Superoxide anion radicals activate hepatic stellate cells after entry through chloride channels: A new target in liver fibrosis

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

It is generally accepted that reactive oxygen species (ROS) play an important role in the pathogenesis of liver fibrosis. ROS, however, constitute a group of species with varying properties making it likely that their contribution to the pathological mechanism varies. LX-2 hepatic stellate cells (HSCs) were exposed to superoxide anion radicals (O2−) generated by xanthine and xanthine oxidase. To rule out that the activation of HSCs is due to hydrogen peroxide derived from O2−, control incubations with copper, zinc-superoxide dismutase and tempol were studied as well. Influx of O2− activated HSCs, evidenced by the expression of α-smooth muscle actin and the secretion of transforming growth factor β1 and collagen. We further found that blockade of chloride channels with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) or indanyloxyacetic acid (IAA-94) prevented the increase of intracellular O2− levels as well as the activation of HSCs. These findings suggest that O2− is involved in the development of liver fibrosis and that entry of O2−, through chloride channels, in stellate cells is critical for their activation. This study provides new insight into the mechanism by which ROS induce liver fibrosis. Furthermore, our data suggest that chloride channels constitute a potential target for new anti-fibrotic drugs.
Original languageEnglish
Pages (from-to)140-144
Number of pages5
JournalEuropean Journal of Pharmacology
Volume724
Issue number5 February
DOIs
Publication statusPublished - 5 Feb 2014

Keywords

  • Hepatic stellate cells
  • Superoxide anion radicals
  • Transforming growth factor-beta
  • Collagen
  • alpha Smooth muscle actin
  • N-ACETYLCYSTEINE
  • EXPRESSION
  • ALPHA
  • BETA

Cite this

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title = "Superoxide anion radicals activate hepatic stellate cells after entry through chloride channels: A new target in liver fibrosis",
abstract = "It is generally accepted that reactive oxygen species (ROS) play an important role in the pathogenesis of liver fibrosis. ROS, however, constitute a group of species with varying properties making it likely that their contribution to the pathological mechanism varies. LX-2 hepatic stellate cells (HSCs) were exposed to superoxide anion radicals (O2−) generated by xanthine and xanthine oxidase. To rule out that the activation of HSCs is due to hydrogen peroxide derived from O2−, control incubations with copper, zinc-superoxide dismutase and tempol were studied as well. Influx of O2− activated HSCs, evidenced by the expression of α-smooth muscle actin and the secretion of transforming growth factor β1 and collagen. We further found that blockade of chloride channels with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) or indanyloxyacetic acid (IAA-94) prevented the increase of intracellular O2− levels as well as the activation of HSCs. These findings suggest that O2− is involved in the development of liver fibrosis and that entry of O2−, through chloride channels, in stellate cells is critical for their activation. This study provides new insight into the mechanism by which ROS induce liver fibrosis. Furthermore, our data suggest that chloride channels constitute a potential target for new anti-fibrotic drugs.",
keywords = "Hepatic stellate cells, Superoxide anion radicals, Transforming growth factor-beta, Collagen, alpha Smooth muscle actin, N-ACETYLCYSTEINE, EXPRESSION, ALPHA, BETA",
author = "{den Hartog}, G.J. and S. Qi and {van Tilburg}, J.H. and G.H. Koek and A. Bast",
year = "2014",
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doi = "10.1016/j.ejphar.2013.12.033",
language = "English",
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journal = "European Journal of Pharmacology",
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Superoxide anion radicals activate hepatic stellate cells after entry through chloride channels : A new target in liver fibrosis. / den Hartog, G.J.; Qi, S.; van Tilburg, J.H.; Koek, G.H.; Bast, A.

In: European Journal of Pharmacology, Vol. 724, No. 5 February, 05.02.2014, p. 140-144.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Superoxide anion radicals activate hepatic stellate cells after entry through chloride channels

T2 - A new target in liver fibrosis

AU - den Hartog, G.J.

AU - Qi, S.

AU - van Tilburg, J.H.

AU - Koek, G.H.

AU - Bast, A.

PY - 2014/2/5

Y1 - 2014/2/5

N2 - It is generally accepted that reactive oxygen species (ROS) play an important role in the pathogenesis of liver fibrosis. ROS, however, constitute a group of species with varying properties making it likely that their contribution to the pathological mechanism varies. LX-2 hepatic stellate cells (HSCs) were exposed to superoxide anion radicals (O2−) generated by xanthine and xanthine oxidase. To rule out that the activation of HSCs is due to hydrogen peroxide derived from O2−, control incubations with copper, zinc-superoxide dismutase and tempol were studied as well. Influx of O2− activated HSCs, evidenced by the expression of α-smooth muscle actin and the secretion of transforming growth factor β1 and collagen. We further found that blockade of chloride channels with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) or indanyloxyacetic acid (IAA-94) prevented the increase of intracellular O2− levels as well as the activation of HSCs. These findings suggest that O2− is involved in the development of liver fibrosis and that entry of O2−, through chloride channels, in stellate cells is critical for their activation. This study provides new insight into the mechanism by which ROS induce liver fibrosis. Furthermore, our data suggest that chloride channels constitute a potential target for new anti-fibrotic drugs.

AB - It is generally accepted that reactive oxygen species (ROS) play an important role in the pathogenesis of liver fibrosis. ROS, however, constitute a group of species with varying properties making it likely that their contribution to the pathological mechanism varies. LX-2 hepatic stellate cells (HSCs) were exposed to superoxide anion radicals (O2−) generated by xanthine and xanthine oxidase. To rule out that the activation of HSCs is due to hydrogen peroxide derived from O2−, control incubations with copper, zinc-superoxide dismutase and tempol were studied as well. Influx of O2− activated HSCs, evidenced by the expression of α-smooth muscle actin and the secretion of transforming growth factor β1 and collagen. We further found that blockade of chloride channels with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) or indanyloxyacetic acid (IAA-94) prevented the increase of intracellular O2− levels as well as the activation of HSCs. These findings suggest that O2− is involved in the development of liver fibrosis and that entry of O2−, through chloride channels, in stellate cells is critical for their activation. This study provides new insight into the mechanism by which ROS induce liver fibrosis. Furthermore, our data suggest that chloride channels constitute a potential target for new anti-fibrotic drugs.

KW - Hepatic stellate cells

KW - Superoxide anion radicals

KW - Transforming growth factor-beta

KW - Collagen

KW - alpha Smooth muscle actin

KW - N-ACETYLCYSTEINE

KW - EXPRESSION

KW - ALPHA

KW - BETA

U2 - 10.1016/j.ejphar.2013.12.033

DO - 10.1016/j.ejphar.2013.12.033

M3 - Article

VL - 724

SP - 140

EP - 144

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 5 February

ER -