肿瘤坏死因子与肝纤维化

肝纤维化的发生机制复杂，涉及细胞、生物因子等多种因素。肿瘤坏死因子作为免疫调节介质，在肝纤维化发生过程中起重要作用。     

肿瘤坏死因子与肝纤维化

肝纤维化的发生机制复杂，涉及细胞、生物因子等多种因素。肿瘤坏死因子作为免疫调节介质，在肝纤维化发生过程中起重要作用。     

肝硬化患者血清一氧化氮和肿瘤坏死因子与肝纤维化的关系

肝硬化的主要病理改变是纤维化,肝纤维化形成过程中影响因素很多,如免疫功能紊乱,内毒素血症等,其中比较明确的是肿瘤坏死因子(ＴＮＦ)[1]。新近发现,ＴＮＦ可促使一氧化氮(ＮＯ)的产生[2],同时ＮＯ可加重肝脏的损害[3]。ＮＯ是否与肝纤维化有关尚不清楚,为此,本文通过检测肝硬化患者血清中ＴＮＦα,ＮＯ和Ⅲ型前胶原(ＰＣⅢ)来分析它们之间的关系。1　对象与方法1.1　对象　肝硬化患者35例均经本院消化科住院确诊。男26例,女9例,平均年龄48(31～65)岁,对照组为体检正常的志愿者30例,男19例,女11例,平均年龄39岁。酒精性肝硬化及药物性肝硬…     

肿瘤坏死因子水平与肝硬化及肝损伤的关系

肿瘤坏死因子（TNFa）是一种主要由单核细胞产生的细胞因子，适量时有抗病毒及免疫调节作用，过量时可直接损伤肝细胞，并与其他淋巴因子共同参与慢性肝病的免疫过程。作者检测46例肝炎后肝硬化病人周围血TNFa含量，目的是观察肝硬化中TNFa水平及其与肝损伤的关系。l对象与方法1．1检测对象正常组4O例，男24例，女16例．平均年龄38．3岁，均为献血员。肝炎后肝硬化组46例，男32例，女14例，平均年龄42．5岁。依据病史、体征、乙肝病毒标志物、生化及影像学等诊断，符合1995年全国病毒性肝炎学会修订的病毒性肝炎防治方案中肝炎后肝硬化…     

脑梗塞头痛患者血浆肿瘤坏死因子（TNF）水平的变化

采用酶联免疫吸附法测定大脑中动脉区脑梗塞（ＣＩ）急性期１８例头痛患者与２２例非头痛患者和２８例对照组血浆ＴＮＦ含量，发现脑梗塞头痛组、非头痛组血浆ＴＮＦ含量（２．３３±０．２２μｇＬ、２．１１±０．２２μｇＬ）均显著（Ｐ＜０．０１）高于对照组（１．６４±０．２２μｇＬ），ＣＩ头痛血浆ＴＮＦ含量显著高于非头痛组（Ｐ＜０．０５）。研究结果提示：ＴＮＦ可能参与了ＣＩ头痛的发病过程。     

肿瘤坏死因子水平与肝硬化及肝损伤的关系

以MTT法测定了46例肝硬化及40例正常对照周围血肿瘤坏死因子水平,旨在了解肝硬化TNFα水平及其与肝损伤的关系。结果肝硬化组TNFα水平(34.38±10.28u/ml/ml)与正常对照组(20.30±3.24u/ml)比较有统计学意义(P<0.001);资料还表明TNFα水平与AST/ALT及血清胆红素浓度有正相关关系(分别是r=0.632,P<0.001和r_s=0.683,P<0.001)。提示肝硬化TNFα浓度异常升高,并可能在肝细胞损伤的发病机制中起一定的作用。     

肝硬化患者血浆和腹水中肿瘤坏死因子及白细胞介素6水平研究

对４５例肝硬化患者血浆及腹水中肿瘤坏死因子（ＴＮＦ－α）及白细胞介素６（ＩＬ－６）水平测定。结果发现合并有自发性细菌性腹膜炎（ＳＢＰ）患者，血浆ＴＮＦ－α、ＩＬ－６水平及腹水中ＴＮＦ－α水平与无ＳＢＰ者相比无明显变化；而腹水ＩＬ－６水平显著升高，经有效治疗后，迅速下降，以１０００ｎｇ／ｍｌ为界，检出ＳＢＰ敏感性为１００％，特异性为８４％。死亡患者最初ＴＮＦ－α及ＩＬ－６水平明显高于存活患者。提示测定该患者腹水ＩＬ－６有助于ＳＢＰ诊断及治疗，结合ＴＮＦ－α可判断患者预后。     

