Abstract
Sepsis is a major clinical challenge and septic encephalopathy is its nasty complication. The pathogenesis and underlying mechanisms of septic encephalopathy are not well understood. This study sought to fully characterize sepsis-associated biochemical and histopathological changes in brains of mice after cecal ligation and puncture, regarded as a highly clinically relevant animal model of polymicrobial sepsis. Real-time PCR analysis showed that gene expression levels of proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, were significantly up-regulated in brain tissues from septic mice, but to a much lesser extent when compared with those in peripheral tissues such as lungs. Blood-brain barrier (BBB) permeability was significantly increased in septic mice, as determined by the measurement of sodium fluorescein and Evans blue content. Sepsis resulted in increases in NADPH oxidase activity and expression of p47phox and p67phox and up-regulation of inducible nitric oxide (NO) synthase in brains, indicating that superoxide, produced by NADPH oxidase, reacts with NO to form peroxynitrite, that maybe lead to the loss of BBB integrity. Light and electron microscopic examination of septic mouse brain showed serious neuronal degeneration, as indicated by hyperchromatic, shrunken, pyknotic, and electron-dense neurons. These histopathogical changes were prevented by treatment with the free radical scavenger edaravone. Together, these results suggest that sepsis can lead to rapid neurodegenerative changes in brains via free radical species production and possibly subsequent injury to the BBB. We may also provide a potentially useful therapeutic tool for treating septic encephalopathy.
Highlights
Sepsis is a systemic inflammatory response syndrome based on the presence of infection and is a major clinical challenge in intensive care medicine
To estimate proinflammatory cytokine levels associated with brain inflammation during Cecal ligation and puncture (CLP)-induced sepsis, we initially performed real-time PCR analysis from total RNA isolated from brain and lung tissues of sham-operated control and CLP mice
Endotoxin activates inflammatory cells of the myeloid lineage that subsequently amplify the inflammatory response by releasing proinflammatory cytokines
Summary
Sepsis is a systemic inflammatory response syndrome based on the presence of infection and is a major clinical challenge in intensive care medicine. Sepsis is a complex syndrome with its wide spectrum of severity. Septic shock is a subset of severe sepsis defined as hypotension that is poorly responsive to fluid resuscitation. The brain may be affected by many systemic disturbances, such as hypotension, hypoxemia, hyper- or hypoglycemia, and organ dysfunction. Brain dysfunction is often one of the first clinical symptoms in sepsis. Septic encephalopathy is a symmetric diffuse brain dysfunction and remains a baffling complication of the sepsis syndrome with limited therapeutic options. Septic encephalopathy is the most common form of encephalopathy among patients in intensive care units. The onset of encephalopathy often precedes failure of other organs such as lung, liver, and kidney, and it is associated with significantly increased mortality [7]
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