Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway.
持续高氨血症通过激活 tnfr1-nf-κ b 通路诱导浦肯野神经元 TNF-a。
- 作者列表："Balzano T","Arenas YM","Dadsetan S","Forteza J","Gil-Perotin S","Cubas-Nuñez L","Casanova B","Gracià F","Varela-Andrés N","Montoliu C","Llansola M","Felipo V
BACKGROUND:Patients with liver cirrhosis may develop hepatic encephalopathy. Rats with chronic hyperammonemia exhibit neurological alterations mediated by peripheral inflammation and neuroinflammation. Motor incoordination is due to increased TNF-a levels and activation of its receptor TNFR1 in the cerebellum. The aims were to assess (a) whether peripheral inflammation is responsible for TNF-a induction in hyperammonemic rats, (b) the cell type(s) in which TNF-a is increased, (c) whether this increase is associated with increased nuclear NF-κB and TNFR1 activation, (d) the time course of TNF-a induction, and (e) if TNF-a is induced in the Purkinje neurons of patients who die with liver cirrhosis. METHODS:We analyzed the level of TNF-a mRNA and NF-κB in microglia, astrocytes, and Purkinje neurons in the cerebellum after 1, 2, and 4 weeks of hyperammonemia. We assessed whether preventing peripheral inflammation by administering an anti-TNF-a antibody prevents TNF-a induction. We tested whether TNF-a induction is reversed by R7050, which inhibits the TNFR1-NF-κB pathway, in ex vivo cerebellar slices. RESULTS:Hyperammonemia induced microglial and astrocyte activation at 1 week. This was followed by TNF-a induction in both glial cell types at 2 weeks and in Purkinje neurons at 4 weeks. The level of TNF-a mRNA increased in parallel with the TNF-a protein level, indicating that TNF-a was synthesized in Purkinje cells. This increase was associated with increased NF-κB nuclear translocation. The nuclear translocation of NF-κB and the increase in TNF-a were reversed by R7050, indicating that they were mediated by the activation of TNFR1. Preventing peripheral inflammation with an anti-TNF-a antibody prevents TNF-a induction. CONCLUSION:Sustained (4 weeks) but not short-term hyperammonemia induces TNF-a in Purkinje neurons in rats. This is mediated by peripheral inflammation. TNF-a is also increased in the Purkinje neurons of patients who die with liver cirrhosis. The results suggest that hyperammonemia induces TNF-a in glial cells and that TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to NF-κB nuclear translocation and the induction of TNF-a expression, which may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy.
背景: 肝硬化患者可发展为肝性脑病。慢性高氨血症大鼠表现为外周炎症和神经炎症介导的神经系统改变。运动不协调是由于 TNF-a 水平增加及其受体 TNFR1 在小脑中的激活。目的是评估 (a) 外周炎症是否导致高血氨大鼠 TNF-a 诱导，(b) TNF-a 增加的细胞类型, (c) 这种增加是否与核 NF-κ b 和 TNFR1 活化增加有关，(d) TNF-a 诱导的时间过程,(E) 是否在肝硬化死亡患者的浦肯野神经元中诱导 TNF-a。 方法: 分析高氨血症 1 、 2 、 4 周后小脑小胶质细胞、星形胶质细胞和浦肯野神经元中 TNF-a mRNA 和 NF-κ b 的水平。我们评估了通过给予抗 TNF-a 抗体预防外周炎症是否可预防 TNF-a 诱导。我们在离体小脑切片中检测了 TNF-a 诱导是否被抑制 tnfr1-nf-κ b 通路的 R7050 逆转。 结果: 高氨血症诱导 1 周时小胶质细胞和星形胶质细胞活化。随后在 2 周和 4 周时在两种胶质细胞类型和浦肯野神经元中诱导 TNF-a。TNF-a mRNA 水平与 TNF-a 蛋白水平平行增加，表明 TNF-a 在浦肯野细胞中合成。这种增加与 NF-κ b 核转位增加有关。R7050 逆转了 NF-κ b 的核转位和 TNF-a 的增加，表明它们是通过 tnfr1 的激活介导的。用抗 TNF-a 抗体预防外周炎症可防止 TNF-a 诱导。 结论: 持续 (4 周) 而非短期高血氨诱导大鼠浦肯野神经元 TNF-a。这是由外周炎症介导的。TNF-a 在肝硬化死亡患者的浦肯野神经元中也升高。结果提示高血氨诱导胶质细胞 TNF-a，胶质细胞释放的 TNF-a 激活浦肯野神经元 TNFR1, 导致 NF-κ b 核转位和 TNF-a 表达的诱导，这可能有助于高氨血症和肝性脑病中观察到的神经系统改变。
METHODS:BACKGROUND:Opioids are often prescribed for pain in cirrhosis and may increase the risk of hepatic encephalopathy (HE). AIMS:To assess the association between opioids and HE in patients with well-compensated cirrhosis. METHODS:We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18-64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1-89 days) and chronic (90-180 days). We assessed whether patients developed HE over the subsequent year (ie 6-18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and HE, adjusting for relevant confounders. RESULTS:The cohort included 6451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short-term and chronic opioid prescriptions respectively. Over the subsequent year, HE occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short-term opioid prescriptions and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of HE was observed with short-term (adjusted hazard ratio, HR 1.44, 95% CI 1.07-1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07-3.12) compared to no opioid prescriptions. CONCLUSION:In this national cohort of privately insured patients with cirrhosis, opioid prescriptions were associated with the risk of incident HE. Opioid use should be minimised in those with cirrhosis and, when required, limited to short duration.
METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.
METHODS:BACKGROUND:Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with liver cirrhosis. In recent years, it has been postulated that the rate of multidrug-resistant organisms (MDROs) is increasing, especially in nosocomial SBP patients. Aim of the present work was to investigate this hypothesis and its possible clinical consequences. MATERIALS AND METHODS:One hundred and three culture-positive patients between 2007 and 2014 were compared with 81 patients between 2015 and 2017, to study the change of microbiological profiles and their clinical consequences. The cirrhosis patients with bacterascites requiring treatment were included as well. RESULTS:The most prevalent Gram-negative bacteria isolated from ascites were Enterobacterales (31.6%) and in Gram-positive pathogens Staphylococci (22.8%). There was a significant increase in MDROs (22.3% ICU 40.7%, P = .048), accompanied by an increased incidence of sepsis (from 21.4% to 37.0%, P = .021), hepatorenal syndrome (from 40.8% to 58.0%, P = .007) and the need of catecholamine therapy (from 21.4% to 38.8%, P = .036). Nosocomial origin correlated with higher MDRO proportion, more complications and lower antimicrobial susceptibility rates in 12 commonly used antibiotics. MDROs were confirmed as an isolated predictor for inpatient mortality and complications in multivariable logistic regression. CONCLUSIONS:The feeling in clinical practice that MDROs have increased in the last 11 years could be confirmed in our study in Munich, Germany. Nosocomial SBP correlated with significantly higher MDRO rates (nearly 50%) and complication rates. In our opinion, an antibiotic combination with comprehensive effect should be taken into account in nosocomial SBP patients in this region.