慢阻肺急性加重期患者血浆肿瘤坏死因子-α和可溶性肿瘤坏死因子受体55、75水平及功能意义

目的：观察慢性阻塞性肺疾病急性加重期（AECOPD）患者血浆中炎性介质与抗炎介质水平变化，阐明COPD全身炎症与肺功能的关系。方法：检测62例COPD急性加重期患者接受β-内酰胺类或喹诺酮类抗菌药物及平喘祛痰治疗及30例健康志愿者人院第1天和治疗第7天血浆中的肿瘤坏死因子α（TNF-α）和可溶性肿瘤坏死因子受体55、75（sTNF-R55、sTNF-R75）的水平及其肺功能（FEV1，FEV1％pre，FEV1/FVC等）。结果：AECOPD治疗后肺功能明显改善。但仍低于健康组（P〈0．05）。AECOPD治疗前后血浆中TNF-α和sTNF—R55、sTNFR-75的水平均高于健康组（P〈0．01）。而吸烟健康组TNF-α水平高于不吸烟组。AECOPD患者第7天血浆中的TNF-α浓度较人院第1天明显下降（822．7±353pg/ml vs 599．2±456．7pg/ml，P〈0．01）；sTNF—R55和sTNFR-75水平数值上有上升。但差异无显著性意义（P〉0．05）；血TNF-α、sTNF—R55和sTNF—R75水平与肺通气功能指标FEV1、FEV1％pre、FEV1/FVC皆无相关性（P〉0.05）。结论：AECOPD患者血中炎性介质（TNF-α）及抗炎介质（sTNF—R55、sTNF—R75）的水平均高于健康志愿者。治疗后炎症介质水平降低，抗炎介质水平上升不明显。COPD全身炎症反应与气流受限关系不大。     

体外循环中血浆肿瘤坏死因子的动态观察

肿瘤坏死因子 (ＴＮＦ)在炎症反应有较为重要的作用。体外循环 (ＣＰＢ)可引起机体广泛的炎症反应 ,主要因素是外科创伤、血液稀释与非生理物质接触、心脏再灌注等 ,激活补体 ,而释放大量炎性介质 ,其中ＴＮＦ在炎症反应中起重要作用。本文观察了心脏直视术体外循环前后病人血浆ＴＮＦ的动态变化 ,初步探讨其意义。1　资料与方法2 0例风湿性心脏病拟行换瓣的病人 ,平均年龄 37 0± 9 3岁 ,术前心功Ⅱ-Ⅲ级 ,术前无肝、肾、肺功能衰竭 ,其中二尖瓣置换 18例 ,主动脉瓣置换 2例 ,术中主动脉阻断时间 47 0± 2 4ｍｉｎ ,转机时间 97 0 0± 40 …     

INF-α,IL-6对大鼠实验性肝坏死的影响

为探讨重组肿瘤坏死因子－α（ｒＴＮＦ－α）、重组白细胞介素－６（ｒＩＬ－６）与内皮素－１（ＥＴ－１）在肝坏死中的作用；用Ｄ－氨基半乳糖（Ｄ－ＧａｌＮ）单独或联合ｒＴＮＦ－α，ｒＩＬ－６对ＳＤ大鼠进行腹腔注射，常规检测其肝功能及ＥＴ－１含量的变化，并通过病理学检查其肝坏死的程度。结果发现，在Ｄ－ＧａｌＮ造成肝坏死的基础上，合用ｒＴＮＦ－α，ｒＩＬ－６可增加肝坏死的程度，使血清中总胆红素（ＴＢＩＬ）、谷丙转氨酶（ＡＬＴ）及ＥＴ－１均明显升高。提示ｒＩＬ－６，ＥＴ－１在ｒＴＮＦ－α介导的肝细胞损伤中起较大的作用。     

急性脑梗死患者血清C-反应蛋白及TNF-α浓度变化的临床研究

目的:探讨血清C-反应蛋白(CRP)、TNF-α在急性脑梗死发病过程中的变化及临床意义。方法:动态检测202例急性脑梗死患者(脑梗死组)血清CRP、TNF-α浓度,分析其与梗死灶大小、病程、病情的相关性,并分别与96例脑出血患者(脑出血组)、健康体检者(对照组)的相应值作比较。结果:脑梗死组血清CRP、TNF-α浓度急性期升高,明显高于另外2组(P<0.01);发病3d达高峰,7d开始下降,21d明显下降,但仍未接近正常水平。梗死灶体积大、病情重则血清CRP、TNF-α浓度高(P<0.01)。结论:急性脑血管病患者存在神经-炎症/免疫-内分泌功能紊乱,CRP、TNF-α参与炎症/免疫发生发展过程,对缺血性脑血管病的防治具有重要的临床应用价值。     

