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Protective Effects of N-Acetyl Cysteine against Diesel Exhaust Particles-Induced Intracellular ROS Generates Pro-Inflammatory Cytokines to Mediate the Vascular Permeability of Capillary-Like Endothelial Tubes.

Tseng CY, Chang JF, Wang JS, Chang YJ, Gordon MK, Chao MW - PLoS ONE (2015)

Bottom Line: Previous studies using in vitro endothelial tubes as a simplified model of capillaries have found that DEP-induced ROS increase vascular permeability with rearrangement or internalization of adherens junctional VE-cadherin away from the plasma membrane.Our data suggests that DEP-induced intracellular ROS and release of the pro-inflammatory cytokines TNF- α and IL-6, which would contribute to VEGF-A secretion and disrupt cell-cell borders and increase vasculature permeability.Addition of NAC suppresses DEP-induced ROS efficiently and reduces subsequent damages by increasing endogenous glutathione.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, College of Engineering, Chung Yuan Christian University, Zhongli district, Taoyuan city, Taiwan; Center of Nanotechnology, Chung Yuan Christian University, Zhongli district, Taoyuan city, Taiwan.

ABSTRACT
Exposure to diesel exhaust particles (DEP) is associated with pulmonary and cardiovascular diseases. Previous studies using in vitro endothelial tubes as a simplified model of capillaries have found that DEP-induced ROS increase vascular permeability with rearrangement or internalization of adherens junctional VE-cadherin away from the plasma membrane. This allows DEPs to penetrate into the cell and capillary lumen. In addition, pro-inflammatory cytokines are up-regulated and mediate vascular permeability in response to DEP. However, the mechanisms through which these DEP-induced pro-inflammatory cytokines increase vascular permeability remain unknown. Hence, we examined the ability of DEP to induce permeability of human umbilical vein endothelial cell tube cells to investigate these mechanisms. Furthermore, supplementation with NAC reduces ROS production following exposure to DEP. HUVEC tube cells contributed to a pro-inflammatory response to DEP-induced intracellular ROS generation. Endothelial oxidative stress induced the release of TNF-α and IL-6 from tube cells, subsequently stimulating the secretion of VEGF-A independent of HO-1. Our data suggests that DEP-induced intracellular ROS and release of the pro-inflammatory cytokines TNF- α and IL-6, which would contribute to VEGF-A secretion and disrupt cell-cell borders and increase vasculature permeability. Addition of NAC suppresses DEP-induced ROS efficiently and reduces subsequent damages by increasing endogenous glutathione.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram depicting DEP-induced mechanisms potentially causing vascular permeability.DEPs cause capillary-like endothelial tubes to produce intracellular oxidative stress, which increases vascular permeability by 3 mechanisms: i) direct rearrangement of the cell-cell junctional VE-cadherin network; ii) activation of HO-1, which subsequently causes release of the vascular permeability factor, VEGFA; iii) inducible TNF-α and IL-6 release, which might increase the release of VEGFA independently of the contribution by HO-1. Administration of NAC blocks these sequential cytotoxic effects from the beginning.
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pone.0131911.g008: Schematic diagram depicting DEP-induced mechanisms potentially causing vascular permeability.DEPs cause capillary-like endothelial tubes to produce intracellular oxidative stress, which increases vascular permeability by 3 mechanisms: i) direct rearrangement of the cell-cell junctional VE-cadherin network; ii) activation of HO-1, which subsequently causes release of the vascular permeability factor, VEGFA; iii) inducible TNF-α and IL-6 release, which might increase the release of VEGFA independently of the contribution by HO-1. Administration of NAC blocks these sequential cytotoxic effects from the beginning.

Mentions: To our knowledge, this is the first study showing that antioxidant, NAC is capable of reducing the oxidative increase of vascular permeability exerted by diesel exhaust particles. There was a common relationship between the effects of DEP on GSH homeostasis in that was positively affected [79, 80]. Our previous experiments have shown that DEPs upregulate HO-1 expression and sequentially induce the release of VEGF-A. Both of these molecules are known to contribute to endothelial permeability. The current study shows that DEP-induced intracellular ROS may cause the release of pro-inflammatory TNF-α and IL-6, which may induce endothelial permeability by promoting VEGF-A secretion independently of HO-1 activation. A schematic depicting how DEPs affect permeability is provided in Fig 8. In this figure, the key mediator is intracellular ROS induced by DEP exposure. The ROS is cytotoxic to the tube cells, while NAC is able to mitigate this free radicals generation. Chao et al (2012) has suggested this intracellular ROS directly increases vascular permeability and stimulates Nrf2 translocation to the nucleus, thereby upregulating HO-1 expression to modulate VEGF-A secretion [12]. Alternatively, intracellular ROS-induced TNF-α and IL-6 contribute to the release of VEGF-A as well. These 3 pathways lead to disruption of the endothelial VE-cadherin network. The pattern of changes in VE-cadherin distribution contains linear discontinuity, submembrane internalization, and globular formation, resulting in discontinuation and permeability of the cell-cell border. Therefore, were these phenomena to occur, even to a small degree, in lung capillaries after exposure to DEP, the particles may gain access to the bloodstream and contribute to the development of adverse cardiovascular events. And a potential protection of NAC against the DEP-induced subsequent damages was determined.


