慢性乙型肝炎患者IFN-α/β受体和细胞因子表达与干扰素疗效间的关系

目的:检测慢性乙型肝炎(CHB)患者α-干扰素治疗前后血清中细胞因子及受体水平及治疗前外周血单个核细胞(PBMCs)中Ⅰ型干扰素受体,并观察α-干扰素疗效,以探讨α-干扰素与病毒复制消长的关系.方法:采用酶标(ELISA)法检测22例CHB患者治疗前后血清中细胞因子及受体(IL-6,IL-2,TNF-α,IL-8,sIL-2R)水平,并用链霉亲和素生物素酶复合物法(SABC)检测α-干扰素治疗前患者PBMCs中IFN-α/β受体表达.结果:治疗应答者血清IL-6,sIL-2R水平下降明显,而IL-2水平则明显上升.22例CHB患者中,干扰素治疗完全应答者7例,其中IFN-α/β受体高表达者6例,占85.71%;干扰素治疗无应答者11者,其中IFN-α/β受体高表达者3例,占27.27%.两者间比较差异有显著性意义(P＜0.05).部分应答者4例,IFN-α/β受体高表达者2例.结论:干扰素治疗CHB患者其疗效与细胞膜上IFN-α/β受体表达水平和血清细胞因子的调节密切相关.应重视对IFN-α/β受体及血清中细胞因子及受体水平的监测,以提高α-干扰素抗乙肝病毒的疗效.     

慢性乙型肝炎患者血清脂联素水平与肝功能及相关因素的关系

目的探讨慢性乙型肝炎（CHB）患者血清脂联素水平与肝功能及相关因素的关系。方法选择77例不同类型CHB患者,应用ELISA法检测血清脂联素水平;同时检测肝功能、血脂、空腹血糖（FBG）、HBVDNA等。测量人体身高、体重,计算体重指数（BMI）。30例健康体检者为正常对照组。结果各组CHB患者血清脂联素水平明显高于正常对照组（P〈0.01）,随肝损害加重而上升。脂联素与AST、TBil和ALP均正相关,与白蛋白（ALB）负相关。结论CHB患者血清脂联素水平升高与肝脏炎症活动有关,可能是机体抵抗炎症的一种机制。     

原发性高血压患者血清脂联素浓度的变化及肾素-血管紧张素系统对其影响

目的:探讨原发性高血压患者血清脂联素浓度的变化及肾素-血管紧张素系统对血清脂联素的影响.方法:本研究入选原发性高血压患者60例及健康人30例(正常对照组),以正常对照组人群胰岛素敏感性指数(ISI)的均数±标准差作为有无胰岛素抵抗的分界线,将原发性高血压患者分成两组,即胰岛素抵抗组23例及无胰岛素抵抗组37例.检测血清脂联素、空腹血糖、血清胰岛素、总胆固醇、高密度脂蛋白胆固醇、甘油三酯、胰岛素敏感性指数、收缩压、舒张压、平均压、身高、体重及体重指数等指标.另外,从60例原发性高血压患者中选出能够完成整个实验,积极配合随访的40例患者,并分成两部分,每部分20例,分别用血管紧张素转换酶抑制剂培哚普利及血管紧张素Ⅱ受体拮抗剂缬沙坦治疗两周,治疗前、后检测上述指标.结果:①胰岛素抵抗组的血清胰岛素和甘油三酯与正常对照组及无胰岛素抵抗组相比,胰岛素抵抗组明显升高(P＜0.01),胰岛素抵抗组的脂联素和胰岛素敏感性指数与正常对照组及无胰岛素抵抗组相比,胰岛素抵抗组明显降低(P＜0.01).②高血压患者用培哚普利及缬沙坦治疗两周后,平均压显著下降(P＜0.05),血清脂联素浓度和胰岛素敏感性指数明显升高(P＜0.05).③原发性高血压患者血清脂联素与收缩压和舒张压呈直线相关(r分别为0.35和0.28,P＜0.01和P＜0.05);血清脂联素与胰岛素敏感性指数和高密度脂蛋白胆固醇呈直线相关(r分别为0.45和0.53,P均＜0.01);血清脂联素与血清胰岛素、体重指数及甘油三酯负相关(r分别为-0.41,-0.61和-0.35,P＜0.01,P＜0.01和P＜0.05);血清脂联素与平均压无明显相关性.结论:原发性高血压患者低脂联素血症与脂代谢紊乱和胰岛素抵抗密切相关.肾素-血管紧张素系统,可提高原发性高血压患者胰岛素敏感性,从而使血清脂联素浓度升高.     

