Impact of genetic variation of tumor necrosis factor-α on gestational hypertension

Background The mechanisms responsible for the pathogeneses of gestational hypertension and preeclampsia are unclear. Tumor necrosis factor-1α （TNF-1α） is a pro-inflammatory Th1-type cytokine. TNFA gene is located in the human leukocyte antigen （HLA） class Ⅲ region of the major histocompatibility complex （MHC） on chromosome 6. The high TNF-1α mRNA expression may be associated with the TNF2 （A） allele, which is the polymorphism of TNF-1α at position - 308 in promoter region. This study assessed whether the TNF2 （A） allele at position -308 plays a role in the alteration of blood pressure （BP） and urinary protein excretion during pregnancy. Methods The original prospective cohort study comprised 1623 pregnant women from January 2000 to October 2001. The G/A polymorphism was done by restriction fragment length polymorphism （RFLP） analysis with Nco I enzyme. Results The distributions of the G/A polymorphism of TNF-1α in the promoter region at position -308 were wild-type 72.4% and variant 27.6%, respectively. The frequency of TNF2 （A） allele was approximately 0.15 for Caucasian pregnant women in the study. It was not significantly different in the distributions of genotypes and G/A allele frequencies among the three groups of pregnant women with gestational hypertension, preexisting hypertension and normal blood pressure （P〉0.05）. The maternal blood pressure in the third trimester was significantly higher in the group of women possessing the TNF2 （A） allele compared to homozygous for the TNF1 （G） allele （systolic BE P〈0.01 and diastolic BE P〈0.05）. The elevated blood pressure in the TNF2 （A） group was accompanied by higher urinary protein excretion in the third trimester （P〈0.05）. The blood pressure and urinary protein excretion did not change apparently between the two groups in the first and second trimesters （P〉0.05）. Conclusions Maternal TNF2 （A） allele of TNF-1α promoter region at position -308 could play a role in the alteration of blood pressures and/or enhancement of urinary protein excretion during pregnancy, and might play an important role in the development of both gestational hypertension and preeclampsia.     

The roles of tumor necrosis factor-α gene polymorphisms in the pathogenesis of non-alcoholic fatty liver diseases

目的 探讨肿瘤坏死因子-α(TNF-α)单核苷酸多态性(SNP)与非酒精性脂肪性肝病(NAFLD)发病及病程进展的相关性.方法 在2005年对普通人群NAFLD流行病学调查的基础上进行队列追踪到2009年(中位数4年),其中696例愿意接受复查,每例再行问卷、体检、血生化和B超检查,应用PCR-RFLP方法检测TNF-α 3个位点:-238、-308和-857的SNP.结果 2005年NAFLD标化患病率为21.29%,至2009年显著升高达46.11%.Hardy-Weinberg检验-238位点基因频率未达到遗传平衡(P<0.05),故予剔除,而-308及-857位点纳入研究.NAFLD患者与正常对照者比较,TNF-α -857位点的基因型及等位基因频率差异均有统计学意义(P<0.05),等位基因T型者的发病危险率(RR)是正常对照者的1.463倍;而-308位点两者差异无统计学意义(P＞0.05).有序logistic回归分析显示,性别对病程无显著影响(P＞0.05),年龄影响显著(P<0.001);校正性别和年龄后,-857位点T/T基因型与病程进展呈正相关,其危险性(OR)是C/C型的8.65倍(P<0.001),而C/T型与C/C型比较差异无统计学意义(P=0.072);-308位点各基因型对病程均无显著影响(P＞0.05).结论 TNF-α -857位点C→T变异(而非-308位点)与NAFLD发病易感性及病程进展两者均呈正相关,T/T型增加疾病发生和进展的风险.     

