Re: Some Interesting Connections
Posted: Mon Oct 07, 2013 10:55 am
Tumor necrosis factor is also associated with blood-brain barrier damage, reduced cerebral blood volume, vasoconstriction, and reduced cerebral oxygen metabolism. In the following study on TNF, MS, and blood-brain barrier damage the researchers found that cerebral spinal fluid levels of TNF-alpha were significantly higher in active MS compared to stable MS or other controls and that TNF has well recognized effects on cerebral endothelial cells.
J Neuroimmunol. 1992 May;38(1-2):27-33.
In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis.
Sharief MK, Thompson EJ.
"Tumor necrosis factor-alpha (TNF-alpha) has well recognized effects on cerebral endothelial cells and, therefore, may mediate disruption of blood-brain barrier in patients with multiple sclerosis (MS). To evaluate the in vivo relationship of TNF-alpha to blood-brain barrier impairment in MS, levels of this cytokine in cerebrospinal fluid (CSF) and serum samples from 38 patients with active MS and 48 controls were correlated with CSF to serum albumin ratios. TNF-alpha was detected in the serum of 74% and the CSF of 66% of patients with active MS. CSF levels of TNF-alpha were significantly higher in active MS compared to stable MS or other controls, and were significantly higher than corresponding serum levels. In patients with active MS, only those with detectable TNF-alpha showed signs of blood-brain barrier damage. Moreover, intrathecal levels of TNF-alpha in active MS correlated with albumin ratios and with the degree of barrier damage. Our findings are important in understanding some of the pathological changes in active multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/1577950
In the following study the researchers found that TNF caused a significant acute reduction in cerebral blood volume and concluded their findings identify vasoconstriction, disrupted tissue homeostasis and damage to the blood-brain barrier as adverse effects of TNF-alpha within the brain.
Brain. 2002 Nov;125(Pt 11):2446-59.
TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway.
Sibson NR, Blamire AM, Perry VH, Gauldie J, Styles P, Anthony DC.
"TNF-alpha expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF-alpha expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF-alpha causes a significant, acute reduction (15-30%) in cerebral blood volume (CBV), which is dependent on TNF-alpha-type 2 receptor (TNFR2) activation, and can be ameliorated by pre-treatment with a non-specific endothelin (ET) receptor antagonist. An acute breakdown of the blood-cerebrospinal fluid barrier (B-CSF-B) and a delayed breakdown of the blood-brain barrier (BBB) were also observed using contrast-enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF-alpha injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-alpha, achieved through the use of an adenoviral vector expressing TNF-alpha cDNA (Ad5TNF-alpha(m)), caused a sustained depression in CBV in accordance with the single TNF-alpha bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF-alpha within the brain, and suggest that antagonists of the endothelin and TNF-alpha type 2 receptors may be therapeutic in TNF-alpha-associated neuropathologies."
http://www.ncbi.nlm.nih.gov/pubmed/12390971
In the following study the researchers concluded their results suggested that TNF may be a "critical" mediator of changes in cerebral circulation and metabolism. The researchers found that tumor necrosis factor led to an acute reduction in cerebral oxygen uptake and a reduction in cerebral blood flow.
Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide.
J Tureen
"Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism..."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC441444/
In the following study the researchers found that patients with MS had reduced cerebral blood flow and oxygen metabolism and concluded there was a correlation between the number and size of lesions and levels of cognitive impairment and these findings.
Ann Nucl Med. 1998 Apr;12(2):89-94.
Clinical significance of reduced cerebral metabolism in multiple sclerosis: a combined PET and MRI study.
Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S.
"Magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS) has provided major insights into the disease's natural history, and many studies have focussed on possible correlations between MRI findings and the clinical manifestations of MS. In contrast, there are few reports on possible relationships between functional imaging data and cognitive function. The present study assessed the relationship between clinical presentation and combined anatomical and functional imaging data in MS. Twenty patients with definite MS underwent MRI and positron emission tomography (PET) to evaluate cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2). The relationships between these neuroimaging findings and clinical data, including the Expanded Disability Status Scale (EDSS), Mini-mental status scale, Hasegawa Dementia Scale and relapse time, were evaluated with Spearman's rank correlation coefficients. A general reduction in rCBF and rCMRO2 in the gray and white matter were found in the MS patients. EDSS was correlated with the number and size of the lesions on MRI and was negatively correlated with rCMRO2. A correlation between the decrease in rCMRO2 and the level of cognitive impairment was also found. The severity of cerebral hypometabolism was also related to the number of relapses. Morphological and functional findings obtained by MRI and PET are closely related to the clinical status in MS. Our results suggest that measurement of cerebral metabolism in MS has the potential to be an objective marker for monitoring disease activity and to provide prognostic information.
In the following study the researchers discuss the role of TNF in ischemic stroke.
Evolution of Cerebral Tumor Necrosis Factor-α Production During Human Ischemic Stroke
Tiina Sairanen, MD; Olli Carpén, MD, PhD; Marja-Liisa Karjalainen-Lindsberg, MD, PhD; Anders Paetau, MD, PhD; Ursula Turpeinen, PhD; Markku Kaste, MD, PhD; Perttu J. Lindsberg, MD, PhD
Tumor-necrosis factor-α (TNF-α) is a cytokine with potent stimulatory actions in immune and vascular responses. It has been suggested to play a role in a legion of neurological disease, including infectious and immunological diseases such as multiple sclerosis, bacterial meningitis, cerebral malaria, and AIDS, as well as noninfectious acute brain insults like ischemic stroke..."
http://stroke.ahajournals.org/content/32/8/1750.full
In the next study the researchers concluded that circulating TNF-alpha generated during sepsis induced the increase in BBB permeability.
J Med Microbiol. 2001 Sep;50(9):812-21.
Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis.
Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY.
"Blood-brain barrier (BBB) permeability during sepsis with Escherichia coli or Streptococcus pneumoniae was examined in a mouse model and measured by a circulating beta-galactosidase tracer. The leakage of brain microvascular vessels during sepsis was confirmed by transmission electron microscopic examination of brain tissues stained with horseradish peroxidase. The increase of BBB permeability induced by E. coli and S. pneumoniae, which was maximal at 3 h and 12 h after injection, respectively, was transient because of rapid clearance of the bacteria from the blood. Tumour necrosis factor-alpha (TNF-alpha) was stained on microvascular vessels of the brain during sepsis and intravenous injection of recombinant TNF-alpha also increased the BBB permeability. The increase in BBB permeability induced by either E. coli or S. pneumoniae could be inhibited by anti-TNF-alpha antibody. It was concluded that circulating TNF-alpha generated during sepsis induced the increase in BBB permeability."
In the following study the researchers concluded that TNF was also involved in the blood-barrier permeability found in acetaminophen-induced acute liver failure.
Eur J Gastroenterol Hepatol. 2011 Jul;23(7):552-8. doi: 10.1097/MEG.0b013e3283470212.
Tumor necrosis factor-α affects blood-brain barrier permeability in acetaminophen-induced acute liver failure.
Wang W, Lv S, Zhou Y, Fu J, Li C, Liu P.
OBJECTIVES: Cerebral edema is a major cause of death during acute liver failure (ALF), but the exact mechanism of this condition is still not entirely clear. The aim of this study was to investigate the role of tumor necrosis factor α (TNFα) in changing the permeability of the blood-brain barrier (BBB) during acetaminophen (APAP)-induced ALF...
RESULTS: BBB permeability increased in APAP-induced ALF mice and correlated with elevated serum TNFα levels. Electron microscopy of mouse brain tissues revealed tight junction (TJ) disruptions and endothelial cell shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein, occludin, was significantly decreased in APAP-induced ALF mice. Changes in BBB permeability and occludin expression could be prevented by administering anti-TNFα-IgG 2 h after APAP challenge.