血清脂联素水平与高血压及心肌纤维化的关系

目的:研究血清脂联素与高血压的关系,探讨高血压患者血清脂联素水平对心肌纤维化的影响,阐明高血压患者血清脂联素水平与心肌纤维化的关系.方法:根据美国预防、检测、评估与治疗高血压全国联合委员会第七次报告(JNC-7)的血压标准,筛选出33例高血压患者(高血压组),并筛选出同期在我院体检中心观察的健康人33例(正常对照组).所有入选者清晨空腹抽取外周静脉血,用酶联免疫法测定血清脂联素、Ⅰ型前胶原羧基端肽(P Ⅰ CP)和Ⅲ型前胶原氨基端肽(P Ⅲ NP)水平.结果:与正常对照组相比,高血压组血清脂联素水平明显降低[(4.21±2.89)ng/ml比(2.69±1.00)ng/ml,P＜0.01];且1级高血压患者与2级高血压患者血清脂联素比较明显升高,差异有统计学意义(P＜0.05).与正常对照组相比,高血压组P Ⅰ CP和P Ⅲ NP水平显著增高,P Ⅰ CP分别为(13.10±6.56)ng/ml比(4.12±1.19)ng/ml,P Ⅲ NP分别为(128.94±56.37)ng/ml比(66.70±11.72)ng/ml,两组比较差异均有统计学意义(P均＜0.01).相关分析表明,血清脂联素水平与P Ⅰ CP及P Ⅲ NP水平呈明显负相关(r分别为-0.245和-0.275,P均＜0.05).结论:高血压患者血清脂联素水平明显降低,血压越高脂联素水平越低,血清脂联素水平与P Ⅰ CP及P Ⅲ NP水平呈明显负相关,推测低水平的脂联素血症在高血压心肌纤维化中可能起重要作用.     

2型糖尿病患者血清抵抗素、脂联素与下肢动脉病变的关系

目的 探讨初诊2型糖尿病患者空腹血清抵抗素、脂联素水平与下肢动脉病变(PAD)的关系.方法 根据踝肱指数(ABI)将96例初诊2型糖尿病患者分为PAD组和非PAD组,另选取52例健康体检者作为正常对照组,测定患者空腹血清抵抗素、脂联素、血糖、血脂及胰岛素,测量身高、体重、血压;计算体重指数(BMI)、胰岛素抵抗指数(HOMA-IR).结果 1.与正常对照组相比,2型糖尿病患者血清抵抗素水平明显升高(P＜0.01),脂联素水平明显降低(P＜0.01).2.与非PAD组相比,PAD组患者年龄明显偏高(P＜0.01),血清总胆固醇(TC)、低密度脂蛋白(LDL)水平升高(P＜0.05)、HOMA-IR、血清抵抗素明显升高(P＜0.01),脂联素水平降低(P＜0.01).3.相关分析表明,2型糖尿病患者血清脂联素与ABI呈正相关(r=0.367,P＜0.05),血清抵抗素与ABI负相关(r=-0.421,P＜0.05).结论 2型糖尿病合并PAD患者血清抵抗素、脂联素水平明显改变且与ABI相关,抵抗素、脂联素可能在2型糖尿病下肢动脉病变的发生发展中起重要作用.     