Variations of tumor necrosis factor-α, leptin and adiponectin in mid-trimester of gestational diabetes mellitus

Background Many cytokines have been found to increase the insulin resistance during pregnancy complicated by glucose metabolism disorder. This study aimed to investigate which comes first, the changes of some cytokines or the abnormal glucose metabolism.
Methods This nested case-control study was undertaken from January 2004 to March 2005. Twenty-two women with gestational diabetes mellitus （GDM）, 10 with gestational impaired glucose tolerance （GIGT）, and 20 healthy pregnant women were chosen from the women who had visited the antenatal clinics and had blood samples prospectively taken and kept during their visit. The levels of tumor necrosis factor-α （TNF-α）, leptin and adiponectin were determined. One-way ANOVA analysis and bivariate correlation analysis were used to assess the laboratory results and their relationship with body mass index （BMI）. Results Women with GDM have the highest values of TNF-α and leptin and the lowest value of adiponectin compared with those with GIGT and the healthy controls （P 〈0.01） at 14-20 weeks of gestation. This was also found when these women progressed to 24-32 weeks. The significantly increased levels of TNF-α and leptin and the decreased level of adiponectin were found at the different periods of gestation within the same group. Positive correlation was shown between the levels of TNF-α and leptin at the two periods of gestation with the BMI at 14-20 weeks, while adiponectin was negatively correlated （P 〈0.05）.
Conclusions The concentrations of TNF-α, leptin and adiponectin may change before the appearance of the abnormal glucose level during pregnancy. Further studies are required to verify the mechanism of this alteration and whether the three cytokines can be predictors for GDM at an early staqe of preqnancy.     

The role of serum leptin and tumor necrosis factor-α in malnutrition of male chronic obstructive pulmonary disease patients

Background Leptin is a protein mainly secreted by adipocytes, and the major function of leptin was its role in body weight regulation. It is suggested that increased levels of circulating leptin may contribute to anorexia in pathologic conditions including chronic obstructive pulmonary disease (COPD). Recent studies have provided evidence for a link between leptin and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α). This study aimed to explore the role of serum leptin in the malnutrition of COPD patients, and to observe the changes of serum leptin levels during acute exacerbation, also to investigate relationship between leptin and TNF-α. Methods Seventy-two COPD patients and 34 control subjects participated in this study. Seventy-two COPD patients were divided into 3 groups: group COPD IA (patients without malnutrition during acute exacerbation, n=25), group COPD IB (patients without malnutrition during stable disease, n=29), group COPD II (patients with malnutrition during stable disease, n=18). To eliminate the effect of sex differences, all patients and controls were male. Body mass index (BMI), percent ideal body weight (IBW％), triceps skin-fold thickness (TSF), mid-upper arm circumference (MAC), mid-upper arm muscle circumference (MAMC), serum leptin and TNF-α levels, serum prealbumin (PA), serum transferrin (TF), serum albumin (Alb), total lymphocytes count (TLC), forced expiratory volume in one second (FEV(1)), maximal inspiration pressure (MIP) and maximal expiration pressure (MEP) were measured in all participants. Leptin levels were measured by radioimmunoassay. TNF-α levels were measured by ELISA. The between group difference and correlation of these parameters were analyzed. Results Serum leptin levels were significantly lower in group COPD II [(4.07±3.42) ng/ml] than in group COPD IB [(9.72±6.67) ng/ml] and controls [(8.21±5.41) ng/ml] (P&lt;0.05). There was no statistically significant difference in serum leptin levels between group COPD IA [(10.82±6.40) ng/ml], group COPD IB [(9.72±6.67) ng/ml] and controls [(8.21±5.41) ng/ml]. There was no statistically significant difference in serum TNF-α levels between group COPD II [(8.03±3.37) pg/ml], group COPD IA [(8.90±1.60) pg/ml], and group COPD IB [(7.25±2.08) pg/ml]. There was no significant correlation between leptin and TNF-α in any group. Conclusions Leptin was not involved in anorexia and weight loss of COPD patients. There was no statistically significant difference in serum leptin levels between COPD patients during stable stage and acute exacerbation, and there was no significant correlation between TNF-α and leptin during the regulation of the energy balance in COPD patients.     

