IL-23／IL-17炎症轴在实验性自身免疫性肝炎中的作用

目的通过建立实验性自身免疫性肝炎小鼠模型,观察外源性IL-23对实验性自身免疫性肝炎模型小鼠中IL-17的影响,探讨其可能的作用机制。方法以肝抗原S-100免疫C57BL／6小鼠制作自身免疫性肝炎动物模型,提取出脾淋巴细胞,将IL-23加入到抗CD,抗体活化后的脾淋巴细胞中进行培养,免疫组化观察IL-17在肝细胞中的分布及表达水平,RT-PCR和ELISA检测IL-17在脾淋巴细胞中的表达。结果与对照组相比,模型组肝细胞中IL-17表达升高;IL-23作用于模型组活化的脾淋巴细胞后IL-17的表达水平明显高于对照组。结论IL-23／IL-17炎症轴在EAH的病理机制中发挥着重要的作用,IL-23可能通过上调IL-17的表迭使AIH模型小鼠症状加重,并为AIH的治疗提供了新的靶点。     

The pharmacokinetics of olsalazine sodium in healthy volunteers after a single i.v. dose and after oral doses with and without food

Summary Olsalazine sodium (5,5-azodisalicylic acid (OLZ)) was given to eight healthy volunteers as a 10 mg i.v. bolus dose and as a 1 g oral dose with and without food. To five fasting participants single oral doses of 2 g and 4 g were given.Blood and urine were collected during three weeks after each dose and were assayed for OLZ, a conjugate identified as a sulphate of OLZ (OLZs), 5-aminosalicylic acid (5-ASA), and N-acetyl-5-aminosalicylic acid (ac-5-ASA).The study showed that: 1. OLZ had a very short elimination half-life, mean 56 min. 2. OLZ was absorbed from the intestinal tract to a very small extent, as seen from the low systemic availability and low urinary excretion, 2.3% and 0.31% respectively, for a 1 g dose taken fasting. 3. OLZ was present in the serum partly as a conjugate, which was identified as an O-sulphate. Following the i.v. dose the serum half-life of the O-sulphate was estimated to be 7 days. 4. Food intake did not influence the systemic availability of OLZ and ac-5-ASA. 5. There was no dose-dependent increase of OLZ absorption with single doses up to 2 g, but a 4-g dose showed a more than two-fold increase in the individual peak serum concentration and in the systemic availability of OLZ. However, there was no significant increase in the mean residence time (MRT) for OLZ or in the serum concentration of either 5-ASA or ac-5-ASA at a dose of 4 g.     

甘草酸对幼鼠实验性结肠炎的治疗作用及其机制研究

目的探究甘草酸对幼鼠实验性结肠炎的治疗作用及其作用机制。方法将75只SD大鼠幼鼠随机分为对照组、模型组、柳氮磺胺吡啶组(0.5 g/kg)和甘草酸40、160 mg/kg组,每组各15只,制备实验性结肠炎模型的同时分别灌肠给药,连续7 d。观察大鼠一般情况,HE染色法观察大鼠结肠组织病理学变化并进行疾病活动指数(DAI)评分、黏膜损伤指数(CMDI)评定,酶联免疫法测定血清中白介素-4(IL-4)、白介素-17(IL-17)、白介素-1β(IL-1β)水平,逆转录-聚合酶链反应(RT-PCR)、Western blotting法检测大鼠结肠组织中NLRP3、白介素-1β(IL-1β)、凋亡相关斑点样蛋白(ASC)、半胱天冬酶(caspase-1)表达。结果与模型组比较,甘草酸组幼鼠体质量逐渐增加,症状改善;炎症细胞浸润有所减少,腺体破坏程度降低;DAI评分、CMDI评分均降低,呈剂量相关性(P0.05);IL-4水平升高,IL-17、IL-1β水平降低,呈剂量相关性(P0.05);NLRP3、ASC、caspase-1、IL-1βmRNA表达和蛋白表达均降低,呈剂量相关性(P0.05)。结论甘草酸能够治疗大鼠实验性结肠炎,可能与抑制NLRP3通路蛋白表达、降低炎症因子水平有关。     

Nanoparticle-based delivery enhances anti-inflammatory effect of low molecular weight heparin in experimental ulcerative colitis