聚乙二醇干扰素α-2a对慢性乙型肝炎患者外周血单个核细胞表面IFNGR1的影响

目的研究聚乙二醇干扰素α-2a(polyethylene glycol interferonα-2a,PEG-IFNα-2a)对慢性乙型肝炎(chronic hepatitis B,CHB)患者外周血中干扰素-γ(interferon-gamma,IFN-γ)及γ干扰素受体1(interferon gamma receptor 1,IFNGR1)水平的影响.方法应用PEG-IFNα-2a治疗的不同时间点抽取CHB患者及健康对照组静脉血,酶联免疫吸附法检测其血清IFN-γ浓度,实时荧光定量RT-PCR技术检测其外周血单个核细胞(peripheral blood mononuelear cells,PBMCs)表面IFNGR1的表达情况.结果 CHB组患者IFN-γ及IFNGR1均高于健康对照组(P0.05).在使用聚乙二醇干扰素抗病毒治疗过程中,CHB患者IFN-γ及IFNGR1在12 wk时达到高峰,此后开始下降,至48 wk时低于治疗前水平,但仍高于健康对照组(P0.05).抗病毒治疗12 wk时,乙型肝炎病毒(hepatitis B virus,HBV)DNA阴转组IFNGR1的表达水平高于HBV DNA未阴转组(2.22±0.65 vs 1.35±0.71),两者差异有统计学意义(P0.05).结论 IFN-γ参与了CHB的发病,治疗12 wk时患者PBMCs表面IFNGR1的表达水平可能作为干扰素抗HBV治疗早期预测干扰素疗效的因子.     

脂联素及其受体mRNA表达与血清游离脂肪酸、肿瘤坏死因子α的研究

目的 了解肿瘤坏死因子-α(TNF-α)和游离脂肪酸(FFA)与脂联素及脂联素受体mRNA表达的关系.方法 19例肥胖和29例正常体重受试者,采用RT-PCR检测腹部皮下与大网膜脂肪组织中脂联素及其受体mRNA的表达水平,同时测定血清脂联素、TNF-α、FFA等指标.结果 (1)肥胖患者的血清TNF-α、FFA高于正常体重组;脂联素降低.(2)肥胖组中网膜脂肪组织脂联素mRNA表达量低于皮下脂肪组织和正常体重组网膜脂肪组织.(3)网膜脂肪组织脂联素mRNA表达量与脂联素水平呈负相关.(4)腹部皮下脂肪组织的脂联素受体1、脂联素受体2 mRNA表达水平与血清脂联素、FFA呈负相关.结论 肥胖人群的血清TNF-α、FFA升高,脂联素降低,且其网膜脂肪组织中脂联素mRNA表达量亦降低;血清FFA升高与腹部皮下脂联素受体表达下调相关.     

妊娠糖尿病患者血清脂联素和TNF-α与胰岛素抵抗的关系

目的 探讨妊娠期糖尿病(GDM)患者血清脂联素和肿瘤坏死因子α(TNF-α)水平与胰岛素抵抗(IR)关系.方法 检测48例GDM患者(GDM组)、30例正常葡萄糖耐量妊娠者(NGT组)血清脂联素、TNF-α,分析两者与IR指数的相关性.结果 与NGT组比较,GDM组血清脂联素水平下降(P<0.01),TNF-α升高(P<0.01).脂联素与IR呈负相关(P<0.01),TNF-α与IR呈正相关(P<0.01).体质量指数(BMI)、脂联素和TNF-α是影响GDM患者IR的独立危险因素.结论 GDM患者血清低脂联素水平、高TNF-α水平与IR密切相关,是GDM发生发展的重要影响因素.     

GDM患者血清脂联素、FFA水平及其与胰岛素抵抗的相关性研究

选取妊娠期糖尿病(GDM)孕妇40例为观察组,其中孕前体重指数(BMI)<25者20例,BMI≥25者20例.另取正常妊娠孕妇60例为对照组,BMI<25者30例,BMI≥25者30例.采用放免法测定两组孕妇空腹脂联素、胰岛素水平,用酶法测定血清游离脂肪酸(FFA)、甘油三脂、总胆固醇、血糖,并计算胰岛素抵抗(IR)指数(HOMA-IR).结果显示观察组孕妇空腹血清脂联素显著低于对照组(P<0.05),FFA、空腹血糖、胰岛索、总胆固醇、甘油三脂显著高于对照组(P均<0.05).当BMI<25时,GDM组血清脂联素显著低于对照组(P<0.05).而当BMI≥25时,两组脂联素水平无差异.HOMA-IR与脂联素呈负相关(r=-0.161,P<0.05),与FFA呈正相关(r=0.24JD,P<0.01).认为GDM孕妇血清脂联素水平降低,FFA水平升高.排除体脂因素后,只有在正常体质量的GDM患者中才有空腹脂联素水平降低.低脂联素和高FFA水平与GDM患者胰岛素抵抗密切相关.     

