Role of nitric oxide in the brain during lipopolysaccharide‐evoked systemic inflammation

Czapski, Grzegorz A.; Cąkała, Magdalena; Chalimoniuk, Małgorzata; Gajkowska, B; Strosznajder, Joanna B.

doi:10.1002/jnr.21294

Cited by 69 publications

(44 citation statements)

References 57 publications

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“…Elevated levels of NO have been detected in a variety of pathophysiologic processes, including inflammation and carcinogenesis (33,34). In our previous study, we found that COX-2 is critically linked to the radiation-induced bystander effect in normal human fibroblasts (14).…”

Section: Discussionmentioning

confidence: 87%

Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects

Zhou¹,

Ivanov²,

Lien³

et al. 2008

Cancer Research

161

150

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Although radiation-induced bystander effects have been well described over the past decade, the mechanisms of the signaling processes involved in the bystander phenomenon remain unclear. In the present study, using the Columbia University charged particle microbeam, we found that mitochondrial DNA-depleted human skin fibroblasts (R o ) showed a higher bystander mutagenic response in confluent monolayers when a fraction of the same population were irradiated with lethal doses compared with their parental mitochondrial-functional cells (R + ). However, using mixed cultures of R o and R + cells and targeting only one population of cells with a lethal dose of A-particles, a decreased bystander mutagenesis was uniformly found in nonirradiated bystander cells of both cell types, indicating that signals from one cell type can modulate expression of bystander response in another cell type. In addition, we found that Bay 11-7082, a pharmacologic inhibitor of nuclear factor-KB (NF-KB) activation, and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a scavenger of nitric oxide (NO), significantly decreased the mutation frequency in both bystander R o and R + cells. Furthermore, we found that NF-KB activity and its dependent proteins, cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), were lower in bystander R o cells when compared with their R + counterparts. Our results indicated that mitochondria play an important role in the regulation of radiation-induced bystander effects and that mitochondriadependent NF-KB/iNOS/NO and NF-KB/COX-2/prostaglandin E2 signaling pathways are important to the process. [Cancer Res 2008;68(7):2233-40]

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Section: Discussionmentioning

confidence: 87%

Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects

Zhou¹,

Ivanov²,

Lien³

et al. 2008

Cancer Research

161

150

View full text Add to dashboard Cite

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“…The cellular and molecular mechanisms involved in SIRSassociated encephalopathy remain unknown (Flierl et al, 2010). Induction of a SIRS by LPS injection in mice and rats evokes microglia activation, cell death, metabolic changes, and loss of neurons in different regions of the brain (Semmler et al, 2005;Czapski et al, 2007;Qin et al, 2007;Semmler et al, 2008;Czapski et al, 2010). Similarly, kidney ischemia, another TLR4-dependent systemic disease resulting in SIRS, induces brain inflammation (Liu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloprotease 8-Dependent Extracellular Matrix Cleavage at the Blood-CSF Barrier Contributes to Lethality during Systemic Inflammatory Diseases

Vandenbroucke¹,

Dejonckheere²,

Lint³

et al. 2012

Journal of Neuroscience

102

116

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Systemic inflammatory response syndrome (SIRS) is a highly mortal inflammatory disease, associated with systemic inflammation and organ dysfunction. SIRS can have a sterile cause or can be initiated by an infection, called sepsis. The prevalence is high, and available treatments are ineffective and mainly supportive. Consequently, there is an urgent need for new treatments. The brain is one of the first organs affected during SIRS, and sepsis and the consequent neurological complications, such as encephalopathy, are correlated with decreased survival. The choroid plexus (CP) that forms the blood-CSF barrier (BCSFB) is thought to act as a brain "immune sensor" involved in the communication between the peripheral immune system and the CNS. Nevertheless, the involvement of BCSFB integrity in systemic inflammatory diseases is seldom investigated. We report that matrix metalloprotease-8 (MMP8) depletion or inhibition protects mice from death and hypothermia in sepsis and renal ischemia/reperfusion. This effect could be attributed to MMP8-dependent leakage of the BCSFB, caused by collagen cleavage in the extracellular matrix of CP cells, which leads to a dramatic change in cellular morphology. Disruption of the BCSFB results in increased CSF cytokine levels, brain inflammation, and downregulation of the brain glucocorticoid receptor. This receptor is necessary for dampening the inflammatory response. Consequently, MMP8 ϩ/ϩ mice, in contrast to MMP8 Ϫ/Ϫ mice, show no anti-inflammatory response and this results in high mortality. In conclusion, we identify MMP8 as an essential mediator in SIRS and, hence, a potential drug target. We also propose that the mechanism of action of MMP8 involves disruption of the BCSFB integrity.