Effect of the Soluble TNF‐Antagonist Etanercept on Tumor Necrosis Factor Bioactivity and Stability

Background: Targeted anti‐tumor necrosis factor (TNF) strategies in patients with rheumatoid arthritis have resulted in new and/or worsening heart failure in individuals who were free of cardiovascular disease. Methods and Results: To determine the mechanism of new and/or worsening heart failure in patients who were receiving the soluble TNF‐antagonist etanercept, we analyzed frozen plasma samples from a previous clinical trial with etanercept in heart failure patients, and conducted complimentary mechanistic in vitro studies. Analysis of the clinical trial data showed that use of etanercept resulted in a significant 70‐fold increase in the level of immunoreactive TNF. Complimentary in vitro studies using an L929 bioassay showed that at low concentrations of etanercept relative to TNF there was an unexpected 1.5‐ to 1.75‐fold increase in the absolute level of TNF bioactivity. We also examined the effect of etanercept on TNF stability and the results showed that there was a two‐fold increase in the mass of bioactive homotrimeric TNF when the molar ratio of TNF to etanercept was approximately 200:1. Conclusion: Etanercept increases the immunoreactive mass of TNF in heart failure patients, as well as augments TNF cytotoxicity in certain settings, thus suggesting one potential mechanism for the worsening heart failure in some patients who were receiving this agent.     

神经节苷脂对新生儿缺血缺氧性脑病的疗效及对血清肿瘤坏死因子-α及白介素-6的影响

目的:观察单唾液酸四己糖神经节苷脂(GMI)对新生儿缺血缺氧性脑病(HIE)的疗效及对血清肿瘤坏死因子-α(TNF-α)及白介素-6(IL-6)的影响。方法:HIE患儿70例,随机分为GMI组与对照组,各35例;在常规治疗基础上,GMI组给予GMI治疗,对照组给予胞二磷胆碱治疗。观察2组临床疗效、治疗后新生儿神经行为测定(NBNA)评分及治疗前后血清TNF-α、IL-6水平。结果:GMI组治疗有效率为97.14%,显著高于对照组的82.86%(P0.05)。NBNA评分结果显示,GMI组行为能力、被动肌张力、主动张力、原始反射及一般评估得分分别为(10.20±1.67)分、(8.28±1.60)分、(8.11±1.51)分、(4.57±1.97)分、(6.12±1.46)分,对照组得分分别为(9.32±1.51)分、(7.33±1.54)分、(7.14±0.98)分、(3.46±1.58)分、(5.05±1.35)分,差异均有统计学意义(P0.05)。治疗前,2组血清TNF-α、IL-6水平差异无显著性(P0.05);治疗后,GMI组血清TNF-α、IL-6水平为(85.56±10.36)pg/L、(97.36±17.59)pg/L,对照组为(124.35±12.49)pg/L、(155.56±16.20)pg/L,差异均有统计学意义(P0.05)。结论:GMI对HIE有较好的疗效,可降低患儿血清TNF-α、IL-6水平。     

肿瘤坏死因子与消化系统免疫性疾病

本研究目的旨在探讨肿瘤坏死因子（TNF）与消化系统免疫性疾病的关系。TNF在消化系统疾病中具有调节免疫、炎症反应、抗肿瘤等作用,是消化系疾病发生、发展、治疗及预后过程中的重要因子。TNF在炎症性肠病的作用机制可能与皮质类固醇的抗炎症作用被血小板激活因子转录抑制有关。TNF在自身免疫性肝炎中的作用为：触发IL-6、IL-1和TNF-α本身产牛的奶联反应：调节HLAⅡ类分子和黏附分子的表达;抑制B细胞的激活和抗体的产生,激活巨噬细胞,促发迟及超敏反应和增加细胞毒性等。可溶性TNF在肿瘤患者中较正常人明显升高。以上理论为消化系统免疫性疾病的治疗提供理论指导,为以TNF为靶细胞的新型免疫新药对免疫相关性疾病的诊疗指引新的方向。     

An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I⁻ variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I⁻ RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3⁻ NK1.1⁺ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I⁻ prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I⁻ tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.     

