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

Xiaoxia Jin,Fenghong Zhao,Tong Wang,Jingjing Guo,Yingjun Liao,Gaoyang Wang,Yaping Jin

doi:10.3390/cells8090987

Abstract

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.

Highlights

Synthetic halohydrocarbon 1,2-dichloroethane (1,2-DCE) is mainly used in the manufacture of polyvinyl chloride worldwide, and as an industrial solvent both in China and other countries.industrial workers may be exposed to high concentrations of 1,2-DCE through the air [1,2]
Studies far have demonstrated that matrix metalloproteinase-9 (MMP-9) is substantially overexpressed in many brain diseases, which acts as a proteolytic enzyme involved in the disruption of the blood–brain barrier (BBB), and an inflammatory mediator playing an important role in neuroinflammation [8,9,10]
We have found that nuclear factor-κB (NF-κB) could be activated through p38 mitogen-activated protein kinases (MAPKs) signaling pathway during the course of 1,2-DCE-induced brain edema in mice [6], it is still unknown whether activation of NF-κB could enhance MMP-9 expression and whether BBB integrity might be disrupted by excessive

Summary

Introduction

Synthetic halohydrocarbon 1,2-dichloroethane (1,2-DCE) is mainly used in the manufacture of polyvinyl chloride worldwide, and as an industrial solvent both in China and other countries.industrial workers may be exposed to high concentrations of 1,2-DCE through the air [1,2]. Studies far have demonstrated that MMP-9 is substantially overexpressed in many brain diseases, which acts as a proteolytic enzyme involved in the disruption of the blood–brain barrier (BBB), and an inflammatory mediator playing an important role in neuroinflammation [8,9,10]. It is well-known that inflammatory reactions are involved in the pathogenesis of brain diseases, and that p38 MAPK act as a critical mediator in these reactions [11,12]. Nuclear factor-κB (NF-κB) as a key transcription factor that plays an important role in the inflammatory reaction by promoting the production of proinflammatory factors and inflammatory mediators [13,14]

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Results

Discussion

Conclusion