Induction of type Ⅱ alveolar epithelial cells apoptosis in mouse by lipopolysaccharide does not require TNF-α

Objective To examine whether lipopolysaccharide (LPS)-induced apoptosis correlates with TNF-α release by type Ⅱ alveolar epithelial cells (AEC Ⅱ), whether TNF-α knockout (TNF KO) abrogates the induction of apoptosis by LPS and whether TNF-α is sufficient to induce apoptosis in this cell type.Methods AEC Ⅱ were isolated from wild type mice and TNF KO mice. Cells were stimulated with LPS or recombinant murine TNF-α for 24 h. TNF-α in culture supernatant was determined by ELISA following LPS stimulation. Apoptosis was determined by the terminal deoxynucleotidyl transferase end-labeling (TUNEL) assay after treatment with either LPS or TNF-α. Results LPS induced apoptosis in wild type AEC Ⅱ in a concentration-dependent manner. LPS-induced AEC Ⅱ apoptosis was accompanied by an 11-fold increase (from 0.073±0.065 ng/ml in control to 0.94±0.14 ng/ml in 50 μg/ml of LPS, P&lt;0.01) in TNF-α release. However, increasing concentrations (5 or 25 ng/ml) of recombinant murine TNF-α failed to induce AEC Ⅱ apoptosis. In addition, apoptosis did occur in AEC Ⅱ isolated from TNF KO mice following LPS stimulation.Conclusions This study confirms that LPS induces TNF-α release and apoptosis in murine AEC Ⅱ in vitro. Exogenous TNF-α failed to induce AEC Ⅱ apoptosis, and apoptosis occurred following LPS stimulation in cells lacking the ability to produce TNF-α. Taken together, these results suggest that LPS-induced AEC Ⅱ apoptosis occurs by a TNF-α-independent mechanism.     

Effects of morphine and fentanyl on tumor necrosis factor-α and interleukin-6 concentrations in human whole blood in vitro

Cytokines are essential for hematopoiesis and immune responses, and play a key role in the defense against infections. Lipopolysaccharide (LPS) is a potent inducer of the agents involved in the pathogenesis of inflammation responses. Tumor necrosis factor-α（TNF-α） and interleukin-6(IL-6) are two important and proinflammatory     

Effect of surfactant protein A on lipopolysaccharide-induced tumor necrosis factor-α expression in human proximal tubular epithelial cells

Background Surfactant protein A （SP-A） contributes to the regulation of sepsis-induced acute lung injury.In a previous study,we demonstrated the expression and localization of SP-A in the kidneys.The present study evaluated the effect of SP-A on lipopolysaccharide （LPS）-induced tumor necrosis factor-α （TNF-α） expression and its underlying mechanisms in the human renal tubular epithelial （HK-2） cells.Methods Indirect immunofiuorescence assay was used to detect SP-A distribution and expression in HK-2 cells.HK-2 cells were treated with various concentrations of LPS （0,0.1,1,2,5,and 10 mg/L） for 8 hours and with 5 mg/L LPS for different times （0,2,4,8,16,and 24 hours） to determine the effects of LPS on SP-A and TNF-α expression.Then,HK-2 cells were transfected with SP-A siRNA to analyze nuclear factor κB （NF-κB） P65 and TNF-α expression of HK-2 cells after LPS-treatment.Results Indirect immunofluorescence assay revealed that SP-A is localized to the membrane and cytoplasm of HK-2 cells.Interestingly,SP-A1/SP-A2 and TNF-α expression were found to be significantly increased in HK-2 cells upon LPS treatment.Transfection of LPS-treated HK-2 cells with SP-A siRNA resulted in significant increases in the levels of NF-κB P65 protein and TNF-α mRNA and protein compared to those in non-transfected LPS-treated HK-2 cells.Conclusion SP-A plays an important role in protecting cells against sepsis-induced acute kidney injury by inhibiting NF-κB activity to modulate LPS-induced increase in TNF-α expression.     