炎症因子与糖尿病及其大血管并发症的相关性及干预治疗的效果

选择正常对照组105例、单纯2型糖尿病(T2DM)组98例、糖尿病合并大血管病变组127例(并发症组),并将并发症组随机分成常规治疗组和普伐他汀治疗组,检测受试者的脂联素、血清超敏C反应蛋白(hsCRP)及血脂水平.结果 :①T2DM组和并发症组的血清hsCRP水平较正常对照组升高,脂联素水平较正常对照组降低(P均<0.05);②并发症组血清hsCRP水平较T2DM组升高,脂联素水平较T2DM组降低(P均<0.05).③2周后普伐他汀治疗组血清hsCRP水平明显下降(P<0.05).认为D2M及其大血管病变患者血清脂联素水平降低,hsCRP水平升高;普伐他汀治疗可降低血清hsCRP,其抗炎作用独立于降脂作用之外.     

α干扰素治疗HBeAg阳性慢性乙型肝炎疗效的预测指标

目的探讨α干扰素(IFN-α)治疗HBeAg阳性慢性乙型肝炎(CHB)疗效的预测指标。方法 165例HBeAg阳性CHB患者接受干扰素-α1b治疗24周,以ALT、HBV DNA基线、IFN-α剂量、肝组织炎症程度为预测指标,分析这些指标与抗病毒应答的相关性。结果 5 ULN1×106copies/mL组(P<0.05,P<0.01),中、重度CHB的有效应答率高于轻度CHB(P<0.01);IFN-α剂量与疗效未显示相关性(P>0.05)。结论干扰素疗效与治疗前ALT、HBV DNA水平及肝组织炎症程度等有密切的关系,可以作为预测IFN-α抗HBV疗效的指标。     

恩替卡韦对 HBeAg 阴性慢性乙型肝炎患者血清脂联素浓度的影响

目的：观察 HBeAg 阴性慢性乙型肝炎患者恩替卡韦治疗前后血清脂联素水平的变化,探讨脂联素和HBeAg 阴性慢性乙型肝炎之间的关系。方法60例 HBeAg 阴性 CHB 患者接受恩替卡韦治疗24周,治疗前后采用ELISA 法检测血清脂联素水平,同时检测肝功能、血脂、空腹血糖、HBV DNA 载量,测量人体身高,体质量,计算体质指数（BMI）。结果CHB 患者使用恩替卡韦治疗24周后,ALT、AST、TBil、HBV DNA 和脂联素水平较治疗前相比明显下降,差异有统计学意义（P ＜0．05）,但 TC、TO、BMI 和 FBG 水平较治疗前相比差异无统计学意义（P ＞0．05）。结论HBeAg 阴性慢性乙型肝炎患者血清脂联素水平与肝脏炎症活动相关,对于 HBeAg 阴性慢性乙型肝炎患者的抗病毒治疗效果以及预后的判断具有一定参考意义。     

α-干扰素治疗慢性乙型肝炎患者外周血单个核细胞TLR4表达和血清Thl／Th2型细胞因子的变化。

目的探讨慢性乙型肝炎患者在α-干扰素治疗前后外周血单个核细胞Toll样受体4（TLR4）的表达及血清Thl/Th2型细胞因子水平的变化及其临床意义。方法 50例HBeAg阳性慢性乙型肝炎患者予以普通α-干扰素治疗。在治疗前及治疗后3月和6月,使用流式细胞仪检测外周血单个核细胞表面TLR4表达;采用ELISA法检测血清IFN-γ和IL-4水平,并同时检测ALT、HBV DNA水平。结果在治疗3个月和6个月时,早期应答组和无应答组患者血清IFN-γ水平均升高,IL-4水平均降低;两组TLR4水平较治疗前均下降,但应答组患者TLR4下降更明显,有显著性差异（P〈0.05）;IFN-γ和IL-4的变化与TLR4的变化无明显相关（P均〉0.05）,TLR4与ALT呈正相关（r=0.78,P〈0.01）,TLR4的变化与HBV DNA变化无相关（P〉0.05）。结论在干扰素-α治疗后,慢性乙型肝炎患者Thl/Th2型细胞因子的变化可能与TLR4表达的变化无相关,而对干扰素治疗的疗效可能与TLR4表达的变化有关.     

