Oxidative Burst of Circulating Neutrophils Following Traumatic Brain Injury in Human

Yiliu Liao,Zhi-Yuan Zhang,Fangyuan Guo,Peng Liu,Zhiren Zhang,Valli De Re

doi:10.1371/journal.pone.0068963

Abstract

Besides secondary injury at the lesional site, Traumatic brain injury (TBI) can cause a systemic inflammatory response, which may cause damage to initially unaffected organs and potentially further exacerbate the original injury. Here we investigated plasma levels of important inflammatory mediators, oxidative activity of circulating leukocytes, particularly focusing on neutrophils, from TBI subjects and control subjects with general trauma from 6 hours to 2 weeks following injury, comparing with values from uninjured subjects. We observed increased plasma level of inflammatory cytokines/molecules TNF-α, IL-6 and CRP, dramatically increased circulating leukocyte counts and elevated expression of TNF-α and iNOS in circulating leukocytes from TBI patients, which suggests a systemic inflammatory response following TBI. Our data further showed increased free radical production in leukocyte homogenates and elevated expression of key oxidative enzymes iNOS, COX-2 and NADPH oxidase (gp91phox) in circulating leukocytes, indicating an intense induction of oxidative burst following TBI, which is significantly greater than that in control subjects with general trauma. Furthermore, flow cytometry assay proved neutrophils as the largest population in circulation after TBI and showed significantly up-regulated oxidative activity and suppressed phagocytosis rate for circulating neutrophils following brain trauma. It suggests that the highly activated neutrophils might play an important role in the secondary damage, even outside the injured brain. Taken together, the potent systemic inflammatory response induced by TBI, especially the intensively increase oxidative activity of circulating leukocytes, mainly neutrophils, may lead to a systemic damage, dysfunction/damage of bystander tissues/organs and even further exacerbate secondary local damage. Controlling these pathophysiological processes may be a promising therapeutic strategy and will protect unaffected organs and the injured brain from the secondary damage.

Highlights

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality among young adults in developed countries [1]
Our present study reported increased plasma level of inflammatory markers tumor necrosis factor-a (TNF-a), IL-6 and C-reactive protein (CRP), dramatically increased circulating leukocyte counts, neutrophils counts, and elevated expression of TNF-a and iNOS in circulating leukocytes from TBI patients, suggesting a systemic inflammatory response following TBI
Flow cytometry assay proved neutrophils as the largest population in circulation after TBI and showed significantly up-regulated oxidative activity and suppressed phagocytosis rate for circulating neutrophils following brain trauma, suggesting the highly activated neutrophils might play an important role in pathological process of the secondary damage, even outside the injury brain

Summary

Introduction

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality among young adults in developed countries [1]. A robust inflammatory response induced by trauma is a key component of TBI It involves the activation of glia and neurons as well as cerebral accumulation of monocytes and lymphocytes, which can exacerbate the focal injury and contributes to the secondary or delayed injury at the injury site [3]. The early, delayed, and systemic effects of acute TBI are the result of inflammatory mediators which initiate systemic inflammatory response, and even subsequent complement deficits and coagulopathy [7]. Inflammatory mediators such as cytokines, free radicals and activation of immune cells are implicated in secondary injury development following brain trauma [11]

Methods

Results

Conclusion