Epithelial administration of low molecular weight heparin (LMWH) has proven its therapeutic efficiency in ulcerative colitis (UC) but still lacks of a sufficiently selective drug delivery system. Polymeric nanoparticles were used here not only to protect LMWH from intestinal degradation but also to provide targeted delivery to inflamed tissue in experimental colitis mice. LMWH was associated with polymethacrylate nanoparticles (NP) type A (PEMT-A) or type B (PEMT-B) of a size: 150?nm resulting in a maximum drug loading: 0.1?mg/mg. In a lipopolysaccharide-stimulated macrophages both, free LMWH and LMWH-NP have significantly reduced the cytokines secretion independently from cellular uptake. The in-vivo therapeutic efficiency was dose dependent as at low doses (100?IU/kg) only minor differences between free LMWH and LMWH-NP were found and the superiority of LMWH-NP became prominent with dose increase (500?IU/kg). Administration of LMWH-NP at 500?IU/kg has markedly improved the clinical activity as compared to LMWH while similarly pathophysiological indicators revealed increased therapeutic outcome in presence of NP compared to LMWH alone: Myeloperoxidase (Colitis control: 10 480?±?5335, LMWH-PEMT-A NP: 1507?±?2165, LMWH-PEMT-B NP: 382?±?143, LMWH: 8549?±?5021 units/g) and tumor necrosis factor: (Colitis control: 1636?±?544, LMWH-PEMT-A NP: 511?±?506, LMWH-PEMT-B NP: 435?±?473, LMWH: 1110?±?309?pg/g). Associating LMWH with NP is improving the anti-inflammatory efficiency of LMWH in-vivo by its protection against degradation in luminal environment and selective drug delivery. Such a combination holds promise for a highly specific therapy by its double selectivity towards the inflamed intestinal tissue. LMWH-PEMT NP have significantly improved the clinical activity in-vivo in comparison to free LMWH.     

IL-17对大鼠心肌梗死后心律失常和心室重塑的影响分析

目的 探讨白细胞介素-17(IL-17)对大鼠心肌梗死后心律失常和心室重塑的影响.方法 液氮冷冻法获取心肌梗死大鼠共72只,按照随机原则分为心梗对照组、IgG1处理组和IL-17抗体处理组,剩余24只大鼠作为空白对照组,四组大鼠组内按照随机原则分别实验处理1个月和2个月,检测四组大鼠心肌IL-17表达水平,记录心律失常和心室重塑相关指标.结果 实验处理后心梗对照组和IgG1处理组大鼠各项指标均未表现出明显差异(P>0.05),心肌梗死各组大鼠心肌IL-17表达水平、心律失常诱发率、Ⅰ/Ⅲ胶原比例均明显高于空白对照组(P<0.05),超声心动图显示心脏功能明显次于空白对照组(P<0.05),IL-17抗体处理组上述指标较心梗对照组和IgG1处理组明显改善(P<0.05),心肌IL-17表达水平与心律失常诱发率呈明显的正相关关系(r=0.89,P<0.05).结论 心肌梗死大鼠心肌IL-17大量表达,对心律失常和心室重塑的形成具有很大的诱导作用.     

The intestinal anti-inflammatory effect of minocycline in experimental colitis involves both its immunomodulatory and antimicrobial properties

Some antibiotics, including minocycline, have recently been reported to display immunomodulatory properties in addition to their antimicrobial activity. The use of a compound with both immunomodulatory and antibacterial properties could be very interesting in the treatment of inflammatory bowel disease (IBD), so the aim of our study was to evaluate the anti-inflammatory effect of minocycline in several experimental models of IBD. Firstly, the immunomodulatory activity of the antibiotic was tested in vitro using Caco-2 intestinal epithelial cells and RAW 264.7 macrophages; minocycline was able to inhibit IL-8 and nitrite production, respectively. In vivo studies were performed in trinitrobenzenesulfonic acid (TNBS)-induced rat colitis and dextran sodium sulfate (DSS)-induced mouse colitis. The results revealed that minocycline exerted an intestinal anti-inflammatory effect when administered as a curative treatment in the TNBS model, modulating both immune and microbiological parameters, being confirmed in the DSS model; whereas none of the other antibiotics tested (tetracycline and metronidazole) showed anti-inflammatory effect. However, minocycline administration before the colitis induction was not able to prevent the development of the intestinal inflammation, thus showing that only its antimicrobial activity is not enough for the anti-inflammatory effect. In conclusion, minocycline displays an anti-inflammatory effect on different models of rodent colitis which could be attributed to the association of its antibacterial and immunomodulatory properties.     