CONCLUSION: TNFα plays a critical role in the development of brain edema in APAP-induced ALF. Increased BBB permeability may be due to the loss of the TJ-associated protein occludin."
J Neuroimmunol. 1992 May;38(1-2):27-33.
In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis.
Sharief MK, Thompson EJ.
"Tumor necrosis factor-alpha (TNF-alpha) has well recognized effects on cerebral endothelial cells and, therefore, may mediate disruption of blood-brain barrier in patients with multiple sclerosis (MS). To evaluate the in vivo relationship of TNF-alpha to blood-brain barrier impairment in MS, levels of this cytokine in cerebrospinal fluid (CSF) and serum samples from 38 patients with active MS and 48 controls were correlated with CSF to serum albumin ratios. TNF-alpha was detected in the serum of 74% and the CSF of 66% of patients with active MS. CSF levels of TNF-alpha were significantly higher in active MS compared to stable MS or other controls, and were significantly higher than corresponding serum levels. In patients with active MS, only those with detectable TNF-alpha showed signs of blood-brain barrier damage. Moreover, intrathecal levels of TNF-alpha in active MS correlated with albumin ratios and with the degree of barrier damage. Our findings are important in understanding some of the pathological changes in active multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/1577950
In the following study the researchers found that TNF caused a significant acute reduction in cerebral blood volume and concluded their findings identify vasoconstriction, disrupted tissue homeostasis and damage to the blood-brain barrier as adverse effects of TNF-alpha within the brain.
Brain. 2002 Nov;125(Pt 11):2446-59.
TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway.
Sibson NR, Blamire AM, Perry VH, Gauldie J, Styles P, Anthony DC.
"TNF-alpha expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF-alpha expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF-alpha causes a significant, acute reduction (15-30%) in cerebral blood volume (CBV), which is dependent on TNF-alpha-type 2 receptor (TNFR2) activation, and can be ameliorated by pre-treatment with a non-specific endothelin (ET) receptor antagonist. An acute breakdown of the blood-cerebrospinal fluid barrier (B-CSF-B) and a delayed breakdown of the blood-brain barrier (BBB) were also observed using contrast-enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF-alpha injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-alpha, achieved through the use of an adenoviral vector expressing TNF-alpha cDNA (Ad5TNF-alpha(m)), caused a sustained depression in CBV in accordance with the single TNF-alpha bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF-alpha within the brain, and suggest that antagonists of the endothelin and TNF-alpha type 2 receptors may be therapeutic in TNF-alpha-associated neuropathologies."
http://www.ncbi.nlm.nih.gov/pubmed/12390971
In the following study the researchers concluded their results suggested that TNF may be a "critical" mediator of changes in cerebral circulation and metabolism. The researchers found that tumor necrosis factor led to an acute reduction in cerebral oxygen uptake and a reduction in cerebral blood flow.
Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide.
J Tureen
"Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism..."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC441444/
In the following study the researchers found that patients with MS had reduced cerebral blood flow and oxygen metabolism and concluded there was a correlation between the number and size of lesions and levels of cognitive impairment and these findings.
Ann Nucl Med. 1998 Apr;12(2):89-94.
Clinical significance of reduced cerebral metabolism in multiple sclerosis: a combined PET and MRI study.
Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S.
"Magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS) has provided major insights into the disease's natural history, and many studies have focussed on possible correlations between MRI findings and the clinical manifestations of MS. In contrast, there are few reports on possible relationships between functional imaging data and cognitive function. The present study assessed the relationship between clinical presentation and combined anatomical and functional imaging data in MS. Twenty patients with definite MS underwent MRI and positron emission tomography (PET) to evaluate cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2). The relationships between these neuroimaging findings and clinical data, including the Expanded Disability Status Scale (EDSS), Mini-mental status scale, Hasegawa Dementia Scale and relapse time, were evaluated with Spearman's rank correlation coefficients. A general reduction in rCBF and rCMRO2 in the gray and white matter were found in the MS patients. EDSS was correlated with the number and size of the lesions on MRI and was negatively correlated with rCMRO2. A correlation between the decrease in rCMRO2 and the level of cognitive impairment was also found. The severity of cerebral hypometabolism was also related to the number of relapses. Morphological and functional findings obtained by MRI and PET are closely related to the clinical status in MS. Our results suggest that measurement of cerebral metabolism in MS has the potential to be an objective marker for monitoring disease activity and to provide prognostic information.
In the following study the researchers discuss the role of TNF in ischemic stroke.
Evolution of Cerebral Tumor Necrosis Factor-α Production During Human Ischemic Stroke
Tiina Sairanen, MD; Olli Carpén, MD, PhD; Marja-Liisa Karjalainen-Lindsberg, MD, PhD; Anders Paetau, MD, PhD; Ursula Turpeinen, PhD; Markku Kaste, MD, PhD; Perttu J. Lindsberg, MD, PhD
Tumor-necrosis factor-α (TNF-α) is a cytokine with potent stimulatory actions in immune and vascular responses. It has been suggested to play a role in a legion of neurological disease, including infectious and immunological diseases such as multiple sclerosis, bacterial meningitis, cerebral malaria, and AIDS, as well as noninfectious acute brain insults like ischemic stroke..."
http://stroke.ahajournals.org/content/32/8/1750.full
In the next study the researchers concluded that circulating TNF-alpha generated during sepsis induced the increase in BBB permeability.
J Med Microbiol. 2001 Sep;50(9):812-21.
Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis.
Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY.
"Blood-brain barrier (BBB) permeability during sepsis with Escherichia coli or Streptococcus pneumoniae was examined in a mouse model and measured by a circulating beta-galactosidase tracer. The leakage of brain microvascular vessels during sepsis was confirmed by transmission electron microscopic examination of brain tissues stained with horseradish peroxidase. The increase of BBB permeability induced by E. coli and S. pneumoniae, which was maximal at 3 h and 12 h after injection, respectively, was transient because of rapid clearance of the bacteria from the blood. Tumour necrosis factor-alpha (TNF-alpha) was stained on microvascular vessels of the brain during sepsis and intravenous injection of recombinant TNF-alpha also increased the BBB permeability. The increase in BBB permeability induced by either E. coli or S. pneumoniae could be inhibited by anti-TNF-alpha antibody. It was concluded that circulating TNF-alpha generated during sepsis induced the increase in BBB permeability."
In the following study the researchers concluded that TNF was also involved in the blood-barrier permeability found in acetaminophen-induced acute liver failure.
Eur J Gastroenterol Hepatol. 2011 Jul;23(7):552-8. doi: 10.1097/MEG.0b013e3283470212.
Tumor necrosis factor-α affects blood-brain barrier permeability in acetaminophen-induced acute liver failure.
Wang W, Lv S, Zhou Y, Fu J, Li C, Liu P.
OBJECTIVES: Cerebral edema is a major cause of death during acute liver failure (ALF), but the exact mechanism of this condition is still not entirely clear. The aim of this study was to investigate the role of tumor necrosis factor α (TNFα) in changing the permeability of the blood-brain barrier (BBB) during acetaminophen (APAP)-induced ALF...
RESULTS: BBB permeability increased in APAP-induced ALF mice and correlated with elevated serum TNFα levels. Electron microscopy of mouse brain tissues revealed tight junction (TJ) disruptions and endothelial cell shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein, occludin, was significantly decreased in APAP-induced ALF mice. Changes in BBB permeability and occludin expression could be prevented by administering anti-TNFα-IgG 2 h after APAP challenge.
CONCLUSION: TNFα plays a critical role in the development of brain edema in APAP-induced ALF. Increased BBB permeability may be due to the loss of the TJ-associated protein occludin."