自身免疫性肝病的治疗药物研究进展

自身免疫性肝病是一组由自身免疫介导的肝脏炎症性疾病,主要包括自身免疫性肝炎、原发性胆汁性胆管炎及原发性硬化性胆管炎等。近年来,自身免疫性肝病逐渐成为肝病领域的研究热点,其治疗药物的研究也有了新的突破。综述自身免疫性肝病治疗药物的研究进展。

     

自身免疫性肝病的药物治疗研究与进展

自身免疫性肝病(autoimmune liver disease,AILD)主要是指由自身免疫介导的肝脏炎症性病变,传统临床上将其分为三种类型:自身免疫性肝炎(autoimmune hepatitis,AIH)、原发性胆汁性胆管炎(primary biliary cholangitis,PBC)和原发性硬化性胆管炎(primary sclerosing cholangitis,PSC)。近年来的研究发现,兼具以上任意两种疾病特征的重叠综合征(overlap syndrome,OS)和免疫球蛋白G(immunoglobulin G,IgG)4相关性肝胆疾病亦可归为AILD的范畴。不同类型的肝病其相应的治疗药物方案存在一定差异,大量关于AILD的理论和临床研究工作也取得了新进展。本文就AILD五种类型的药物治疗方案进行综述,为AILD的临床治疗提供建议,以提高患者生活质量。     

纳米药物免疫调节治疗的研究进展

近年来研究发现,纳米粒子技术平台为复杂的、难治性的自身免疫或炎症性疾病的治疗带来一场新的技术革命,纳米粒子结合特异的自身抗原能重建多种自身免疫病模型的外周免疫耐受,减少免疫病理损伤。该文从纳米粒子的理化特征、给药途径以及诱导或重建免疫耐受的作用与机制等方面,综述了近年来自身免疫或炎症性疾病纳米药物免疫调节治疗的研究进展和趋势,为寻求新的治疗方法治疗炎症相关疾病提供理论基础。     

抗肺癌血管生成机制及靶向治疗药物研究进展

肿瘤血管生成是一个受众多生长因子调节的复杂的病理生理过程。抗肿瘤血管生成的机制主要有：抑制促血管生成因子与配体的表达和结合及相应的信号传递途径,抑制血管内皮细胞的增殖、迁移,诱导其凋亡,抑制基底膜的降解等。随着肿瘤血管生成机制的逐步阐明,进一步证实了血管生成与肿瘤发生、发展的关系,而抗血管生成治疗也因其具有高效性、广普性、不易产生耐药性及无明显毒副反应等优点成为当今肿瘤治疗领域的热点。     

NMDA受体拮抗剂治疗药物依赖的研究进展

药物依赖，是以失去控制地应用某种成瘾物质为特征的慢性、复发性疾病。这些成瘾物质包括酒精、阿片类药物、精神兴奋剂、镇静药和大麻等。药物依赖是一个世界范围内日趋严重的医学和社会问题，世界各国无一幸免地受到毒品的侵袭。在我国，毒品问题也很严重，在耗费大量社会财富的同时，还引发了诸如犯罪、艾滋病等诸多社会问题。因此，有效地控制药物依赖显得日趋重要。目前治疗药物依赖所用的药物主要是基于滥用药物的一些受体激动剂或拮抗剂。由于药物依赖机制的复杂性，涉及多通路多机制，至今尚未找到根本性的防治手段和药物。     

大环内酯类药物治疗铜绿假单胞茵慢性感染机制的研究进展

近年来大量研究表明长期应用大环内酯类药物或大环内酯类药物与其它抗生素联用均能有效控制铜绿假单胞菌所致的慢性感染.大环内酯类在治疗铜绿假单胞菌慢性感染方面主要具有①抑制铜绿假单胞菌藻酸盐和表多糖的产生;②影响铜绿假单胞菌Ⅲ型分泌系统,减少毒力因子的产生;③破坏铜绿假单胞菌表面结构,抑制细菌对宿主的黏附;④抑制细菌QS系统.减少自身信号诱导分子的合成;⑤增加炎症细胞聚集.减少炎性细胞凋亡,对抗机体的炎症反应;⑥增加呼吸道痰液的清除,降低痰液粘稠度;⑦对铜绿假单胞菌具有暴露时间依从性杀菌活性等方面的功能,能最终达到对铜绿假单胞菌慢性感染的有效控制.     

