Interleukin-6 Drives Key Pathologic Outcomes in Experimental Acetaminophen-induced Liver Failure

2021 ◽  
Author(s):  
Katherine Roth ◽  
Jenna Strickland ◽  
Romina Gonzalez-Pons ◽  
Asmita Pant ◽  
Ting-Chieh Yen ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Hepatic Encephalopathy ◽  
Liver Failure ◽  
Interleukin 6 ◽  
Dead Cell ◽  
Dependent Manner ◽  
Apap Overdose ◽  
Liver Repair ◽  
The Impact

Background and Aims: In severe cases of acetaminophen (APAP) overdose, acute liver injury rapidly progresses to acute liver failure (ALF), producing life-threatening complications including, hepatic encephalopathy (HE) and multi-organ failure (MOF). Systemic levels of interleukin-6 (IL-6) and IL-10 are highest in ALF patients with the most severe complications and the poorest prognosis. The mechanistic basis for dysregulation of these cytokines, and their association with outcome in ALF, remain poorly defined. Methods: To investigate the impact of IL-6 and IL-10 in ALF, we used an experimental setting of failed liver repair after APAP overdose in which a high dose of APAP is administered (i.e., 500-600 mg/kg). Mice were treated with neutralizing antibodies to block IL-6 and IL-10. Results: In mice with APAP-induced ALF, high levels of IL-10 reduced monocyte recruitment and trafficking in the liver resulting in impaired clearance of dead cell debris. Kupffer cells in these mice, displayed features of myeloid-derived suppressor cells, including high level expression of IL-10 and PD-L1, which were increased in an IL-6-dependent manner. Similar to ALF patients with HE, cerebral blood flow was reduced in mice with APAP-induced ALF. Remarkably, although IL-6 is hepatoprotective in mice treated with low doses of APAP (i.e., 300 mg/kg), IL-6 neutralization in mice with APAP-induced ALF fully restored cerebral blood flow and reduced mortality. Conclusion: Collectively, these studies demonstrate that exaggerated production of IL-6 in APAP-induced ALF triggers immune suppression (i.e., high levels of IL-10 and PD-L1), reduces cerebral blood flow (a feature of hepatic encephalopathy), disrupts liver repair (i.e., failed clearance of dead cells), and increases mortality.

scholarly journals Striatal iron content is linked to reduced fronto-striatal brain function under working memory load

2019 ◽  
Author(s):  
Karen M. Rodrigue ◽  
Ana M. Daugherty ◽  
Chris M. Foster ◽  
Kristen M. Kennedy
Keyword(s):  
Working Memory ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Iron Content ◽  
Brain Function ◽  
Memory Load ◽  
Dependent Manner ◽  
Working Memory Load ◽  
Functional Brain ◽  
The Impact

AbstractNon-heme iron accumulation contributes to age-related decline in brain structure and cognition via a cascade of oxidative stress and inflammation, although its effect on brain function is largely unexplored. Thus, we examine the impact of striatal iron on dynamic range of BOLD modulation to working memory load. N=166 healthy adults (age 20-94) underwent cognitive testing and an imaging session including n-back (0-, 2-, 3-, and 4-back fMRI), R2*-weighted imaging, and pcASL to measure cerebral blood flow. A statistical model was constructed to predict voxelwise BOLD modulation by age, striatal iron content and an age × iron interaction, controlling for cerebral blood flow, sex, and task response time. A significant interaction between age and striatal iron content on BOLD modulation was found selectively in the putamen, caudate, and inferior frontal gyrus. Greater iron was associated with reduced modulation to difficulty, particularly in middle-aged and younger adults with greater iron content. Further, iron-related decreases in modulation were associated with poorer executive function in an age-dependent manner. These results suggest that iron may contribute to differences in functional brain activation prior to older adulthood, highlighting the potential role of iron as an early factor contributing to trajectories of functional brain aging.

scholarly journals Blockade of Cerebral Blood Flow Response to Insulin-Induced Hypoglycemia by Caffeine and Glibenclamide in Conscious Rats

