Abstract
2-Chloroethanol (2-CE) is one of the reactive metabolites of 1,2-DCE in vivo, which might contribute to brain edema formation induced by 1,2-dichloroethane (1,2-DCE) poisoning. Thus, the purpose of this study was to explore the roles of mitogen-activated protein kinase (MAPK) signal pathways in upregulation of matrix metalloproteinase-9 (MMP-9) in 2-CE exposed rat astrocytes. Expression of p38 MAPK (p38), extracellular signal regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and MMP-9 at both protein and gene levels in rat astrocytes were determined using western blot and real-time RT-PCR methods. The results showed that both protein and mRNA levels of MMP-9 in 2-CE exposed astrocytes significantly increased. Meanwhile, protein levels of phosphorylated p38 (p-p38), ERK1/2 (p-ERK1/2) and JNK1/2 (p-JNK1/2) in 2-CE exposed astrocytes also significantly increased. In addition, both protein and mRNA levels of MMP-9 significantly decreased in response to reduced protein levels of p-p38, p-ERK1/2 and p-JNK1/2 achieved by supplement with their specific inhibitors, indicating that activation of MAPK signal pathways might play an important role in upregulation of MMP-9 expression at the transcriptional level in 2-CE exposed astrocytes. Furthermore, since pretreatment of n-acetyl-l-cysteine (NAC), a powerful antioxidant amino acid, could attenuate the elevated levels of MMP-9, p-p38, p-ERK2 and p-JNK1/2 in 2-CE exposed astrocytes, activation of MAPK signal pathways in 2-CE exposed astrocytes could be mediated partially by reactive oxygen species (ROS), which was most likely generated in the metabolism of 2-CE.
Highlights
1,2-Dichloroethane (1,2-DCE, CAS number: 107-06-2) is a synthetic organic chemical that is mainly used for production of vinyl chloride
The former is called as vasogenic brain edema and due to breakdown of bloodbrain barrier (BBB), which allows passage of plasma proteins and water into the extracellular compartment, while the latter called as cytotoxic brain edema is due to excessive intake of water by injured brain cells (Simard and Rivest, 2007)
Our recent studies demonstrated that mRNA levels of matrix metalloproteinase-9 (MMP-9) in the cerebral tissues of 1,2-DCE poisoned mice significantly increased at the early phase of brain edema formation (Wang G. et al, 2014)
Summary
1,2-Dichloroethane (1,2-DCE, CAS number: 107-06-2) is a synthetic organic chemical that is mainly used for production of vinyl chloride. We hypothesized that upregulation of MMP-9 expression may play the key roles in the pathological processes of brain edema formation induced by 1,2-DCE poisoning. The mitogen-activated protein kinase (MAPK) signal pathways comprise three main groups of kinase, which are extracellular signal related kinases (ERKs), p38 MAPKs (p38) and c-Jun amino terminal kinases (JNKs; Tejima et al, 2007; Hsieh et al, 2010; Ralay Ranaivo et al, 2011) These intracellular signal pathways transport extracellular signals into the nucleus in response to multi-stimuli. They play the pivotal roles in many essential cellular processes, and are considered as the important regulators in pathogenesis of diseases. It has been reported that in response to suppressed MMP-9 expression in the brain achieved by the specific MAPK inhibitor, the concomitant edema and cortical injury in mice after brain trauma were ameliorated (Mori et al, 2002), suggested that MAPK signal pathways can play the key roles in modulation of MMP-9 expression
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