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The Role of Hydrogen Sulfide in Ocular Inflammation /

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Role of Hydrogen Sulfide in Ocular Inflammation // Anthonia Chinyeaka Okolie.
Author:	Okolie, Anthonia Chinyeaka,
Description:	1 electronic resource (244 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Pharmaceutical sciences. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31938086
ISBN:	9798315799702

The Role of Hydrogen Sulfide in Ocular Inflammation /
Okolie, Anthonia Chinyeaka,

The Role of Hydrogen Sulfide in Ocular Inflammation /Anthonia Chinyeaka Okolie. - 1 electronic resource (244 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

In the eye, inflammation plays a significant underlying role in the development of inflammatory diseases such as uveitis, as well as in degenerative eye diseases such as diabetic retinopathy and age-related macular degeneration. Uveitis is an inflammatory condition involving the anterior uvea, as well as the adjacent structures in the eye and is a major cause of blindness, accounting for 5-10% of visual impairment worldwide. There is evidence for an anti-inflammatory role for H2S in several mammalian tissues and organs. We hypothesize that an inflammatory phenotype in the anterior uvea arises due to H2S deficiency and that replenishing this gas (using H2S-releasing compounds) can ameliorate the deleterious effects of inflammatory processes in the eye. In the present study, we investigated (a) the activity of enzymes for the biosynthesis of endogenous H2S and their role in an ex vivo porcine model of anterior uveal inflammation, (b) the pharmacologic effects of exogenously administered H2S-releasing compounds in an ex vivo porcine model of anterior uveal inflammation and (c) the role of oxidative stress in the observed anti-inflammatory actions of H2S in an ex vivo porcine model of anterior uveal inflammation. We measured basal and stimulated concentrations of H2S in the porcine ICB explants using the newly developed LC-MS/MS methodology and found that LPS (5 ng/ml - 100 ng/ml) caused a concentration-related decrease in H2S levels in the porcine ICB explants. Interestingly, we observed that a substrate for the biosynthesis of the gas, SAC (10 nM - 1000 nM) reversed the LPS (50 ng/ml)-induced decrease in endogenous H2S concentrations. We next measured the activity of enzymes for the biosynthesis of H2S, CBS, CSE, and 3-MST in the absence and presence of inflammation induced by LPS (5 ng/ml - 100 ng/ml). Except for CSE, LPS elicited a concentration-dependent decrease in the basal expression of both CBS and 3-MST in the porcine ICB explants, reaching a maximum at 5 ng/ml. The decrease in the basal expression of CBS and 3-MST induced by LPS (25 ng/ml) was reversed in the presence of SAC (10 nM - 1000 nM). Treatment with LPS (5 ng/ml - 200 ng/ml) produced an increase in the release of pro-inflammatory mediators, TNF-α, IL-6, and PGE2 into the culture media. In contrast, LPS (5 ng/ml - 100 ng/ml) treatment caused a concentration-dependent decrease in the release of IL-10, a key anti-inflammatory cytokine. Also, we found that both fast- and slow-releasing H2S compounds (NaHS, GYY4137) and organosulfur compounds derived from garlic (SAC, DADS, and DATTS) elicited concentration-dependent attenuation of LPS-induced increases in the levels of TNF-α, IL-6, and PGE2 in the culture media of porcine ICB explants with the following rank order of potency: DATTS > SAC > DADS > GYY4137 > NaHS. LPS-induced PGE2 release was found to be significantly increased in the presence of enzyme inhibitors, AOAA and HMPSNE, a response reversed by SAC. We next studied the role of oxidative stress in the pharmacological actions of H2S-releasing compounds during LPS-induced inflammation in the porcine ICB explants. On its own, LPS (5 ng/ml - 50 ng/ml) caused a concentration-dependent reduction in superoxide dismutase (SOD) and a concentration-dependent increase in xanthine oxidase (XOD) levels, responses that were reversed by SAC. Furthermore, we observed that AOAA (1 µM) and HMPSNE (0.1 µM) increased the LPS-induced attenuation of SOD activity but increased the effect of these enzymes on XOD activity, responses that were reversed in the presence of SAC (100 nM). We also investigated the role of transcription factors Nrf2 and NF-ĸB in the pathways associated with the anti-inflammatory action of H2S-releasing compounds. LPS (5 ng/ml - 25 ng/ml) reduced the expression levels of Nrf2 in the porcine ICB explants, a response that was reversed and even enhanced by SAC (100 nM - 1000 nM). On the other hand, NF-ĸB, in the presence of LPS (25 ng/ml), there was an upregulation of the expression of this transcription factor, a response that was reversed by SAC (100 nM - 1000 nM). We conclude that H2S plays an important role in the pathogenesis of inflammation in the anterior uvea and that porcine iris-ciliary body explants can serve as a model for studying this disease when induced by LPS. Data from the present study supports an anti-inflammatory role for H2S-releasing compounds, a response that is dependent on the endogenous supply of this gas, contributions of anti-inflammatory cytokines and antioxidant enzymes, and the involvement of the transcription factors Nrf2 and NF-ĸB.

