Abstract
Subacute poisoning of 1,2-dichloroethane (1,2-DCE) has become a serious occupational problem in China, and brain edema is its main pathological consequence, but little is known about the underlying mechanisms. As the metabolite of 1,2-DCE, 2-chloroethanol (2-CE) is more reactive, and might play an important role in the toxic effects of 1,2-DCE. In our previous studies, we found that matrix metalloproteinases-9 (MMP-9) expression was enhanced in mouse brains upon treatment with 1,2-DCE, and in rat astrocytes exposed to 2-CE. In the present study, we analyzed the association of nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) with MMP-9 overexpression in astrocytes treated with 2-CE. MMP-9, p65, c-Jun, and c-Fos were significantly upregulated by 2-CE treatment, which also enhanced phosphorylation of c-Jun, c-Fos and inhibitor of κBα (IκBα), and nuclear translocation of p65. Furthermore, inhibition of IκBα phosphorylation and AP-1 activity with the specific inhibitors could attenuate MMP-9 overexpression in the cells. On the other hand, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway suppressed the activation of both NF-κB and AP-1 in 2-CE-treated astrocytes. In conclusion, MMP-9 overexpression induced by 2-CE in astrocytes could be mediated at least in part through the p38 signaling pathway via activation of both NF-κB and AP-1. This study might provide novel clues for clarifying the mechanisms underlying 1,2-DCE associated cerebral edema.
Highlights
The synthetic halohydrocarbon 1,2-dichloroethane (1,2-DCE) is mainly used as the monomer in the manufacture of polyvinyl chloride, and as an industrial solvent and glue thinner
Accumulated evidence has demonstrated that astrocytes are necessary for neuronal survival and function by maintenance of blood brain barrier (BBB) integrity and extracellular homeostasis
Astrocytes can be activated in pathophysiological conditions, and secrete a variety of proinflammatory cytokines, such as matrix metalloproteinases-9 (MMP-9), which degrades the proteins in the tight junctions of BBB, leading to breakdown in BBB integrity and brain edema formation
Summary
The synthetic halohydrocarbon 1,2-dichloroethane (1,2-DCE) is mainly used as the monomer in the manufacture of polyvinyl chloride, and as an industrial solvent and glue thinner. It presents a significant occupational hazard to factory workers as exposure to high concentrations of 1,2-DCE vapors is lethal. In the last thirty years, a number of cases of subacute poisoning of 1,2-DCE have been reported in China [1]. Brain edema is the main pathological consequence of 1,2-DCE poisoning [2,3], but little is known regarding the underlying mechanisms. Previous studies have shown that 2-chloroethanol (2-CE), a metabolite of 1,2-DCE generated in vivo via microsomal CYP2E1, is more reactive than its parent molecule, and might play an important role in the toxic effects of 1,2-DCE [4,5,6]. Our studies showed that matrix metalloproteinases-9 (MMP-9) was transcriptionally upregulated in 2-CE-treated astrocytes in vitro [7], Cells 2018, 7, 96; doi:10.3390/cells7080096 www.mdpi.com/journal/cells
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