结核性胸膜炎患者外周血及胸水中Th17细胞和白细胞介素-17水平变化

目的 探讨结核性胸膜炎外周血和胸水中Th17细胞和白细胞介素-17(IL-17)的表达水平及临床意义.方法 初治结核性胸膜炎(结核组)患者30例和非结核性胸膜炎(胸膜炎组)20例,另选择健康体检人员(对照组)20例.采用流式细胞术和双抗体夹心免疫酶标法(ELISA)测定血清及胸水中Th17细胞的百分率及IL-17的含量.结果 结核组外周血中Th17细胞的百分比和IL-17的含量显著高于对照组和胸膜炎组(P＜0.05).结核组胸水中Th17细胞的百分比和IL-17的含量明显高于胸膜炎组(P＜0.05).结核组患者在规则治疗1、3、7、14 d时,外周血和胸水中Th17细胞的百分比和IL-17的含量均逐渐下降,外周血中TH17细胞的百分比于治疗1d时显著低于入院时水平(P＜0.05),胸水中Th17细胞的百分比于治疗3d时显著低于入院时水平(P＜0.05),外周血中IL-17的含量于治疗3d时显著低于人院时水平(P＜0.05),胸水中IL-17的含量于治疗7d时显著低于入院时水平(P＜0.05).结论 Th17/IL-17参与了结核性胸膜炎的发病机制,且与其病程发展及治疗效果密切相关.     

The effective therapy of cyclosporine A with drug delivery system in experimental colitis

Cyclosporine A (CyA) is a useful immunosuppressive agent for steroid-dependent or steroid-refractory ulcerative colitis. However, side effects have been reported in clinical trials of ulcerative colitis treated with CyA. Biodegradable microspheres (MS) have been investigated as drug delivery system. We evaluated the effect of a drug delivery system with poly(d,l-lactic acid)-MS containing CyA. Colitis was induced in C57BL/6 mice by 3% dextran sulfate sodium (DSS). Mice with DSS-induced colitis were treated with oral administration of CyA or CyA-MS: CyA (0.2?mg/kg/day)-MS; CyA (2?mg/kg/kg)-MS). Serum levels of CyA were significantly less elevated after oral administration of CyA (2?mg/kg/day)-MS compared with CyA (2?mg/kg/day) (CyA (2?mg/kg/day), 44.7 ± 0.8?ng/ml; CyA (2?mg/kg/day)-MS, 7.7 ± 1.3?ng/ml). The body weight at day 10 was significantly recovered in the mice treated with CyA (0.2?mg/kg/day)-MS and CyA (2?mg/kg/day)-MS compared with CyA (0). The histological score and myeloperoxidase activity in the mice treated with CyA-MS was significantly lower than CyA (0). Gene expressions of interleukin-1β (IL-1β), IL-6, and CXCL1 in the mice treated with CyA (0.2?mg/kg/day)-MS and CyA (2?mg/kg/day)-MS were downregulated compared with CyA (0)-MS. CyA-MS might be possible to treat ulcerative colitis effectively by decreasing the total dosage without the elevation of the serum level or the side effects of CyA.     

丹参茎叶酚酸组分对溃疡性结肠炎模型小鼠的干预作用

目的研究丹参茎叶总酚酸及其主要效应成分丹酚酸B和迷迭香酸组分单独或混合使用对溃疡性结肠炎(ulcera-tive colitis,UC)模型小鼠的保护作用,以期为丹参茎叶酚酸类成分的资源化利用提供科学依据。方法小鼠自由饮用2%葡聚糖硫酸钠7 d建立UC模型,再连续灌胃给药7 d,给药期间记录小鼠体重变化及疾病活动指数(DAI)评分。实验结束后,取结肠分别进行长度测量,HE染色,ELISA法测TNF-α、IL-6和IL-4含量,实时荧光PCR测IL-6、COX2和IL-17A mRNA水平。结果与正常对照组相比,模型组小鼠体重明显减轻,结肠明显短缩,结肠组织TNF-α、IL-6和IL-4水平及IL-6、COX2和IL-17A mRNA表达明显升高,丹参茎叶总酚酸及其主要效应成分丹酚酸B和迷迭香酸单独或混合给药干预后上述指标得到改善。结论丹参茎叶总酚酸及丹酚酸B和迷迭香酸单独或混合给药均能够改善UC模型小鼠肠道症状和减轻炎症反应,为丹参茎叶抗UC研究与开发利用提供了科学依据。     

