Intrathecal and Serum Interleukin-6 and the Acute-Phase Response in Patients With Severe Traumatic Brain Injuries

Kossmann, Thomas; Hans, Volkmar; Imhof, Hans-Georg; Stocker, Reto; Grob, Peter J.; Trentz, O; Morganti-Kossmann, Maria Cristina

doi:10.1097/00024382-199511000-00001

Cited by 257 publications

(154 citation statements)

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“…33 In TBI patients, IL-6 has been reported to be highly elevated in CSF and to a lesser extent in serum; serum concentrations were associated with increased acute phase proteins (C-reactive protein, fibrinogen, and ␣1-antitrypsin) and with severe BBB dysfunction. 34 Interleukin-6 has also been detected in brain tissue in several experimental models of TBI. 24,35,36 Studies using BBB ϭ blood-brain barrier; HU-211 ϭ dexanabinol; PTX ϭ pentoxifylline; TBI ϭ traumatic brain injury.…”

Section: Interleukin-6mentioning

confidence: 99%

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

2010

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Summary:Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is no effective treatment available to patients, and morbidity and mortality remain high. The damage to the brain occurs in two phases, the initial primary phase being the injury itself, which is irreversible and amenable only to preventive measures to minimize the extent of damage, followed by an ongoing secondary phase, which begins at the time of injury and continues in the ensuing days to weeks. This delayed phase leads to a variety of physiological, cellular, and molecular responses aimed at restoring the homeostasis of the damaged tissue, which, if not controlled, will lead to secondary insults. The development of secondary brain injury represents a window of opportunity in which pharmaceutical compounds with neuroprotective properties could be administered. To establish effective treatments for TBI victims, it is imperative that the complex molecular cascades contributing to secondary injury be fully elucidated. One pathway known to be activated in response to TBI is cellular and humoral inflammation. Neuroinflammation within the injured brain has long been considered to intensify the damage sustained following TBI. However, the accumulated findings from years of clinical and experimental research support the notion that the action of inflammation may differ in the acute and delayed phase after TBI, and that maintaining limited inflammation is essential for repair. This review addresses the role of several cytokines and chemokines following focal and diffuse TBI, as well as the controversies around the use of therapeutic anti-inflammatory treatments versus genetic deletion of cytokine expression.

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Section: Interleukin-6mentioning

confidence: 99%

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

2010

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“…Distinct similarities exist between melatonin and certain cytokines and, in particular, their temporal profiles after injury. When comparing the temporal profile of endogenous CSF melatonin to that of interleukin-6 (IL-6) (Kossmann et al, 1995), it is evident that melatonin peaks at approximately the same times as this cytokine after TBI. Indeed, preliminary data from the laboratory investigating IL-6 concentrations on days 1 to 5 following TBI reveal a trend towards a positive relationship between melatonin and IL-6 (r = 0.223, P = 0.052, n = 77 samples) in CSF, but no significant correlation in serum measurements was found.…”

Section: Anti-inflammatory Properties Of Melatoninmentioning

confidence: 99%

Endogenous Melatonin Increases in Cerebrospinal Fluid of Patients after Severe Traumatic Brain Injury and Correlates with Oxidative Stress and Metabolic Disarray

Seifman

Adamides

Nguyen

et al. 2008

J Cereb Blood Flow Metab

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Oxidative stress plays a significant role in secondary damage after severe traumatic brain injury (TBI); and melatonin exhibits both direct and indirect antioxidant effects. Melatonin deficiency is deleterious in TBI animal models, and its administration confers neuroprotection, reducing cerebral oedema, and improving neurobehavioural outcome. This study aimed to measure the endogenous cerebrospinal fluid (CSF) and serum melatonin levels post-TBI in humans and to identify relationships with markers of oxidative stress via 8-isoprostaglandin-F 2a (isoprostane), brain metabolism and neurologic outcome. Cerebrospinal fluid and serum samples of 39 TBI patients were assessed for melatonin, isoprostane, and various metabolites. Cerebrospinal fluid but not serum melatonin levels were markedly elevated (7.28±0.92 versus 1.47±0.35 pg/mL, P < 0.0005). Isoprostane levels also increased in both CSF (127.62 ± 16.85 versus 18.28 ± 4.88 pg/mL, P < 0.0005) and serum (562.46±50.78 versus 126.15±40.08 pg/mL (P < 0.0005). A strong correlation between CSF melatonin and CSF isoprostane on day 1 after injury (r = 0.563, P = 0.002) suggests that melatonin production increases in conjunction with lipid peroxidation in TBI. Relationships between CSF melatonin and pyruvate (r = 0.369, P = 0.049) and glutamate (r = 0.373, P = 0.046) indicate that melatonin production increases with metabolic disarray. In conclusion, endogenous CSF melatonin levels increase after TBI, whereas serum levels do not. This elevation is likely to represent a response to oxidative stress and metabolic disarray, although further studies are required to elucidate these relationships.