Role of p38MAPK in mediating TNF-α-induced apoptosis of rat glioma cell line C6

Objective: To study the role of p38MAPK in mediating TNF-α-induced apoptosis of rat glioma cell line C6. Methods: Effect of TNF-α on the proliferation of C6 cells was determined by MTT assay. The TNF-α induced apoptosis was detected by transmission electron microscopy and flow cytometry. The expression of p38MAPK was detected by SABC method and Western-blot. The effect of SB202190, a specific inhibitor of p38MAPK, on TNF-α-induced apoptosis was observed by flow cytometry and SABC method. Results: Inhibitory rate of TNF-α(2×105 U/L) on C6 cells was 43. 75% . In the TNF-α treated group, apoptotic cells were observed by transmission electron microscopy and the apoptotic rate was 37. 5% by flow cytometry. p38MAPK positive signals were detected by SABC method and Western-blot. In the SB202190 treated group, the apoptotic rate was 7. 0% and no p38MAPK signals were found. Conclusion: Apoptosis of C6 cells and expression of p38MAPK can be induced by TNF-α. The activation of p38MAPK promotes the apoptosi     

重组人肿瘤坏死因子致肺癌细胞(LC-6)凋亡的研究

目的：探讨重组人肿瘤坏死因子（ｒｈＴＮＦ）引起肺癌细胞（ＬＣ－６）死亡的机制。方法：应用原位细胞毒性分析、ＤＮＡ解降片段琼脂糖凝胶电泳、形态学和流式细胞学测定的动态分析。结果：ｒｈＴＮＦ作用于肺癌细胞（ＬＣ－６）数小时后,引起细胞核ＤＮＡ解成寡聚核苷酸片断,说明肺癌细胞（ＬＣ－６）以细胞凋亡的方式死亡,并且细胞凋亡的程度与重组人肿瘤坏死因子作用的时间及浓度呈正相关。单纯应用放线菌素Ｄ后则肺癌细胞（     

Role of tumor necrosis factor-alpha in the pathogenesis of atrial fibrillation

Background  Tumor necrosis factor-alpha (TNF-α) is a pleiotropic proinflammatory cytokine and contributes to many kinds of cardiovascular diseases via its receptors (TNFR1/TNFR2). We hypothesize that TNF-α plays a role in the pathogenesis of chronic atrial fibrillation (AF).

Methods  Sixty-seven consecutive patients who were scheduled to have cardiac surgery were enrolled into the study. Thirty-one patients with rheumatic heart disease (RHD) and AF were enrolled as study group (AF group). The sinus rhythm (SR) control groups consisted of 20 patients with RHD and 16 patients with coronary artery disease (CAD). Peripheral blood sample was collected before the operation. About 5 mm3 left atrial tissue was disserted during the operation and was separated into three parts for Western blotting, real time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) analysis.

Results  Compared with the controls (RHD SR and CAD SR), the levels of TNF-α ((14.40±5.45) pg/ml vs. (4.20±3.19) pg/ml vs. (2.68±2.20) pg/ml, P=0.000) and its soluble receptor 1 (sTNFR1) ((1623.9±558.6) pg/ml vs. (1222.3±175.6) pg/ml vs. (1387.5±362.2) pg/ml, P=0.001) in plasma were higher in patients with AF. TNF-α level had positive correlation with the left atrial diameter (LAD) (r=0.642, P=0.000). Western blotting analysis showed that the protein levels of TNF-α (0.618±0.236 vs. 0.234±0.178 vs. 0.180±0.103, P=0.000) were higher in patients with AF. The RT-PCR analysis results demonstrated that the mRNA expression of TNF-α (0.103±0.047 vs. 0.031±0.027 vs. 0.023±0.018, P=0.000) increased in patients with AF. IHC analysis displayed that, comparing to the SR, the expression of TNF-α (0.125±0.025 vs. 0.080±0.027 vs. 0.070±0.023, P=0.000) increased in the AF group. The protein level and mRNA expression of TNF-α also had positive correlation with left atrium diameter (LAD) (r=0.415, P=0.000 and r=0.499, P=0.000).

Conclusions  The results revealed that TNF-α elevated in the plasma and left atrial tissue and had positive correlation with LAD in patients of chronic AF. TNF-α might involve in the pathogenesis of chronic AF.