治疗自身免疫病药物研究进展

自身免疫病(类风湿关节炎、系统性红斑狼疮、炎症性肠病等)是一类以局部或全身性异常炎症免疫反应为特征的疾病。目前,治疗自身免疫病药物主要分为非甾体抗炎药、甾体抗炎药、改善病情抗风湿药(化学药物、天然药物以及生物制剂)等。随着对自身免疫病病理机制的深入阐明和新药物靶点的发现,靶向细胞因子、受体和信号分子的新型生物制剂获得较快发展。靶向JAK/STAT信号通路的多个小分子药物,近年来也被研发应用于临床。炎症免疫反应软调节药物是一类具有抗炎免疫调节作用、不良反应少的药物,该类药物将是治疗自身免疫病药物研发的新策略和主要方向之一。该文综述了治疗自身免疫病药物的研究进展。     

Amiodarone minimizes experimental autoimmune myocarditis in rats

Amiodarone, a promising drug for the treatment of tachyarrythmias, was recently found to have immunomodulatory effects in vitro. We hypothesized that amiodarone would affect the immune system in vivo and examined the effect of amiodarone on myocarditis in rats. We induced experimental autoimmune myocarditis in rats by cardiac myosin immunization and treated the animals with an intraperitoneal injection of amiodarone at 25 mg/kg/every other day, 10 times after the induction of experimental autoimmune myocarditis. In the treated group, both microscopic and macroscopic examinations showed reduced heart weights, a mild and localized infiltration of inflammatory cells and fibrosis in the myocardium, and a mild congestion in the liver and lungs as compared with the control group. The phenotypic distribution of lymphocytes in peripheral blood showed a significant decrease in the CD4/CD8a ratio in the treated group, but not in the control group. The proportion of mast cells involved in inflammatory cell infiltration was lower in the treated group than the control group. In vitro, amiodarone inhibited the proliferation of mast cells by arresting them in the G2 phase of the cell cycle. These results indicated that amiodarone minimized the progression of experimental autoimmune myocarditis, suggesting a potential therapeutic role for amiodarone treatment in patients suffering from myocarditis, especially myocarditis complicated by cardiac arrhythmias. One possible mechanism by which amiodarone minimizes the progression of experimental autoimmune myocarditis may be to affect the immune system via the immunomodulatory effects on T cell and mast cell functions.     

Regulation of inflammation and myocardial fibrosis in experimental autoimmune myocarditis

Autoimmune responses and inflammation are involved in the pathogenesis of many cardiovascular diseases. There is compelling evidence that inflammatory mechanisms may contribute to progressive heart failure. Thus, myocardial infiltration of lymphocytes and mononuclear cells, increased expression of pro-inflammatory chemokines and cytokines and circulating autoantibodies are frequently observed in myocarditis and dilated cardiomyopathy (DCM). Experimental autoimmune myocarditis (EAM) in rodents may be elicited by immunization of cardiac myosin and EAM in rats mimics human fulminant myocarditis in the acute phase and human DCM in the chronic phase. Our animal model, EAM was demonstrated to progress into the clinicopathological state similar to DCM in the chronic phase, and was found to be characterized by the enlargement of the heart, dilatation of ventricles, diffuse and extensive myocardial fibrosis, besides being a cellular immunity and inflammation mediated disease. Severity of myocarditis was characterized by increased inflammation, cardiac fibrosis and decreased myocardial performance in rats with DCM. Pharmacological interventions such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) significantly attenuated the myosin-induced inflammation and cardiac fibrosis and thereby improving myocardial function in rats with DCM. A growing body of evidence shows that ACEI and ARBs contribute to the pharmaceutical management of patients with heart failure mediated by immune and inflammatory response. The purpose of this review is to emphasize the role of inflammation and myocardial fibrosis in rats with DCM after EAM and study the effects of pharmacological interventions such as ACEI, ARBs in the treatment of heart failure through the suppression of inflammatory cytokines and fibrosis.     