Protective Effects of N-Acetyl Cysteine against Diesel Exhaust Particles-Induced Intracellular ROS Generates Pro-Inflammatory Cytokines to Mediate the Vascular Permeability of Capillary-Like Endothelial Tubes.

Tseng CY, Chang JF, Wang JS, Chang YJ, Gordon MK, Chao MW - PLoS ONE (2015)

Schematic diagram depicting DEP-induced mechanisms potentially causing vascular permeability.DEPs cause capillary-like endothelial tubes to produce intracellular oxidative stress, which increases vascular permeability by 3 mechanisms: i) direct rearrangement of the cell-cell junctional VE-cadherin network; ii) activation of HO-1, which subsequently causes release of the vascular permeability factor, VEGFA; iii) inducible TNF-α and IL-6 release, which might increase the release of VEGFA independently of the contribution by HO-1. Administration of NAC blocks these sequential cytotoxic effects from the beginning.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492618&req=5

pone.0131911.g008: Schematic diagram depicting DEP-induced mechanisms potentially causing vascular permeability.DEPs cause capillary-like endothelial tubes to produce intracellular oxidative stress, which increases vascular permeability by 3 mechanisms: i) direct rearrangement of the cell-cell junctional VE-cadherin network; ii) activation of HO-1, which subsequently causes release of the vascular permeability factor, VEGFA; iii) inducible TNF-α and IL-6 release, which might increase the release of VEGFA independently of the contribution by HO-1. Administration of NAC blocks these sequential cytotoxic effects from the beginning.
Mentions: To our knowledge, this is the first study showing that antioxidant, NAC is capable of reducing the oxidative increase of vascular permeability exerted by diesel exhaust particles. There was a common relationship between the effects of DEP on GSH homeostasis in that was positively affected [79, 80]. Our previous experiments have shown that DEPs upregulate HO-1 expression and sequentially induce the release of VEGF-A. Both of these molecules are known to contribute to endothelial permeability. The current study shows that DEP-induced intracellular ROS may cause the release of pro-inflammatory TNF-α and IL-6, which may induce endothelial permeability by promoting VEGF-A secretion independently of HO-1 activation. A schematic depicting how DEPs affect permeability is provided in Fig 8. In this figure, the key mediator is intracellular ROS induced by DEP exposure. The ROS is cytotoxic to the tube cells, while NAC is able to mitigate this free radicals generation. Chao et al (2012) has suggested this intracellular ROS directly increases vascular permeability and stimulates Nrf2 translocation to the nucleus, thereby upregulating HO-1 expression to modulate VEGF-A secretion [12]. Alternatively, intracellular ROS-induced TNF-α and IL-6 contribute to the release of VEGF-A as well. These 3 pathways lead to disruption of the endothelial VE-cadherin network. The pattern of changes in VE-cadherin distribution contains linear discontinuity, submembrane internalization, and globular formation, resulting in discontinuation and permeability of the cell-cell border. Therefore, were these phenomena to occur, even to a small degree, in lung capillaries after exposure to DEP, the particles may gain access to the bloodstream and contribute to the development of adverse cardiovascular events. And a potential protection of NAC against the DEP-induced subsequent damages was determined.

Bottom Line: Previous studies using in vitro endothelial tubes as a simplified model of capillaries have found that DEP-induced ROS increase vascular permeability with rearrangement or internalization of adherens junctional VE-cadherin away from the plasma membrane.Our data suggests that DEP-induced intracellular ROS and release of the pro-inflammatory cytokines TNF- α and IL-6, which would contribute to VEGF-A secretion and disrupt cell-cell borders and increase vasculature permeability.Addition of NAC suppresses DEP-induced ROS efficiently and reduces subsequent damages by increasing endogenous glutathione.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, College of Engineering, Chung Yuan Christian University, Zhongli district, Taoyuan city, Taiwan; Center of Nanotechnology, Chung Yuan Christian University, Zhongli district, Taoyuan city, Taiwan.

ABSTRACT
Exposure to diesel exhaust particles (DEP) is associated with pulmonary and cardiovascular diseases. Previous studies using in vitro endothelial tubes as a simplified model of capillaries have found that DEP-induced ROS increase vascular permeability with rearrangement or internalization of adherens junctional VE-cadherin away from the plasma membrane. This allows DEPs to penetrate into the cell and capillary lumen. In addition, pro-inflammatory cytokines are up-regulated and mediate vascular permeability in response to DEP. However, the mechanisms through which these DEP-induced pro-inflammatory cytokines increase vascular permeability remain unknown. Hence, we examined the ability of DEP to induce permeability of human umbilical vein endothelial cell tube cells to investigate these mechanisms. Furthermore, supplementation with NAC reduces ROS production following exposure to DEP. HUVEC tube cells contributed to a pro-inflammatory response to DEP-induced intracellular ROS generation. Endothelial oxidative stress induced the release of TNF-α and IL-6 from tube cells, subsequently stimulating the secretion of VEGF-A independent of HO-1. Our data suggests that DEP-induced intracellular ROS and release of the pro-inflammatory cytokines TNF- α and IL-6, which would contribute to VEGF-A secretion and disrupt cell-cell borders and increase vasculature permeability. Addition of NAC suppresses DEP-induced ROS efficiently and reduces subsequent damages by increasing endogenous glutathione.

No MeSH data available.


Related in: MedlinePlus