Preactivation of the interferon signalling in liver is correlated with nonresponse to interferon alpha therapy in patients chronically infected with hepatitis B virus

Interferon alpha (IFN-α) therapy is widely used to treat patients with chronic hepatitis B (CHB) but the sustained response rate is low, and the molecular mechanisms for the ineffectiveness of IFN-α treatments are not known. We screened differentially expressed genes between responders (Rs) and nonresponders (NRs) in patients with CHB treated with IFN-α to explore the molecular basis for treatment failure. Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy. Gene expression levels were compared between seven patients who did not respond to therapy (NR) and six who did respond (R). Gene ontology category and KEGG pathway were analysed for differentially expressed genes, and the selected differentially expressed genes were confirmed using real-time polymerase chain reaction. We identified 3592 genes whose expression levels differed significantly between all Rs and NRs (P < 0.05); many of these genes are IFN-stimulated genes (ISGs) and immune-related genes. The ISGs were more highly expressed, while immune-related genes were inhibited in NRs before IFN-α treatment. Two ISGs (CEB1 and USP18) that are linked in an IFN inhibitory pathway are highly expressed in NRs, and a potential antiviral gene ISG20 was inhibited in NRs, suggesting a possible rationale for treatment nonresponse. Patients who do or do not respond to IFN have different liver gene expression profiles before IFN-α treatment. Preactivation of the IFN signalling pathway leading to the increased expression of inhibitory ISGs and inhibition of immune response in the pretreatment livers was associated with treatment failure.     

Comparison of Interferon-α-based therapy and nucleos(t)ide analogs in preventing adverse outcomes in patients with chronic hepatitis B

BackgroundWhether interferon (IFN)-α therapy is better than nucleos(t)ide analogs (NAs) in the prevention of adverse outcomes, including hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is still uncertain or controversial. This study aimed to compare the cumulative incidence of adverse outcomes in patients with CHB on IFN-α- and NA-based therapies.MethodsThis was a retrospective study of patients with CHB on antivirals. Patients treated with IFN-α (IFN-α or peginterferon-α) with or without NAs were defined as the IFN-α group, and those only receiving NAs were defined as the NAs group. Propensity score matching (PSM) was used to minimize baseline bias. Cox regression models were performed to select possible factors related to adverse outcomes development.ResultsAll 1247 patients were divided into the IFN-α (n = 877) and NAs (n = 370) groups. 26patients (20 and 6 in the NAs and IFN-α groups) developed adverse outcomes (decompensated cirrhosis, liver failure, HCC, liver transplantation and deaths) during a median follow-up of 5.2 years. The cumulative adverse outcomes occurrence at 10 years was significantly lower in the IFN-α group than in the NAs group in all (1.1% vs. 11.9%, P <0.001) and treatment-naïve (1.1% vs. 12.4%, P <0.001) patients. Similar trends were observed after PSM and differentiation of cirrhosis. Multivariate analysis before and after PSM showed that IFN-α-based treatment was independently associated with a lower adverse outcomes incidence (before/after PSM: P = 0.001/P = 0.002). HCC risk stratification analyses revealed that the superiority of IFN-α in preventing HCC was more significant in patients with high-risk HCC.ConclusionsIFN-α-based therapy was superior to NAs in preventing adverse outcomes in patients with CHB regardless of cirrhosis, and in reducing HCC in those with a high risk of HCC.     

阿德福韦酯对慢性乙型肝炎患者Th1/Th2型细胞因子的影响

目的分析细胞因子IFN-γ、TNF-α、IL-10、IL-6、IL-4、IL-2在慢性乙型肝炎患者治疗后血清中的浓度改变及其临床意义。方法应用微阵列流式细胞术(CBA)体外检测慢性乙型肝炎患者治疗前、治疗12周、24周、48周的血清细胞因子IFN-γ、TNF-α、IL-10、IL-6、IL-4、IL-2的浓度。结果慢性乙型肝炎患者阿德福韦酯治疗后外周血清的TH1/TH2细胞因子浓度度,比较治疗前,均是显著升高的(P0.05),除IL-6外,各细胞因子在治疗过程中均未有显著变化(P0.05);治疗12周时的血清IL-6的浓度与HBVDNA成负相关,治疗24周,IL-6、IL-10、TNF-α与HBVDNA成负相关(P0.05)。结论阿德福韦酯除直接抑制病毒作用外,还可能通过免疫调节作用抑制病毒复制。     

Adiponectin: a new independent predictor of liver steatosis and response to IFN-alpha treatment in chronic hepatitis C.