可溶性肿瘤坏死因子受体Ⅱ在慢性心功能不全患者中的变化

目的:观察慢性充血性心力衰竭患者血清可溶性坏死因子受体II(sTNFR II)的改变与临床意义。方法:sTNFR II采用酶联免疫双抗体夹心法测定。结果:对照组(n=30)sTNFR II为2.59±0.58μg/L,实验组(n=30)sTNFR II为8.62±5.32μg/L,两组间有极显著差异(P<0.01)。实验组的轻度组(n=12)sTNFR II为5.3l±1.54μg/L,重度组(n=18)sTN-FR II为10.87±5.78μg/L,两组间有极显著差异(P<0.01)。对照组与实验组的心力衰竭轻、重组间有极显著差异(P<0.01),TNF的变化与病情呈正相关,相关程度较高(r=0.5,P<0.01)。结论:心力衰竭患者血清sTNFR II值升高,并与心力衰竭的严重程度相关。sTNFR II可以作为判断心力衰竭严重程度的指标之一。     

Tumor Necrosis Factor Activity Increases in the Early Response to Trauma

Objectives : 1) To determine whether tumor necrosis factor (TNF) up-regulation occurs in the first hours following severe injury. 2) To determine whether the time from injury to blood sampling affects the probability of detecting TNF.
Methods : A prospective, cross-sectional study was performed using a convenience sample of adult major trauma patients ("patients") treated at a university hospital ED (Level-1 trauma center) and 20 healthy volunteers ("controls"). The time interval from injury to specimen collection (ΔT), the injury severity scale (ISS) score, patient demographics, and quantitative cytokine [TNF and interleukin (IL-6, IL-8)] levels were measured. In the patients, cytokine levels were analyzed as a function of ΔT (using first hourly cutoff points and then the median T as an arbitrary cutoff point) with and without potential confounders (e.g., ISS, age, gender).
Results : The mean ΔT was 92.8 ± 49.2 min (range 10–210 min, median 82 min). In the controls, TNF activity was present in 96%, with a mean level of 125 pg/mL. The controls showed no baseline IL-6 activity and only 10% had a measurable baseline IL-8 level. In the patients, TNF was present in 93%, with a mean level of 628 ±138 pg/mL. When the patients' specimens were divided at the median to obtain roughly equal-sized groups, more TNF levels were elevated >2.5 SD above the controls in the early vs late group (51% vs 30%; p = 0.07). The mean levels of TNF and IL-8 also were higher in the early vs late group (756 vs 530 and 287 vs 135, respectively; p < 0.05).
Conclusions : TNF levels are elevated in the immediate 4 hours post-injury. Previous investigators' inability to detect TNF activity increases may be related to delays in sampling. These results are consistent with the theory that increased TNF activity occurs early after major trauma and may initiate subsequent cytokine activity.     

Systematic Review of Tumor Necrosis Factor Inhibitor Discontinuation Studies in Rheumatoid Arthritis

Background

Anti–tumor necrosis factor agents (anti-TNFs) have changed the course of rheumatoid arthritis (RA) for more than a decade. Use of these medications often results in remission, or at least low disease activity (LDA), but at a substantial cost. It has been postulated that discontinuation of these medications among patients with RA in remission or LDA may be possible without an associated increase in RA disease activity.

Objective

The goal of this systematic literature review was to summarize published articles regarding discontinuation of anti-TNFs in patients with RA.

Methods

A systematic literature review was conducted to identify English-language articles indexed in PubMed from July 1999 through June 2013 reporting results regarding anti-TNF discontinuation in patients with RA. Study designs included observational longitudinal studies and clinical trials. Outcomes had to include 1 of the following: time to flare after anti-TNF discontinuation, failure to remain in remission, or proportion of patients in LDA or remission at the end of the study.

Results

Ten studies examined discontinuation of anti-TNF therapies in RA. Inclusion criteria varied significantly across studies in terms of disease activity status (remission or LDA) and duration of this disease status (1 year or 1 month) before discontinuation being attempted. Results from larger studies (eg, >100 patients) suggest that the proportion of patients who discontinued anti-TNF and did not have an increase in disease activity ranged from 24% to 81%. In 3 studies that evaluated durability of LDA or remission after anti-TNF discontinuation, the mean time to relapse varied from 15 weeks to 17 months. In studies that analyzed radiographic data, once therapies were reinitiated after an increase in disease activity was detected, patients generally did not experience progression in structural damage.

Conclusions

Discontinuation of anti-TNF therapy is achievable for many RA patients who start in clinical remission or LDA. However, heterogeneous inclusion criteria and highly variable outcome definitions across studies make it difficult to efficiently summarize the literature on this topic or to conduct a meta-analysis. There is a lack of evidence regarding how to best predict which patients have the greatest likelihood of continuing to do well after discontinuation of anti-TNF therapy.