English

ISBN: 9798315799702Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Anterior uvea

The Role of Hydrogen Sulfide in Ocular Inflammation /
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520 $a In the eye, inflammation plays a significant underlying role in the development of inflammatory diseases such as uveitis, as well as in degenerative eye diseases such as diabetic retinopathy and age-related macular degeneration. Uveitis is an inflammatory condition involving the anterior uvea, as well as the adjacent structures in the eye and is a major cause of blindness, accounting for 5-10% of visual impairment worldwide. There is evidence for an anti-inflammatory role for H2S in several mammalian tissues and organs. We hypothesize that an inflammatory phenotype in the anterior uvea arises due to H2S deficiency and that replenishing this gas (using H2S-releasing compounds) can ameliorate the deleterious effects of inflammatory processes in the eye. In the present study, we investigated (a) the activity of enzymes for the biosynthesis of endogenous H2S and their role in an ex vivo porcine model of anterior uveal inflammation, (b) the pharmacologic effects of exogenously administered H2S-releasing compounds in an ex vivo porcine model of anterior uveal inflammation and (c) the role of oxidative stress in the observed anti-inflammatory actions of H2S in an ex vivo porcine model of anterior uveal inflammation. We measured basal and stimulated concentrations of H2S in the porcine ICB explants using the newly developed LC-MS/MS methodology and found that LPS (5 ng/ml - 100 ng/ml) caused a concentration-related decrease in H2S levels in the porcine ICB explants. Interestingly, we observed that a substrate for the biosynthesis of the gas, SAC (10 nM - 1000 nM) reversed the LPS (50 ng/ml)-induced decrease in endogenous H2S concentrations. We next measured the activity of enzymes for the biosynthesis of H2S, CBS, CSE, and 3-MST in the absence and presence of inflammation induced by LPS (5 ng/ml - 100 ng/ml). Except for CSE, LPS elicited a concentration-dependent decrease in the basal expression of both CBS and 3-MST in the porcine ICB explants, reaching a maximum at 5 ng/ml. The decrease in the basal expression of CBS and 3-MST induced by LPS (25 ng/ml) was reversed in the presence of SAC (10 nM - 1000 nM). Treatment with LPS (5 ng/ml - 200 ng/ml) produced an increase in the release of pro-inflammatory mediators, TNF-α, IL-6, and PGE2 into the culture media. In contrast, LPS (5 ng/ml - 100 ng/ml) treatment caused a concentration-dependent decrease in the release of IL-10, a key anti-inflammatory cytokine. Also, we found that both fast- and slow-releasing H2S compounds (NaHS, GYY4137) and organosulfur compounds derived from garlic (SAC, DADS, and DATTS) elicited concentration-dependent attenuation of LPS-induced increases in the levels of TNF-α, IL-6, and PGE2 in the culture media of porcine ICB explants with the following rank order of potency: DATTS > SAC > DADS > GYY4137 > NaHS. LPS-induced PGE2 release was found to be significantly increased in the presence of enzyme inhibitors, AOAA and HMPSNE, a response reversed by SAC. We next studied the role of oxidative stress in the pharmacological actions of H2S-releasing compounds during LPS-induced inflammation in the porcine ICB explants. On its own, LPS (5 ng/ml - 50 ng/ml) caused a concentration-dependent reduction in superoxide dismutase (SOD) and a concentration-dependent increase in xanthine oxidase (XOD) levels, responses that were reversed by SAC. Furthermore, we observed that AOAA (1 µM) and HMPSNE (0.1 µM) increased the LPS-induced attenuation of SOD activity but increased the effect of these enzymes on XOD activity, responses that were reversed in the presence of SAC (100 nM). We also investigated the role of transcription factors Nrf2 and NF-ĸB in the pathways associated with the anti-inflammatory action of H2S-releasing compounds. LPS (5 ng/ml - 25 ng/ml) reduced the expression levels of Nrf2 in the porcine ICB explants, a response that was reversed and even enhanced by SAC (100 nM - 1000 nM). On the other hand, NF-ĸB, in the presence of LPS (25 ng/ml), there was an upregulation of the expression of this transcription factor, a response that was reversed by SAC (100 nM - 1000 nM). We conclude that H2S plays an important role in the pathogenesis of inflammation in the anterior uvea and that porcine iris-ciliary body explants can serve as a model for studying this disease when induced by LPS. Data from the present study supports an anti-inflammatory role for H2S-releasing compounds, a response that is dependent on the endogenous supply of this gas, contributions of anti-inflammatory cytokines and antioxidant enzymes, and the involvement of the transcription factors Nrf2 and NF-ĸB.
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