The effect of methylsulfonylmethane on the experimental colitis in the rat

Methylsulfonylmethane (MSM), naturally occurring in green plants, fruits and vegetables, has been shown to exert anti-inflammatory and antioxidant effects. MSM is an organosulfur compound and a normal oxidative metabolite of dimethyl sulfoxide. This study was carried out to investigate the effect of MSM in a rat model of experimental colitis. Colitis was induced by intracolonic instillation of 1 ml of 5% of acetic acid. Rats were treated with MSM (400 mg/kg/day, orally) for 4 days. Animals were euthanized and distal colon evaluated histologically and biochemically. Tissue samples were used to measurement of malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT), glutathione (GSH) and proinflammatory cytokine (TNF-α and IL-1β) levels. Results showed that MSM decreased macroscopic and microscopic colonic damage scores caused by administration of acetic acid. MSM treatment also significantly reduced colonic levels of MDA, MPO and IL-1β, while increased the levels of GSH and CAT compared with acetic acid-induced colitis group. It seems that MSM as a natural product may have a protective effect in an experimental ulcerative colitis.     

Beneficial effect of a novel non-steroidal anti-inflammatory agent with basic character and antioxidant properties on experimental colitis in rats

Ulcerative colitis is a chronic disorder of unknown etiology. Conservative treatment remains empirical, even today. The aim of this study was to test the efficacy of a novel non-steroidal anti-inflammatory agent [5-(2-hydroxy-ethylamino)-1-cyclohexyl-2-pentanone] (compound A), with basic character and antioxidant properties on an experimental model of ulcerative colitis in rats. The effect of this compound was compared with that of methylprednisolone on the histological abnormalities and serum levels of tumor necrosis factor-alpha (TNF-alpha) in experimental colitis produced by 2,4,6-trinitrobenzenesulfonic acid (TNB). A total number of 24 rats were randomly assigned to one of four groups of six rats each. Group 1: colitis without treatment (disease control), group 2: normal animals (control), group 3: induction of experimental colitis treated with methylprednisolone (5.3 x 10(-3) mmol/kg i.v. every day for 7 days) and group 4: induction of experimental colitis plus administration of compound A (0.6 mmol/kg i.v. every day for 7 days). The administration of compound A resulted in a statistically significant reduction of the extent of tissue damage and of certain histological features (edema, inflammatory infiltration) (P<0.05). Compound A also resulted in a statistically significant reduction of the levels of serum TNF-alpha, compared to those of controls (P<0.005). The beneficial effect of this compound was probably due to the combination, on a single molecule, of anti-inflammatory and antioxidant properties as well as to its basic character. The reduction of the serum TNF-alpha levels could be one of the possible mechanism(s) of action of the compound. Further studies are necessary to establish the direct mechanism of action(s) of the drug and to evaluate its long-term efficacy and safety.     

阿德福韦酯联合干扰素对慢性乙型病毒性肝炎患者血清IL-17的影响

目的探讨阿德福韦酯联合干扰素对慢性乙肝患者血清白细胞介素-17（IL-17）的影响。方法 92例慢性乙肝患者随机分为两组,观察组46例,对照组46例,对照组采用阿德福韦酯治疗,观察组采用干扰素联合阿德福韦酯治疗,治疗12月后观察疗效。治疗前后测定血清IL-17。结果观察组患者的ALT复常率、HBV-DNA阴转率和HbeAg阴转率均高于对照组（P〈0.05）。两组治疗后患者的血清IL-17均有明显降低,并且治疗后与对照组比较,观察组降低更明显（P〈0.05）。结论阿德福韦酯联合干扰素可以通过降低IL-17表达改善慢性乙肝病情。     