Oleuropein prevents the development of experimental autoimmune myocarditis in rats

Oleuropein (OLE) is a natural secoiridoid that is derived from Olea europaea. OLE possesses cardioprotective effects in experimental models of hypertension, myocardial infarction, atherosclerosis and hyperlipidaemia. In the present study, the effects of OLE on experimental autoimmune myocarditis (EAM) were evaluated. EAM in rats were induced by subcutaneous injections of porcine cardiac myosin. Cardiac function parameters, myocardial pathology, myocardial inflammatory cell infiltration and nuclear factor kappa-B (NF-κB) expression were measured. Our data showed that the postmyocarditis rats exhibited increased left ventricular end systolic diameters, left ventricular end diastolic diameters, left ventricular end-diastolic pressures (LVEDP), and decreased ejection fractions. However, OLE significantly suppressed these changes in EAM rats. Histological analysis revealed that myosin induced miliary foci of discolouration on endocardial surfaces and extensive myocardial injuries with inflammatory cell infiltration were significantly improved by OLE therapy. A definitive positive correlation between the histological scores and LVEDP was observed. Moreover, OLE inhibited CD4⁺, CD8⁺ cells and macrophage infiltration in myocardium and decreased the serum production of tumour necrosis factor-a (TNF-a), interleukin-1β (IL-1β) and IL-6 in EAM rats. Expectedly, the myocardial levels of NF-κB p65, p-IκBa, IKKa were significantly attenuated by OLE, indicating the inhibitory effects of OLE on the NF-κB pathway. Furthermore, OLE decreased the myocardial expressions of phosphorylated-p38 MAPK, phosphorylated-ERK, and did not change the levels of p38 MAPK and ERK in EAM rats. Collectively, our results suggest that OLE effectively prevents the development of myocarditis, at least in part, by inhibiting the MAPKs and NF-κB mediated inflammatory responses.     

TNFSF13B在实验性自身免疫性心肌炎小鼠心肌组织中的表达及意义

目的：探讨肿瘤坏死因子超家簇成员TNFSF13B在实验性自身免疫性心肌炎小鼠心肌组织中的表达及其意义。方法：用包含心肌肌球蛋白致病性抗原表位的人工合成多肽在d1、d8免疫遗传易感BALB／c小鼠，建立实验性自身免疫性心肌炎动物模型。在初次免疫后d14、d21，取实验组小鼠和对照组小鼠的心肌组织作病理学检查，用免疫组化技术检测TNFSF13B在心肌组织中的表达情况，用ELISA法测血清中抗心肌肌球蛋白自身抗体滴度。结果：初次免疫后d14，实验组15只（15／18）小鼠出现心肌炎症，至d21，实验组17只（17／18）小鼠出现心肌炎症，且程度进一步加重，而对照组小鼠未出现心肌炎症；TNFSF13B在炎症小鼠心肌中的表达明显，而在对照组小鼠心肌中未发现TNFSF13B的表达；与对照组小鼠相比，出现心肌炎症的小鼠血清中有较高滴度的抗心肌肌球蛋白自身抗体。结论：TNFSF13B参与了自身免疫性心肌炎的发生发展过程。     

Suppression of experimental autoimmune myocarditis by sodium fusidate (fusidin)

Fusidic acid and its sodium salt sodium fusidate (fusidin) are widely used antibiotics that possess immunomodulating properties. It has been shown that fusidin ameliorates the course of several organ-specific immunoinflammatory diseases and thus we investigated the effect of fusidin on myosin-induced experimental autoimmune myocarditis (EAM) in rats, a well-established animal model for human giant cell myocarditis and postmyocarditis dilated cardiomyopathy (DCM). Fusidin at doses of 80 mg kg(-1) was administrated i.m. to male Dark Agouti (DA) rats, either from days 0 to 10 (early treatment group), or from days 10 to 20 (late treatment group) after induction of EAM. Efficacy of fusidin treatment was determined on day 21 of EAM development. It was observed that both early and late treatment with fusidin markedly ameliorated clinical, histological and immunohistochemical signs of the disease. The treated rats had significantly decreased incidence of EAM, heart weight and heart weight/body weight ratio (Hw/Bw) compared with untreated animals. In contrast to the severe myocardial damage and cellular infiltration in the EAM rats, there was only focal infiltration of inflammatory cells in the myocardium of the treated rats. In both treated groups the mean microscopic score was markedly lower compared with vehicle-treated animals. In addition, the number of CD4+, ED1+ and OX6+ cells was significantly lower in myocardium of fusidin-treated rats than that in untreated group. The present findings suggest that fusidin exhibited both early and late therapeutical effect in EAM.     

