Bench-to-bedside review: Burn-induced cerebral inflammation – a neglected entity?

Abstract

Severe burn injury remains a major burden on patients and healthcare systems. Following severe burns, the injured tissues mount a local inflammatory response aiming to restore homeostasis. With excessive burn load, the immune response becomes disproportionate and patients may develop an overshooting systemic inflammatory response, compromising multiple physiological barriers in the lung, kidney, liver, and brain. If the blood-brain barrier is breached, systemic inflammatory molecules and phagocytes readily enter the brain and activate sessile cells of the central nervous system. Copious amounts of reactive oxygen species, reactive nitrogen species, proteases, cytokines/chemokines, and complement proteins are being released by these inflammatory cells, resulting in additional neuronal damage and life-threatening cerebral edema. Despite the correlation between cerebral complications in severe burn victims with mortality, burn-induced neuroinflammation continues to fly under the radar as an underestimated entity in the critically ill burn patient. In this paper, we illustrate the molecular events leading to blood-brain barrier breakdown, with a focus on the subsequent neuroinflammatory changes leading to cerebral edema in patients with severe burns. IntroductionSevere burn injury remains a significant health issue for society and a life-threatening event for the victim. Each year, more than 1.2 million people in the United States alone suffer burn injuries [1]; some 100,000 of these patients are hospitalized, accounting for a total of 2 million hospital days [2]. Thermal injuries mainly affect patients younger than 50 years of age [3] and remain one of the leading causes of childhood deaths, according to the Children's Burn Awareness Program. While the overall mortality has been reported to be 5%, it rapidly increases with advancing age and burn size up to 96% [3]. Most fatalities (65%) seem to be linked to burn-induced multiple organ failure, and 93% of burn patients present with clinical signs of the systemic inflammatory response syndrome before succumbing to their injuries [4].One of the critically impaired yet frequently overlooked organs in severe burn victims is the brain, despite the fact that cerebral complications in severe burn victims have been shown to highly correlate with mortality [5]. Hypoxic brain injury has been found as a primary cause of death in up to 10% of severe burn patients in an age-dependent manner [6]. The present review focuses on the neuroinflammatory changes occurring after severe burn injury and on the molecular mechanisms involved in their pathogenesis. Breakdown of the blood-brain barrier and development of cerebral edemaUnder physiological conditions, the blood-brain barrier (BBB) tightly regulates the molecules that enter the brain tissue. During the systemic inflammatory response syndrome, sepsis, or severe burn injury, however, this physical barrier between the systemic circulation and the cerebral parenchyma can be seriously compromised.When peripheral tissues are ex...

Surgically Induced Neuropathic Pain

“…An example is limitation of the inflammatory response by the local injection of corticosteroid (Li et al, 2011), or the use of transcranial magnetic stimulation to inhibit nociceptive transmission (Leo and Latif, 2007). Surgery induces inflammation – cellular responses around the wound (Thacker et al, 2007) and if pain signals reach the CNS, changes in glial and other cells involved in neuroinflammation (Myers et al, 2006; Saab et al, 2008; Flierl et al, 2009). In addition the use of anesthetics such as ketamine – a drug that has profound anitinflammatory effects (Loix et al, 2011), may help diminish surgical and postsurgical inflrammation when used during surgery (Welters et al, 2011), and as in the case with PTSD (McGhee et al, 2008), may limit chronic pain as has been shown in other pain studies (Correll et al, 2004; Sigtermans et al, 2009).…”

Elevated Serum Ubiquitin Carboxy-Terminal Hydrolase L1 Is Associated with Abnormal Blood–Brain Barrier Function after Traumatic Brain Injury

“…However, BBB status may also be influenced by extracranial processes, most notably systemic inflammation (Flierl et al, 2009a(Flierl et al, , 2010. Systemic inflammation occurs after TBI (Flierl et al, 2009b), but also after isolated extracranial trauma (Kobbe et al, 2008).…”

Burn injury induces gelsolin expression and cleavage in the brain of mice

“…In vitro study has shown that cytoplasmic gelsolin levels were increased in PC12 cells under oxidative stress (Ji et al, 2008, possibly as a response to counteract actions of apoptotic factors. Likewise, burn injury could lead to oxidative stress (Liu et al, 2010) and inflammatory response in the brain (Flierl et al, 2009). In our study, a small, but discernible elevation of gelsolin mRNA as well as protein expression in a precise temporal and spatial pattern was observed in the brain after burn injury.…”