奥美拉唑在葡聚糖硫酸钠诱导的溃疡性结肠炎大鼠肝肾肠微粒体中的代谢研究

目的：研究葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎（UC）模型大鼠不同病期肝、肾、肠微粒体中奥美拉唑（OME）代谢酶活性的变化。方法：DSS诱导UC急性期（UCA）和恢复期（UCR）大鼠模型。同时制备UCA、UCR以及正常对照（NOR）组大鼠的肝、肾、肠微粒体。将不同浓度的OME与微粒体共孵育,用LC/MS/MS检测样品中5-OH OME的生成量,比较OME在各组微粒体中的代谢活性。结果：连续饮用5% DSS 7 d,UCA和UCR组大鼠表现出明显的结肠炎症状。DSS停药后7 d,UCR组大鼠症状有所好转。UCA组肝微粒体中5-OH OME的生成速率低于NOR组,UCR组的生成速率恢复到正常水平。UCA组的CL_int与NOR组相比降低了45%。OME在3组大鼠肾和肠微粒体中的代谢活性无显著差异。结论：OME在肝微粒中的代谢会受到UC的影响而改变,可能会影响到OME在患者体内的药动学。     

The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis

The mechanism of action of 5-aminosalicylic acid (5-ASA), the active therapeutic moiety of a number of clinically used anti-colitic agents, is unclear. The present study investigates whether the beneficial effects in vivo could involve induction of the heat shock protein, heme oxygenase-1 (HO-1), known to provide endogenous anti-oxidant and anti-inflammatory moieties which can modulate colonic inflammation. The effects of 5-ASA on the colonic expression and activity of HO-1 along with its effect on the inflammatory damage have been evaluated in the colitis provoked by instillation of trinitrobenzene sulphonic acid (TNBS) over 48 h in the rat. Intracolonic administration of 5-ASA (8, 25 and 75 mg/kg/day) dose-dependently reduced the TNBS-provoked macroscopic colonic inflammatory injury, myeloperoxidase (MPO) activity and TNF-alpha levels, while also dose-dependently increasing colonic heme oxygenase enzyme activity. Colonic HO-1 protein expression, determined by Western blot analysis in this colitis model, was likewise further induced by 5-ASA. Intracolonic administration of 5-ASA alone under unchallenged conditions also induced colonic HO-1 protein expression and stimulated heme oxygenase enzyme activity. Administration of zinc protoporphyrin (50 micromol/kg/day, s.c.), which prevented the increase in colonic heme oxygenase activity, abolished the anti-colitic effect of 5-ASA. These results suggest that 5-ASA may exert its colonic anti-oxidant and anti-inflammatory effects in vivo in part through the up-regulation of HO-1 enzyme expression and activity.     

乌梅水煎物对实验性溃疡性结肠炎小鼠的作用

目的探讨乌梅对溃疡性结肠炎(UC)小鼠结肠组织过氧化物歧化酶(SOD)活性及丙二醛(MDA)含量的影响。方法采用3%葡聚糖硫酸钠(DSS)溶液给小鼠自由饮水,建立小鼠溃疡性结肠炎模型,造模成功后,正常组、模型组给予0.33 ml生理盐水灌胃,乌梅低、中、高剂量组分别按设计剂量灌胃,每天1次,均连续给药10 d,期间进行隐血试验和观察粪便性状以及进行疾病活动度(DAI)评分;肉眼观察结合显微镜观察结肠组织形态学评分;测定病变结肠组织中SOD活性与MDA含量。结果发现乌梅中、高剂量组的小鼠无肉眼血便,可见松散大便。乌梅低、中、高剂量组的DAI均降低,中、高剂量组与模型组比较具有极显著性差异(P<0.01),在结肠黏膜病理改变中,乌梅高剂量组黏膜糜烂不严重,溃疡小,黏膜充血、水肿程度轻;在测定的SOD活力值中,中、高剂量组与模型组比较具有极显著性差异(P<0.01),均明显高于模型组。中剂量组与正常组比较具有显著性差异(P<0.05),高剂量组与正常组比较无显著性差异。测得MDA含量中,中、高剂量组与模型组比较具有极显著性差异(P<0.01),均明显低于模型组。结论提示自由基与UC的结肠组织损伤密切相关,参考UC的病理过程,乌梅对UC有明显治疗效果,并可能通过提高病变组织的SOD活性与降低MDA含量来发挥治疗作用。     