OBJECTIVES: To compare serum adiponectin and tumor necrosis factor (TNF)-alpha among patients with viral liver diseases; to investigate associations of serum adiponectin and TNF-alpha with histological or viral characteristics of chronic hepatitis C (CHC); to investigate adiponectin and TNF-alpha alterations during interferon (IFN)-alpha treatment; and to assess the relationship between serum adiponectin and TNF-alpha and response rates to treatment. METHODS: Adiponectin (mug/mL) and TNF-alpha (pg/mL) determinations by enzyme-linked immunosorbent assay (ELISA) in serial samples (before, the middle, the end, and 6 months after the end of treatment) from 83 CHC and 59 chronic hepatitis B (CHB) patients. Forty-three blood donors served as healthy controls. Patients were treated with IFN-alpha (4.5 MU/t.i.w.) for 12 months in CHB cases, and IFN-alpha (3 MU/t.i.w.) plus ribavirin for 6-12 months according to hepatitis C virus (HCV) genotype in CHC cases. RESULTS: After adjustment for gender and body mass index (BMI), HCV genotype 3 overweight patients (BMI > 25 kg/m(2)) had significantly lower adiponectin (7.3 +/- 2.7) at baseline compared with non-3 HCV genotype overweight patients (P < 0.05). Lower adiponectin (HCV genotype 3, P= 0.02 and HCV genotype 1, P= 0.025) and higher TNF-alpha (P= 0.025) at baseline were identified as independent predictors of liver steatosis in CHC patients. Lower adiponectin was also identified as an independent predictor of no virological response at the end of treatment (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.66-0.87, P < 0.001). At the end of IFN-alpha therapy, only HCV genotype 3 patients had significantly higher serum adiponectin (10.4 +/- 6.3) compared with its levels before treatment (8.7 +/- 4.7, P < 0.05). CONCLUSIONS: This study suggests that HCV genotype 3 may directly affect adiponectin. This is further supported by the significant increase in adiponectin at the end of treatment only in HCV genotype 3 patients. Serum adiponectin at baseline appears to be an independent predictor of liver steatosis and for the achievement of end-of-treatment virological response, while serum TNF-alpha at baseline was identified as an independent predictor only of liver steatosis.     

IKB激酶在系统性红斑狼疮患者中表达及与干扰素-α产生的关系

目的 研究系统性红斑狼疮(SEE)患者外周血白细胞中IKB激酶(IKK-α)、干扰素(IFN)-αmRNA的表达,并检测血浆中IFN-α的水平,以探讨SLE患者中IKK-α在IFN-α产生中的作用.方法 SYBR green dye I实时定量聚合酶链反应(PCR)方法检测外周血白细胞IKK-α和IFN-α的表达;酶联免疫吸附试验(ELISA)法检测血清IFN-α的水平.结果 ①SLE患者外周血IKK-α mRNA表达高于对照组(P<0.05);在活动组SLE患者中IKK-α mRNA的表达高于非活动组SLE患者(P<0.01).②SLE患者IFN-αmRNA的表达低于对照组(P<0.01),IFN-α mRNA的表达在非活动组SLE患者中低于活动组SLE患者(P<0.01).③SLE患者血清中IFN-α的水平高于对照组(P<0.01),其中,活动组SLE患者血浆IFN-α水平显著高于非活动组患者(P<0.05);SLE患者血浆中IFN-α浓度与抗双链DNA(dsDNA)抗体呈正相关(P=0.001),与补体C3水平呈负相关(P=0.005).④SLE患者IKK-α mRNA的表达与血浆中IFN-α的水平呈正相关(P=0.001).结论 SLE患者IKK-α mRNA的表达明显增高,且与血浆中IFN-α的水平呈正相关;而血浆中IFN-α的水平与SLE的发病及病情活动相关,提示IKK-α可能在SLE的发病中发挥重要的作用.