Inhaled Nitric Oxide Protects Cerebral Autoregulation and Reduces Hippocampal Necrosis After Traumatic Brain Injury Through Inhibition of ET-1, ERK MAPK and IL-6 Upregulation in Pigs
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Traumatic brain injury (TBI) is an important contributor to morbidity and mortality. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Extracellular signal-related kinase (ERK) mitogen activated protein kinase (MAPK) and ET-1 are upregulated and contribute to impairment of cerebral autoregulation and histopathology after porcine fluid percussion brain injury (FPI). Recent studies show that inhaled nitric oxide (iNO) prevents impairment of cerebral autoregulation and histopathology after FPI in pigs. Unrelated studies indicated an association between ERK and increased IL-6 after FPI. However, the role of IL-6 in central nervous system (CNS) pathology is not well understood. We investigated whether iNO protects autoregulation and limits histopathology after FPI in pigs due to modulation of brain injury associated upregulation of ET-1, ERK MAPK, and IL-6.
Lateral FPI was produced in anesthetized pigs equipped with a closed cranial window and iNO administered at 30 min or 2 h post injury.
CSF ET-1, ERK MAPK, and IL-6 were increased by FPI, but release was blocked by iNO administered at 30 min or 2 h after TBI. The IL-6 antagonist LMT-28 prevented impairment of cerebral autoregulation and hippocampal CA1 and CA3 neuronal necrosis after FPI. Papaverine induced dilation was unchanged by FPI and LMT-28. Protection lasted for at least 2 h after iNO administration was stopped.
These data indicate that iNO protects cerebral autoregulation and reduces hippocampal necrosis after traumatic brain injury through inhibition of ET-1, ERK MAPK, and IL-6 upregulation in pigs.
KeywordsCerebral autoregulation Endothelin Nitric oxide IL-6 Signal transduction Traumatic brain injury
VC participated in pig TBI experiments, contributed to histopathologic analysis of brain tissue, and helped in the writing of the manuscript. PP participated in pig TBI experiments, contributed to histopathologic analysis of brain tissue and performed ELISA analysis of CSF samples. HH participated in pig TBI experiments, contributed to histopathologic analysis of brain tissue and performed ELISA analysis of CSF samples. WA designed the study, participated in pig TBI experiments, analyzed and interpreted the data, and wrote the manuscript.
Sources of Support
This investigator initiated research was funded by Mallinckrodt Pharmaceuticals.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
All protocols were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania under protocol number 805838.
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