卡介菌多糖核酸辅助治疗对初始涂阳肺结核患者血清VIP和IL-17的影响

目的 探讨卡介菌多糖核酸辅助治疗对初始涂阳肺结核患者血清血管活性肠肽VIP和白细胞介素-17(IL-17)的影响.方法 106例初始涂阳肺结核患者随机分为两组,对照组50例,治疗组56例,对照组采用单纯化疗,治疗组在化疗的基础上加用卡介菌多糖核酸.两组所有患者治疗前后测定血清VIP和IL-17.结果 对照组总有效率为80%,治疗组总有效率为91.1%,两组比较有统计学差异(P<0.05).两组患者治疗前血清VIP和IL-17无明显差异(P>0.05).治疗后两组均可减少VIP和IL-17的表达,并且治疗后治疗组降低程度更明显(P<0.05).结论 卡介菌多糖核酸辅助治疗可以明显降低初始涂阳肺结核患者血清VIP和IL-17.     

IL-21／STAT3通路在溃疡性结肠炎小鼠发病中的表达及其意义

目的探讨IL-21／STAT3通路在溃疡性结肠炎（ulcerativecolitis,UC）小鼠肠道中的表达及其作用。方法20只BALB／C小鼠随机分为正常组和DSS模型组各10只。小鼠UC模型用葡聚糖硫酸钠dextransodiumsulphate,DSS）诱导,观察小鼠疾病活动指数（DAI）评分、病变结肠常规病理切片,采用ELISA法检测血清IL-6、IL-21含量,免疫组化检测结肠STAT3表达。结果模型组小鼠DAI评分、血清IL-6和IL-21含量、结肠病理评分、黏膜STAT3表达水平均较正常组高,差异有显著性（P〈0．05）。结论溃疡性结肠炎小鼠血清炎症介质及肠道STAT3表达水平明显升高,推测IL-21／STAT3通路可能参与UC小鼠肠道炎症损伤,阻断病变肠道IL-21／STAT3通路,减少STAT3蛋白表达或许是治疗UC的作用靶点。     

白细胞介素-17和叉头状螺旋转录因子3在子痫前期发病机制中的作用及剖宫产术后自控镇痛对其表达的影响

目的 探究白细胞介素-17(IL-17)和叉头状螺旋转录因子3(Foxp3)在子痫前期发病机制中的作用,对比重度子痫前期产妇剖宫产术后,超声引导下双侧腹横肌平面(TAP)阻滞复合静脉泵自控镇痛(PCIA)与硬膜外镇痛对疼痛控制及外周血中IL-17和Foxp3表达水平的影响.方法 筛选2016年2月至2020年2月苏州市...     

丁酸梭菌对实验性结肠炎小鼠肠黏膜趋化因子RANTES和单核细胞趋化蛋白-1表达的影响

目的观察丁酸梭菌对实验性结肠炎小鼠肠黏膜趋化因子RANTES和单核细胞趋化蛋白(MCP)-1表达的影响,并探讨其可能的作用机制。方法采用2.5%的葡聚糖硫酸钠(DSS)建立小鼠结肠炎模型。55只BALB/c小鼠随机分为健康对照组,阴性对照(生理盐水)组,阳性对照(美沙拉嗪)组,模型对照组,丁酸梭菌108CFU/mL组。用疾病活动指数(DAI)评分和病理组织学积分检测干预组的疗效;免疫组化法检测结肠组织中趋化因子RANTES和MCP-1蛋白的表达;反转录-聚合酶链反应(RT-PCR)法检测结肠组织中RAN-TES、MCP-1基因的表达。结果丁酸梭菌可改善小鼠一般情况,降低DAI积分,与模型对照组、阴性对照组相比,RANTES和MCP-1蛋白、基因的表达量均减少(P<0.05);其效果与美沙拉嗪相当。结论丁酸梭菌对急性期实验性结肠炎小鼠有治疗作用,其部分机制可能与通过减少结肠黏膜趋化因子RANTES和MCP-1的表达有关。