Involvement of CYP2E1 in the Course of Brain Edema Induced by Subacute Poisoning With 1,2-Dichloroethane in Mice

Jin, Xinqiao; Liao, Yingjun; Tan, Xiaoqiong; Wang, Gaoyang; Zhao, Fenghong; Jin, Yaping

doi:10.3389/fphar.2018.01317

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…Consistent with our previous studies [7,25], brain edema formed in the brain of mice in the 1,2 DCE-intoxicated group, which was indicated by increased brain water content and morphological changes of brain edema (Figure 1A,B). Moreover, compared with the control group, NF-κB binding activities in the brain of mice increased dramatically in the intoxicated group (Figure 1C), suggesting that NF-κB was activated during the course of 1,2-DCE-induced brain edema.…”

Section: Resultssupporting

confidence: 92%

Neuroinflammatory Reactions in the Brain of 1,2-DCE-Intoxicated Mice during Brain Edema

Jin

Wang

Liao

et al. 2019

Cells

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We previously reported that expression of matrix metalloproteinase-9 (MMP-9) mRNA and protein was upregulated during 1,2-dichloroethane (1,2-DCE) induced brain edema in mice. We also found that the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway resulted in MMP-9 overexpression and nuclear factor-κB (NF-κB) activation in mice treated with 1,2-DCE. In this study, we further hypothesized that inflammatory reactions mediated by the p38 MAPK/ NF-κB signaling pathway might be involved in MMP-9 overexpression, blood–brain barrier (BBB) disruption and edema formation in the brain of 1,2-DCE-intoxicated mice. Our results revealed that subacute poisoning by 1,2-DCE upregulates protein levels of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), interleukin-1β (IL-1β), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and p-p65 in mouse brains. Pretreatment with an inhibitor against p38 MAPK attenuates these changes. Moreover, pretreatment with an inhibitor against NF-κB attenuates alterations in brain water content, pathological indications notable in brain edema, as well as mRNA and protein expression on levels of MMP-9, VCAM-1, ICAM-1, iNOS, and IL-1β, tight junction proteins (TJs), GFAP and Iba-1 in the brain of 1,2-DCE-intoxicated mice. Furthermore, pretreatment with an inhibitor against MMP-9 obstructs the decrease of TJs in the brain of 1,2-DCE-intoxicated mice. Lastly, pretreatment with an antagonist against the IL-1β receptor also attenuates changes in protein levels of p-p38 MAPK, p-p65, p-IκB, VCAM -1, ICAM-1, IL-1β, and Iba-1 in the brain of 1,2-DCE-intoxicated-mice. Taken together, findings from the current study indicate that the p38 MAPK/ NF-κB signaling pathway might be involved in the activation of glial cells, and the overproduction of proinflammatory factors, which might induce inflammatory reactions in the brain of 1,2-DCE-intoxicated mice that leads to brain edema.

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Section: Resultssupporting

confidence: 92%

Neuroinflammatory Reactions in the Brain of 1,2-DCE-Intoxicated Mice during Brain Edema

Jin

Wang

Liao

et al. 2019

Cells

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“…CYP2E1 is the main enzyme that is implicated in 1,2-DCE metabolism in vivo [33]. Although its expression in the brain is much lower than in the liver, the enzyme is highly concentrated and inducible in the cortical astrocytes [34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

A1 astrocytes activated by 2-Chloroethanol via the ROS-induced p38 MAPK/NF-κB and AP-1 pathways modulate microglia polarization

