Cerebrospinal Fluid Levels of High-Mobility Group Box 1 and Cytochrome C Predict Outcome after Pediatric Traumatic Brain Injury

Abstract

High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is passively released from damaged and necrotic cells, and actively released from immune cells. In contrast, cytochrome c is released from mitochondria in apoptotic cells, and is considered a reliable biomarker of apoptosis. Thus, HMGB1 and cytochrome c may in part reflect the degree of necrosis and apoptosis present after traumatic brain injury (TBI), where both are felt to contribute to cell death and neurological morbidity. Ventricular cerebrospinal fluid (CSF) was obtained from children admitted to the intensive care unit (ICU) after TBI (n = 37). CSF levels of HMGB1 and cytochrome c were determined at four time intervals (0-24 h, 25-48 h, 49-72 h, and > 72 h after injury) using enzyme-linked immunosorbent assay (ELISA). Lumbar CSF from children without TBI served as controls (n = 12). CSF HMGB1 levels were: control = 1.78 -0. In conclusion, increased CSF levels of HMGB1 and cytochrome c were associated with poor outcome after TBI in infants and children. These data are also consistent with the designation of HMGB1 as a ''danger signal.'' Distinctly increased CSF cytochrome c levels in infants and children with AHT and poor outcome suggests that apoptosis may play an important role in this unique patient population.

HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

“…Its elevation is associated with the severity of brain damage following TBI [28]. Previous studies revealed that HMGB1 was translocated from the nucleus to the cytoplasm, and was released out of necrotic cells at early stages following TBI [9, 29].…”

High Mobility Group Box 1 and Traumatic Brain Injury

“…Alicia and colleagues demonstrated that concentrations of HMGB1 are elevated in Cerebrospinal fluid (CSF) after trauma, and furthermore, these were separately related to poor outcomes [23]. They proposed that increased CSF HMGB1 is separately related to 6-month Glasgow Coma Scale (GOS) score 1 -3 which reflects a poor outcome.…”

“…Studies have shown that damage induced by trauma or ischemia can evoke HMGB1 secretion from necrotic tissue which may provide danger signal that alerts the immune system to the existence of injured cells [23] [26]. The traumatic events leading to the secretion of HMGB1 into the CSF also initiate the secretion of other DAMP into the CSF with successive activation of the innate immune response [25].…”

The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction

“…This injury-induced excess of catecholamine also lends itself to hypertension, abnormal heart variability and neurological deficits (44,90,112). More recent clinical studies implicate the production and release of inflammatory mediators, including HMGB1 (8,49,75,122). Though organ failure scoring systems, present clinical markers and single cytokine estimates have failed to predict the onset of organ dysfunction in the clinical setting, patterns of early circulating trauma markers such as HMGB1 may serve to guide and streamline damage control following TBI.…”

“…Some clinical studies of mechanical trauma in the absence of head injury fail to find a correlation between HMGB1 levels in plasma and measures of morbidity (88). However, other studies which included patients with trauma to the head suggest that the release of HMGB1 is predictive of both mortality and neurological dysfunction in adult and pediatric patients (8,28,42). The presence of the increased HMGB1 levels in both plasma and cerebrospinal fluid may ultimately reflect release from damaged and dying cells in the brain.…”