1997 ◽  
Vol 17 (12) ◽  
pp. 1309-1318 ◽  
Author(s):  
Naoaki Horinaka ◽  
Tang-Yong Kuang ◽  
Hazel Pak ◽  
Robert Wang ◽  
Jane Jehle ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Degradation Products ◽  
Dependent Manner ◽  
Conscious Rats ◽  
Intravenous Injections ◽  
Adenosine Receptor Antagonist ◽  
Flow Response ◽  
Arterial Plasma ◽  
Dose Dependent

The possibility that adenosine and ATP-sensitive potassium channels (KATP) might be involved in the mechanisms of the increases in cerebral blood flow (CBF) that occur in insulin-induced hypoglycemia was examined. Cerebral blood flow was measured by the [14C]iodoantipyrine method in conscious rats during insulin-induced, moderate hypoglycemia (2 to 3 mmol/L glucose in arterial plasma) after intravenous injections of 10 to 20 mg/kg of caffeine, an adenosine receptor antagonist, or intracisternal infusion of 1 to 2 μmol/L glibenclamide, a KATP channel inhibitor. Cerebral blood flow was also measured in corresponding normoglycemic and drug-free control groups. Cerebral blood flow was 51% higher in untreated hypoglycemic than in untreated normoglycemic rats ( P < 0.01). Caffeine had a small, statistically insignificant effect on CBF in normoglycemic rats, but reduced the CBF response to hypoglycemia in a dose-dependent manner, i.e., 27% increase with 10 mg/kg and complete elimination with 20 mg/kg. Chemical determinations by HPLC in extracts of freeze-blown brains showed significant increases in the levels of adenosine and its degradation products, inosine and hypoxanthine, during hypoglycemia ( P < 0.05). Intracisternal glibenclamide had little effect on CBF in normoglycemia, but, like caffeine, produced dose-dependent reductions in the magnitude of the increases in CBF during hypoglycemia, i.e., +66% with glibenclamide-free artificial CSF administration, +25% with 1 μmol/L glibenclamide, and almost complete blockade (+5%) with 2 μmol/L glibenclamide. These results suggest that adenosine and KATP channels may play a role in the increases in CBF during hypoglycemia.

scholarly journals Venous blood ammonia can be associated with cerebral blood flow in hepatic encephalopathy

Hepatology ◽  
2013 ◽  
Vol 58 (2) ◽  
pp. 832-833 ◽  
Author(s):  
Gang Zheng ◽  
Long Jiang Zhang ◽  
Yue Cao ◽  
Guang Ming Lu
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Hepatic Encephalopathy ◽  
Venous Blood ◽  
Blood Ammonia

scholarly journals Hyperlipidemia Disrupts Cerebrovascular Reflexes and Worsens Ischemic Perfusion Defect

2013 ◽  
Vol 33 (6) ◽  
pp. 954-962 ◽  
Author(s):  
Cenk Ayata ◽  
Hwa Kyoung Shin ◽  
Ergin Dileköz ◽  
Dmitriy N Atochin ◽  
Satoshi Kashiwagi ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Apolipoprotein E ◽  
Knockout Mice ◽  
Perfusion Defect ◽  
Laser Speckle ◽  
Wild Type ◽  
Apolipoprotein E Knockout Mice ◽  
The Impact ◽  
Cerebrovascular Reflexes

Hyperlipidemia is a highly prevalent risk factor for coronary and cervical atherosclerosis and stroke. However, even in the absence of overt atherosclerosis, hyperlipidemia disrupts endothelial and smooth muscle function. We investigated the impact of hyperlipidemia on resting-brain perfusion, fundamental cerebrovascular reflexes, and dynamic perfusion defect during acute focal ischemia in hyperlipidemic apolipoprotein E knockout mice before the development of flow-limiting atherosclerotic stenoses. Despite elevated blood pressures, absolute resting cerebral blood flow was reduced by 20% in apolipoprotein E knockout compared with wild type when measured by [14C]-iodoamphetamine technique. Noninvasive, high spatiotemporal resolution laser speckle flow imaging revealed that the lower autoregulatory limit was elevated in apolipoprotein E knockout mice (60 vs. 40 mm Hg), and cortical hyperemic responses to hypercapnia and functional activation were attenuated by 30% and 64%, respectively. Distal middle cerebral artery occlusion caused significantly larger perfusion defects and infarct volumes in apolipoprotein E knockout compared with wild type. Cerebrovascular dysfunction showed a direct relationship to the duration of high-fat diet. These data suggest that hyperlipidemia disrupts cerebral blood flow regulation and diminishes collateral perfusion in acute stroke in the absence of hemodynamically significant atherosclerosis.

