterygium group to the other pathological groups, some moderate differences were detected (principally in men). Taking into account all patients with primary pterygium that used the service of the hospital (including those excluded from the study), the percentage of recurrence was 17% for all patients, 19% for men and 16% for women. Among the pterygium groups with a limited quantity of patients, recurrence occurred in 2 with systemic treatment (1 man and 1 woman, 13% and 11%, respectively, of the treatment group considered by gender), and in 3 with topical treatment (1 man and 2 women, 9% and 11%, respectively, of the treatment group by gender). However, it is incorrect to make a statistical comparison of these data with those from all patients because the treatment groups had the low quantity of patients. Tissue samples obtaining The pterygium samples were obtained during pterygium resection surgery. The surgery was performed by dissecting the head of the pterygium of the cornea, followed by resection of the body in a block. During the process, the conjunctiva was taken together with the subconjunctival brovascular tissue. The bare sclera was covered with a conjunctival autograft taken from the upper or lower conjunctiva and xed with nylon 10.0 sutures in separate stitches. The control samples were obtained from the resection of conjunctiva resulting from extracapsular cataract extraction.
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