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“…Oatp1a4 has been shown to be involved in blood-to-brain transport of the neuroprotective prostaglandin PGE1 (Taogoshi et al, 2005). Because peripheral inflammation is associated with increased neuronal apoptosis (Czapski et al, 2007) and PGE1 can prevent neuronal cell death (Kawamura et al, 1997), enhanced Oatp1a4 activity may be a particularly critical mechanism of neuroprotection by increasing CNS prostaglandin delivery during disease. In addition, we observed an increase in k out after peripheral inflammatory pain, which implies taurocholate efflux.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Pain Signals an Increase in Functional Expression of Organic Anion Transporting Polypeptide 1a4 at the Blood-Brain Barrier

Ronaldson

Finch

DeMarco

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

155

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Pain is a dominant symptom associated with inflammatory conditions. Pharmacotherapy with opioids may be limited by poor blood-brain barrier (BBB) permeability. One approach that may improve central nervous system (CNS) delivery is to target endogenous BBB transporters such as organic anion-transporting polypeptide 1a4 (Oatp1a4). It is critical to identify and characterize biological mechanisms that enable peripheral pain/inflammation to "transmit" upstream signals and alter CNS drug transport processes. Our goal was to investigate, in vivo, BBB functional expression of Oatp1a4 in animals subjected to peripheral inflammatory pain. Inflammatory pain was induced in female Sprague-Dawley rats (200 -250 g) by subcutaneous injection of 3% -carrageenan into the right hind paw; control animals were injected with 0.9% saline. In rat brain microvessels, Oatp1a4 expression was increased during acute pain/ inflammation. Uptake of taurocholate and [D-penicillamine 2,5 ]-enkephalin, two established Oatp substrates, was increased in animals subjected to peripheral pain, suggesting increased Oatp1a4-mediated transport. Inhibition of inflammatory pain with the anti-inflammatory drug diclofenac attenuated these changes in Oatp1a4 functional expression, suggesting that inflammation in the periphery can modulate BBB transporters. In addition, diclofenac prevented changes in the peripheral signaling cytokine transforming growth factor-␤1 (TGF-␤1) levels and brain microvascular TGF-␤ receptor expression induced by inflammatory pain. Pretreatment with the pharmacological TGF-␤ receptor inhibitor 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide (SB431542) increased Oatp1a4 functional expression in -carrageenan-treated animals and saline controls, suggesting that TGF-␤ signaling is involved in Oatp1a4 regulation at the BBB. Our findings indicate that BBB transporters (i.e., Oatp1a4) can be targeted during drug development to improve CNS delivery of highly promising therapeutics.

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Role of nitric oxide in the brain during lipopolysaccharide‐evoked systemic inflammation

Cited by 69 publications

References 57 publications

Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects

Mitochondrial Function and Nuclear Factor-κB–Mediated Signaling in Radiation-Induced Bystander Effects

Matrix Metalloprotease 8-Dependent Extracellular Matrix Cleavage at the Blood-CSF Barrier Contributes to Lethality during Systemic Inflammatory Diseases

Inflammatory Pain Signals an Increase in Functional Expression of Organic Anion Transporting Polypeptide 1a4 at the Blood-Brain Barrier

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