scholarly journals Impact of blood pressure changes in cerebral blood perfusion of patients with ischemic Moyamoya disease evaluated by SPECT

2020 ◽  
pp. 0271678X2096745
Author(s):  
Zhao Liming ◽  
Sun Weiliang ◽  
Jia Jia ◽  
Liang Hao ◽  
Liu Yang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Moyamoya Disease ◽  
Emission Computed Tomography ◽  
Study Cohort ◽  
Pressure Changes ◽  
The Impact

Our aim was to determine the impact of targeted blood pressure modifications on cerebral blood flow in ischemic moyamoya disease patients assessed by single-photon emission computed tomography (SPECT). From March to September 2018, we prospectively collected data of 154 moyamoya disease patients and selected 40 patients with ischemic moyamoya disease. All patients underwent in-hospital blood pressure monitoring to determine the mean arterial pressure baseline values. The study cohort was subdivided into two subgroups: (1) Group A or relative high blood pressure (RHBP) with an induced mean arterial pressure 10–20% higher than baseline and (2) Group B or relative low blood pressure (RLBP) including patients with mean arterial pressure 10–20% lower than baseline. All patients underwent initial SPECT study on admission-day, and on the following day, every subgroup underwent a second SPECT study under their respective targeted blood pressure values. In general, RHBP patients showed an increment in perfusion of 10.13% (SD 2.94%), whereas RLBP patients showed a reduction of perfusion of 12.19% (SD 2.68%). Cerebral blood flow of moyamoya disease patients is susceptible to small blood pressure changes, and cerebral autoregulation might be affected due to short dynamic blood pressure modifications.

Effects of estrogen on cerebral blood flow and pial microvasculature in rabbits

2000 ◽  
Vol 279 (3) ◽  
pp. H1208-H1214 ◽  
Author(s):  
M. T. Littleton-Kearney ◽  
D. M. Agnew ◽  
R. J. Traystman ◽  
P. D. Hurn
Keyword(s):  
Blood Flow ◽  
Estrogen Receptor ◽  
Cerebral Blood Flow ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Pial Arteries ◽  
Concentration Dependent Manner ◽  
Cranial Window ◽  
Pial Arterioles

We tested the hypothesis that intracarotid estrogen infusion increases cerebral blood flow (CBF) in a concentration-dependent manner and direct application of estrogen on pial arterioles yields estrogen receptor-mediated vasodilation. Rabbits of both genders were infused with estrogen via a branch of the carotid artery. Estrogen doses of 20 or 0.05 μg · ml−1 · min−1 were used to achieve supraphysiological or physiological plasma estrogen levels, respectively. CBF and cerebral vascular resistance were determined at baseline, during the infusion, and 60-min postinfusion, and effects on pial diameter were assessed via a cranial window. Pial arteriolar response to estrogen alone and to estrogen after administration of tamoxifen (10−7), an antiestrogen drug that binds to both known estrogen receptor subtypes, was tested. No gender differences were observed; therefore, data were combined for both males and females. Systemic estrogen infusion did not increase regional CBF. Estradiol dilated pial arteries only at concentrations ranging from 10−4–10−7 M ( P ≤ 0.05). Pretreatment with tamoxifen alone had no effect on arteriolar diameter but inhibited estrogen-induced vasodilation ( P < 0.001). Our data suggest that estrogen does not increase CBF under steady-state conditions in rabbits. In the pial circulation, topically applied estradiol at micromolar concentrations dilates vessels. The onset is rapid and dependent on estrogen receptor activation.

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