TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1

Abstract

In this study, we demonstrate that mice deficient in TNFR1 (TNFR1 -/-) were resistant to LPSinduced encephalopathy. Systemic administration of lipopolysaccharide (LPS) induces a widespread inflammatory response similar to that observed in sepsis. Following LPS administration TNFR1 -/-mice had less caspase-dependent apoptosis in brain cells and fewer neutrophils infiltrating the brain (p<0.039), compared to control C57Bl6 (TNFR1 +/+ ) mice. TNFR1-dependent increase in aquaporin (AQP)-4 mRNA and protein expression was observed with a concomitant increase in water content, in brain (18% increase in C57Bl6 mice treated with LPS vs those treated with saline), similar to cerebral edema observed in sepsis. Furthermore, absence of TNFR1 partially but significantly reduced the activation of astrocytes, as shown by immunofluorescence and markedly inhibited iNOS mRNA expression (p<0.01).Septic Encephalopathy is a devastating complication of sepsis. Although, considerable work has been done to identify the mechanism causing the pathological alterations in this setting, the culprit still remains an enigma. Our results demonstrate for the first time that endotoxemia leads to inflammation in brain, with alteration in blood-brain barrier, up-regulation of AQP4 and associated edema, neutrophil infiltration, astrocytosis, as well as apoptotic cellular death, all of which appear to be mediated by TNF-α signaling through TNFR1. KeywordsRodent; Septic Encephalopathy; Lipopolysaccharide; Apoptosis; Aquaporin 4 Neuroimmunology Sepsis is a condition characterized by uncontrolled infection and affects many organs including brain (Green et al., 2004), with an attendant high mortality rate. Administration of bacterial endotoxin (LPS), a cell wall component of gram-negative bacteria, to mice cause pathogenesis, mimicking what occurs in clinical sepsis (Gardenfors et al., 2002;Radzivil et al., 1990). Septic encephalopathy could be due to multiple factors including inflammatory cells and their mediators, reduced cerebral blood flow, disruption of the blood-brain barrier (BBB), cerebral edema and inflammation (Papadopoulos et al., 2000). One of the mediators of inflammation that play a key role in sepsis, tumor necrosis factor (TNF-α), is increased in circulation following LPS administration (Tsao et al., 2001;Merrill and Benveniste, 1996). Serum TNF-α is an acute phase response and does not correlate with the alterations in brain, Address correspondence and reprint requests to Dr. Jessy J. Alexander, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100, Chicago, IL 60637. jalexand@medicine.bsd.uchicago.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered w...

Effects of Ecballium elaterium on brain in a rat model of sepsis-associated encephalopathy

“…Also, they reported that interleukin 6 levels in brain tissue are not significantly changed after 24 h. In the literature, TNF-alpha was commonly measured as a marker for sepsis associated encephalopathy in the brain tissue. The interleukin 6 levels were measured in serum [1,19,21–24]. …”

“…TNF-α increases neuronal apoptosis and brain edema by stimulating neutrophil infiltration in the brain tissue. It has been shown that TNF-α is related to aquaporin 4 receptor up-regulation and cerebral edema, and has a key role in SAE [21]. Long-term memory deficit and neuronal loss was seen in experimental models, similar to signs in patients with sepsis [30].…”

Neuro-oxidative-nitrosative stress in sepsis

“…Accordingly, we recently reported evidence of a similar vicious cycle during acute inspiratory hypoxia in healthy humans (Bailey et al, 2009). In the healthy state, iNOS activation is low, but this enzyme may be induced in glial cells and increase NO production in response to a variety of noxious stimuli (Pacher et al, 2007), such as TNF-a and IL-1b (Wong et al, 1996;Alexander et al, 2008) and, possibly, decreased ambient NO levels (Galijasevic et al, 2003). A decreased NO bioavailability may therefore act in concert with focal inflammation to enhance iNOS expression.…”

Cerebral Perfusion in Sepsis

“…In an animal model, these authors demonstrated that endotoxemia-triggered infl ammation in the brain led to an alteration in the blood-brain barrier, including an upregulation of aquaporin 4 and associated brain edema. Th is sequence of events appeared to be mediated by TNF-α signaling through the TNF receptor 1 [14].…”

“…In an animal model, these authors demonstrated that endotoxemia-triggered infl ammation in the brain led to an alteration in the blood-brain barrier, including an upregulation of aquaporin 4 and associated brain edema. Th is sequence of events appeared to be mediated by TNF-α signaling through the TNF receptor 1 [14].In a recent magnetic resonance imaging (MRI) study in nine humans with septic shock and brain dysfunction, sepsis-induced lesions could be documented in the white matter suggesting blood-brain barrier breakdown [15]. However, in a pathologic study no evidence of cerebral edema was reported in 23 patients who died of septic shock [4].…”