Interleukin-10 delivered by mesenchymal stem cells attenuates experimental autoimmune myocarditis

BackgroundsAutoimmune myocarditis is characterized by over-activated immune system attacking the cardiomyocytes, resulting in heart function decline. In the current study, we investigated the therapeutic advantages of delivering Interleukin-10 (IL-10) by mesenchymal stem cells (MSCs), both of which had immune suppression functions, in treating experimental autoimmune myocarditis.MethodsThe mouse model of autoimmune myocarditis was established by subcutaneous injection of troponin I in A/J mice. Mouse bone marrow derived mesenchymal stem cells (BM-MSCs) with or without IL-10 overexpression, or the recombinant IL-10 protein were delivered into the mice via tail-vein injection. The inflammation and fibrosis levels of the heart were evaluated with qPCR, ELISA and histological staining. Serum level of anti-troponin-I was assessed by ELISA. Heart function analysis was conducted with echocardiography.ResultsBM-MSCs overexpressing IL-10 had enhanced immune suppression functions. They also showed improved therapeutic effects from the perspective of heart function and cardiac fibrosis. The anti-troponin-I level was significantly reduced by MSCs overexpressing IL-10 when comparing with the MSCs or IL-10 protein injection.ConclusionIL-10 delivered by MSCs showed therapeutic advantages in treating experimental autoimmune myocarditis.     

Fusidin ameliorates experimental autoimmune myocarditis in rats by inhibiting TNF-alpha production

Experimental autoimmune myocarditis (EAM) represents a model for human autoimmune myocarditis, a condition for which no optimal treatment is currently available. It has been reported that tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in pathogenesis of EAM. The immunomodulating antibiotic fusidic acid and its sodium salt (sodium fusidate-fusidin) were previously shown to reduce TNF-alpha production and its end-organ cytotoxicity, thus proving beneficial in several animal models of organ-specific autoimmune diseases. To investigate the effects of fusidin on EAM the drug was given at dose 80 mg/kg i.m. to EAM rats. Fusidin was administered as an early, from day 0 to 10, or late treatment, from day 10 to 21, after induction of disease. Both early and late treatment with fusidin markedly ameliorated the clinical and histological signs of the disease. Fusidin-treated rats had significantly decreased blood levels of TNF-a compared with vehicle-treated animals. Similarly, TNF-alpha production by in vitro sensitized lymph node cells in both fusidin treated groups was significantly lower than that in EAM rats. The present findings suggest that fusidin ameliorated EAM, at least partly, through an inhibitory action on the secretion of TNF-alpha.     

FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes

FTY720 is a new immunosuppressant agent and selectively decreases the number of circulating lymphocytes. In this study, we compared the effects of FTY720 with those of tacrolimus on experimental autoimmune myocarditis (EAM) in rats. A significant decrease in circulating lymphocyte counts was noted after a single administration of FTY720 in normal rats. At day 0, 7-week-old male Lewis rats were immunized with purified porcine cardiac myosin emulsified in complete Freund's adjuvant. FTY720 or tacrolimus was administered intraperitoneally daily. The number of myocarditis-affected areas in the FTY720 treatment groups with doses of 0.1 mg/kg/ day was significantly lower than those in control groups at days 14 and 28. In addition, at day 28, the myocarditis-affected areas in the FTY720 treatment group were significantly smaller than those in the tacrolimus treatment group receiving the same dose. Effects of early administration (days 0-10) and delayed administration (days 11-20) of FTY720 also were examined. At day 28, the myocarditis-affected areas in the early therapy group were significantly lower than those in the control group. In conclusion, we demonstrated that the development of EAM could be prevented by FTY720. These data also indicated that lymphocyte-mediated immunity is critically involved in the development of EAM.     

精神科药物治疗的基因组学研究进展

药物基因组学通过候选基因的多态性预测药物疗效，其研究基础是确定与药物作用和疾病病理生理机制相关的候选基因多态性，并评价药物疗效。精神科的药物基因组学目前主要关注多巴胺和5-羟色胺受体基因的多态性。目前尚不能根据基因型进行个体化药物治疗，但用药物基因组学的基本原理，可能会对临床用药产生巨大影响。