Wang¹,

Sun²,

Tang³

et al. 2021

Preprint

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Background1,2-Dichloroethane (1,2-DCE) is a synthetic organic chemical that causes brain edema under subacute poisoning. Our previous studies indicated that the neuroinflammation could be induced due to activation of both astrocytes and microglia during the course of brain edema in 1,2-DCE intoxicated mice. However, the crosstalk between the two glial cells in 1,2-DCE-induced neuroinflammation is unclear. In the current studies, we hypothesized that astrocytes are the first responder to the effects of 1,2-DCE in the brain, as they adhere to the cerebral capillaries, and they are an essential component of the blood-brain barrier (BBB).MethodsWe used primary cultured rat astrocytes and microglia, as well as a highly aggressively proliferating immortalized (HAPI) microglia cell line to study the effects of astrocytes on microglia polarization following exposure to 2-CE.ResultsFindings from the present studies demonstrated that treatment of primary rat astrocytes with 2-chloroethanol (2-CE), the intermediate metabolite of 1,2-DCE in vivo, can stimulate the activation of A1 reactive astrocytes (A1s) through p38 mitogen-activated protein kinase (p38 MAPK)/ nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) signaling pathways by the reactive oxygen species (ROS) produced during 2-CE metabolism. A1s activated by 2-CE can upregulate the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), and stimulate the M1 polarization of microglia through IL-1β and TNF-α released by 2-CE activated A1s. Microglia are less sensitive to 2-CE than astrocytes, since treatment of primary rat microglia with 30 mM 2-CE alone failed to activate them, though this dose of 2-CE can activate A1s and in turn stimulate M1 polarization of microglia through the factors released by A1s.ConclusionThe neuroinflammation induced by 1,2-DCE in the brain of mice is most probably triggered by the activation of astrocytes. The understanding of the multidimensional roles of reactive astrocytes may further the development of new treatment strategies in reducing neuroinflammation and brain edema following 1,2-DCE-induced toxic encephalopathy.

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“…It has been reported that CYP2E1 can convert 1,2-DCE into 2-CE, chloroacetaldehyde and chloroacetic acid [38][39][40][41]. Because of the high oxidase activity, CYP2E1-mediated metabolism of 1,2-DCE and its intermediates can lead to the generation of ROS, as a consequence induce oxidative damage in the brain [20,33] The present results revealed that CYP2E1 knockdown reversed 2-CE-induced augmentation of ROS production and A1s induction, suggesting that ROS production is involved in A1 activation. Using the ROS scavenger NAC, we further determined that ROS induce A1s.…”

Section: Discussionmentioning

confidence: 99%

A1 Reactive Astrocytes Activated by 2-chloroethanol Modulate M1 Microglia Polarization through Upregulating IL-1β and TNF-α

Wang

Sun

Tang

et al. 2021

Preprint

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Background1,2-Dichloroethane (1,2-DCE) is a synthetic organic chemical that causes brain edema under subacute poisoning. Our previous studies indicated that the neuroinflammation could be induced due to activation of both astrocytes and microglia during the course of brain edema in 1,2-DCE intoxicated mice. However, the crosstalk between the two glial cells in 1,2-DCE-induced neuroinflammation is unclear. In the current studies, we hypothesized that astrocytes are the first responder to the effects of 1,2-DCE in the brain, as they adhere to the cerebral capillaries, and they are an essential component of the blood-brain barrier (BBB).MethodsWe used primary cultured rat astrocytes and microglia, as well as a highly aggressively proliferating immortalized (HAPI) microglia cell line to study the effects of astrocytes on microglia polarization following exposure to 2-CE. ResultsFindings from the present studies demonstrated that treatment of primary rat astrocytes with 2-chloroethanol (2-CE), the intermediate metabolite of 1,2-DCE in vivo, can stimulate the activation of A1 reactive astrocytes (A1s) through p38 mitogen-activated protein kinase (p38 MAPK)/ nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) signaling pathways by the reactive oxygen species (ROS) produced during 2-CE metabolism. A1s activated by 2-CE can upregulate the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), and stimulate the M1 polarization of microglia through IL-1β and TNF-α released by 2-CE activated A1s. Microglia are less sensitive to 2-CE than astrocytes, since treatment of primary rat microglia with 30 mM 2-CE alone failed to activate them, though this dose of 2-CE can activate A1s and in turn stimulate M1 polarization of microglia through the factors released by A1s. ConclusionThe neuroinflammation induced by 1,2-DCE in the brain of mice is most probably triggered by the activation of astrocytes. The understanding of the multidimensional roles of reactive astrocytes may further the development of new treatment strategies in reducing neuroinflammation and brain edema following 1,2-DCE-induced toxic encephalopathy.

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Involvement of CYP2E1 in the Course of Brain Edema Induced by Subacute Poisoning With 1,2-Dichloroethane in Mice

Cited by 10 publications

References 43 publications

Neuroinflammatory Reactions in the Brain of 1,2-DCE-Intoxicated Mice during Brain Edema

Neuroinflammatory Reactions in the Brain of 1,2-DCE-Intoxicated Mice during Brain Edema

A1 astrocytes activated by 2-Chloroethanol via the ROS-induced p38 MAPK/NF-κB and AP-1 pathways modulate microglia polarization

A1 Reactive Astrocytes Activated by 2-chloroethanol Modulate M1 Microglia Polarization through Upregulating IL-1β and TNF-α

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