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“…The tumor necrosis factor-alpha (TNF-a), interleukin-1beta (IL-b), IL-6, and transforming growth factor-b have been identified in the cerebrospinal fluid (CSF), plasma, or brain tissues of animals after cerebral ischemic or traumatic insults (Taupin et al, 1993;Wang et al 1995;Loddick et al, 1998;Stover et al, 2000). IL-6 production has also been demonstrated clinically, with ventricular CSF and plasma levels being elevated for days following TBI (McClain et al, 1991;Kossmann et al, 1995Kossmann et al, , 1996Aibiki et al, 1999;Csuka et al, 1999;Volkmar et al, 1999;Schwerdtfeger et al, 2001;Singhal et al, 2002;Winter et al, 2002;Buttram et al, 2007). Recent experimental and clinical studies have reported a positive correlation between IL-6 levels and injury severity and prognosis (Tarkowski et al, 1995;Juttler et al, 2002;Woiciechowsky et al, 2002;Minambres, et al, 2003;Frugier et al, 2010;Leyet et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Temporal Profile of Cerebrospinal Fluid, Plasma, and Brain Interleukin-6 After Normothermic Fluid-Percussion Brain Injury: Effect of Secondary Hypoxia

Chatzipanteli

Vitarbo

Alonso

et al. 2012

Therapeutic Hypothermia and Temperature Management

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Interleukin-6 (IL-6) is a proinflammatory cytokine that may play multiple roles in the pathogenesis of traumatic brain injury (TBI). The present study determined time-dependent changes in IL-6 concentrations in vulnerable brain regions, cerebrospinal fluid (CSF) samples, and plasma after normothermic TBI. Because secondary insults are common in head injured patients, we also assessed the consequences of a post-traumatic secondary hypoxic insult on this pleiotropic cytokine. Male Sprague-Dawley rats were intubated, anesthetized, and underwent a moderate parasagittal fluid-percussion brain injury (1.8-2.1 atm, 37°C) followed by either 30 minutes of normoxic or hypoxic (pO 2 = 30-40 mmHg) gas levels. Rats were sacrificed 3, 6, or 24 hours after TBI or shamoperated procedures. Brain samples, including the ipsilateral cerebral cortex and hippocampus were dissected and analyzed. Plasma and CSF samples were collected at similar times and stored at -80°C until analysis. IL-6 levels were significantly increased ( p < 0.05) at 3, 6, and 24 hours in the cerebral cortex and at 6 hours in the hippocampus after TBI. IL-6 levels in the TBI normoxic group for both structures returned to control levels by 24 hours. Plasma levels of IL-6 were elevated at all time points, while CSF levels were high at 3 and 6 hours, but normalized by 24 hours. Post-traumatic hypoxia led to significantly elevated ( p < 0.05) IL-6 protein levels in the cerebral cortex at 24 hours compared to sham-operated controls. These findings demonstrate that moderate TBI leads to an early increase in IL-6 brain, plasma, and CSF protein levels. Secondary post-traumatic hypoxia, a common secondary injury mechanism, led to prolonged elevations in plasma IL-6 levels that may participate in the pathophysiology of this complicated TBI model.

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Intrathecal and Serum Interleukin-6 and the Acute-Phase Response in Patients With Severe Traumatic Brain Injuries

Cited by 257 publications

References 0 publications

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

Endogenous Melatonin Increases in Cerebrospinal Fluid of Patients after Severe Traumatic Brain Injury and Correlates with Oxidative Stress and Metabolic Disarray

Temporal Profile of Cerebrospinal Fluid, Plasma, and Brain Interleukin-6 After Normothermic Fluid-Percussion Brain Injury: Effect of Secondary Hypoxia

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