Roles of elevated 20-HETE in the breakdown of blood brain barrier and the severity of brain edema in experimental traumatic brain injury

摘要

Breakdown of the blood brain barrier (BBB) is a secondary injury following traumatic brain injury (TBI) and can lead to the development of brain edema. However, the factors that contribute to the disruption of the BBB and increase the severity of brain edema in TBI remain to be elucidated. 20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid. The inhibition of 20-HETEsynthesis by HET0016 has been suggested as a strategy to decrease brain edema. The present study aimed to investigate whether the elevated production of 20-HETE in cerebral tissue may contribute to BBB breakdown and increase the severity of brain edema in rats with TBI. BBB permeability was quantified using dynamic contrast-enhanced magnetic resonance imaging and brain edema was measured according to brain water content. Superoxide production in injured tissue was also assessed. Liquid chromatography-mass spectrometry was used to evaluate 20-HETE production in injured tissue. Western blot analysis was used to assess the expression of occludin, zonula occludens (ZO)-1, matrix metalloproteinase (MMP)-9, and proteins of the c-Jun N-terminal kinase (JNK) pathway. A total of 3, 24 and 72 h following the induction of TBI, 20-HETE levels, BBB permeability and brain edema were identified to be increased, accompanied by an increase in superoxide production. Conversely, superoxide dismutase levels, in addition to the total antioxidative capability were decreased. In addition, the expression of MMP-9 and proteins of the JNK pathway was upregulated, whereas the expression of occludin and ZO-1 was observed to be suppressed. These results suggested that 20-HETE may aggravate BBB disruption following TBI, via enhancing the expression of MMP-9 and tight junction proteins. Furthermore, oxidative stress and the JNK signaling pathway may be involved in BBB dysregulation. In conclusion, the results of the present demonstrated that the production of 20-HETE was increased in cerebral tissue following traumatic injury, thus suggesting that it may contribute to the compromise of BBB integrity and the development of brain edema.