     

干扰素-γ和肿瘤坏死因子-α对表达乙肝病毒的HepG2.2.15细胞的协同致凋亡作用

目的研究干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）对表达乙肝病毒的HepG2.2.15细胞的协同致凋亡作用及其意义。方法光学显微镜观察细胞形态,MTT方法定量测定细胞成活力,用琼脂糖凝胶电泳阶梯状条带分析有无凋亡。结果1 000U/mL IFN-γ单独或与5ng/mL TNF-α联合能诱导表达乙肝病毒的HepG2.2.15细胞凋亡。用拉米夫定抑制乙肝病毒能降低IFN-γ和TNF-α对HepG2.2.15细胞的致凋亡作用。结论IFN-γ和TNF-α对表达乙肝病毒的HepG2.2.15细胞有协同致凋亡作用。拉米夫定能降低IFN-γ和TNF-α对HepG2.2.15细胞的致凋亡作用。     

吗啡对心衰大鼠肿瘤坏死因子-α及心肌细胞凋亡的影响

目的　探讨吗啡治疗在充血性心力衰竭中的作用机制及其对肿瘤坏死因子 -α(TNF -α)及心肌细胞凋亡的影响。方法　雄性Wistar大鼠随机分为假手术组 (A且 )、心衰组 (B组 )、美托洛尔组 (C组 )和吗啡组 (D组 )。结扎左冠状动脉前降支造成大鼠心肌梗死后心衰模型。大鼠MI后 8周及给予相应药物治疗一周后 ,检测血清中TNF -α的含量及心肌细胞凋亡、心肌组织Bcl- 2基因蛋白表达。结果　D组第九周血清中TNF -α的含量与B、C组差异有显著性 (P <0 0 1 ) ,B、C组差异无显著性 (P >0 0 5 ) ;B、C、D组凋亡指数均高于A组 ,D组凋亡指数明显低于B、C组 ;D组Bcl- 2基因蛋白表达高于B、C组。结论　吗啡作用于阿片受体 ,抑制TNF -α的产生 ,促进心肌细胞Bcl- 2基因蛋白表达 ,抑制心肌细胞的凋亡 ,在CHF的治疗中有积极的意义。     

肿瘤坏死因子、白细胞介素-6与心力衰竭患者心功能的关系

目的 研究心衰患者血清TNFα和IL－6水平,观察不同病因和心功能改善后TNFα和IL－6水平变化。方法 采用酶联免疫吸附实验57主衰患者治疗前后和20例健康体检者血清TNFα和IL－6水平。结果 中重度心衰组患者血清TNFα明显高于对照组和轻中度心衰组（P＜0．01）,所有心衰患者血清IL－6水平均明显高于对照组（P＜0．01）。且中重度心患者高于轻中度肾衰患者（P＜0．01）,不同病因心衰患者血清TNFα和IL－6水平差异不显著（P＞0．05）。经治疗心功能改善后,中重度心衰组患者血清TNFα和TL－6水平明显降低（P＜0．05）。结论 中重度心衰患者血清TNFα和IL－6水平升高,且随着心功能改善而降低,细胞因子水平与心衰病因无关。     

吸烟大鼠肺组织病理学改变及与VEGF表达相关性研究

目的探讨被动吸烟大鼠肺组织病理变化及其与血管内皮生长因子(VEGF)表达的相关关系。方法以12周龄雌性SD大鼠为研究对象,采用被动吸烟法,取被动吸烟3、6、9周的大鼠肺组织进行病理学检查及VEGF免疫组织化学检测,将两者进行相关性分析。结果吸烟大鼠支气管肺组织内出现以淋巴细胞为主的炎症细胞浸润,纤毛脱落,杯状上皮细胞化生。吸烟6周时出现部分肺泡壁破裂,肺泡腔扩大。吸烟9周大鼠与同龄对照组大鼠比较,其平均肺泡数减少(P<0.05),肺泡内衬间隔增加(P<0.05),呈现轻度肺气肿样改变。VEGF表达下降与肺泡数减少呈正相关(P<0.05),与肺泡间隔数增加呈负相关(P<0.05)。结论被动吸烟大鼠肺组织病理变化符合肺气肿样改变,且与VEGF的变化呈一定的相关性。VEGF可能是吸烟致大鼠肺气肿发病过程的重要影响因素。     

Expressions of tumor necrosis factor-converting enzyme and ErbB3 in rats with chronic obstructive pulmonary disease

Background Chronic obstructive pulmonary disease (COPD) is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha (TNF-α) is found to take part in systemic inflammation, and ErbB3 plays an important role in mucin hypersecretion of COPD. Since TNF-α converting enzyme (TACE) is involved in the activation of both TNF-α and ErbB3, we established rat models of COPD to investigate the expressions of TACE, TNF-α and ErbB3 and to explore the correlations among TACE,TNF-α and ErbB3 respectively. Methods Thirty Wistar male rats were randomly divided into COPD group (group C, n=10), saline solution parallel group (group P, n=8), and normal control group (group N, n=8). Group C was challenged with passive cigarette smoking and intratracheal instillation of lipopolysaccharide. Six weeks later pulmonary functions were tested, bronchoalveolar fluid and arterial blood gases were assayed, and histopathological evaluations were performed in turn. The expressions of TACE, TNF-α and ErbB3 in lungs of all rats were determined histochemically. Results The expressions of TACE, TNF-α and ErbB3 were significantly higher in group C than in group N (P&lt;0.01). The contents of TNF-α in serum (P&lt;0.01) and bronchoalveolar lavage fluid (BALF) (P&lt;0.01) were elevated more significantly in group C than in group N. A positive correlation existed between TACE and TNF-α (r=0.784, P&lt;0.01) and between TACE and ErbB3 (r=0.526, P&lt;0.01) respectively. Conclusions TNF-α and ErbB3 are involved in the pathogenesis of COPD. TACE contributes to the progress of COPD indirectly through the function of TNF-α and ErbB3.     

慢性阻塞性肺疾病患者血清CTRP-9 水平 及其临床意义

目的 探讨慢性阻塞性肺疾病（COPD）患者血清C1q 肿瘤坏死因子相关蛋白9（CTRP-9） 水平及其临床意义。方法 选取2016 年10 月—2017 年10 月罗定市人民医院就诊的90 例COPD 稳定期 患者作为观察组,另选取同期于该院体检的90 例健康居民作为对照组。分别采集两组血浆标本,应用酶联 免疫吸附试验法测定两组血清CTRP-9 水平,采用肺功能仪测量两组第1 秒用力呼气容积占预计值百分比 （FEV1%pred）,并分析两组评价指标的相关性。结果 观察组血清CTRP-9 水平高于对照组（P<0.05）;观 察组FEV1%pred 低于对照组（P <0.05）;Pearson 相关性分析结果显示,观察组血清CTRP-9 水平与患者肺 功能指标FEV1%pred 呈负相关（r =-0.803,P =0.004）。结论 CTRP-9 在COPD 患者血清中呈高表达,且 其表达水平与患者肺功能存在相关性。     

汉防己甲素对肺纤维化大鼠肺泡巨噬细胞释放肿瘤坏死因子的影响

目的 :动态观察汉防己甲素 (Tetrandrine ,Tet)对博莱霉素A5(BLMA5)致肺纤维化大鼠支气管肺泡灌洗液 (BALF)中细胞总数、分类计数及肺泡巨噬细胞 (AM)释放肿瘤坏死因子α(TNF α)的影响 ,探讨Tet防治肺纤维化机制。方法 :将 48只SD大鼠一次性气管内注入BLMA5制备肺纤维化模型 ,随机分为 :模型组 (n =2 4 )及Tet组(n =2 4 ) ,在实验的第 3d、7d、1 4d、2 8d分批处死后进行支气管肺泡灌洗并收集灌洗液 ,另取 8只为正常对照组 ,于实验的第 2 8d一次性处死记数细胞总数及分类计数 ,采用ELISA法测定肺泡AM培养上清中TNF α水平。结果 :模型组各期BALF细胞计数及肺泡巨噬细胞培养上清TNF α含量较正常对照组明显增高 (P <0 .0 5 ,P <0 .0 1 ) ,Tet组较模型组明显降低 (P <0 .0 5 ,P <0 .0 1 )。结论 :抑制TNF α释放可能是汉防己甲素防治鼠肺纤维化的机制之一。