IL-36Ra抑制炎性痛小鼠脊髓A1型星形胶质细胞极化

目的评价不同剂量IL-36Ra对炎性痛小鼠痛行为以及脊髓A1型星形胶质细胞极化的影响。方法雄性C57BL/6小鼠32只,采用足底注射完全弗氏佐剂(CFA)建立炎性痛模型。随机将小鼠分为CFA+生理盐水组、CFA+IL-36Ra 50 ng组、CFA+IL-36Ra 100 ng组以及CFA+IL-36Ra 200 ng组,每组8只。各组小鼠在造模后d 1~d 7,每日1次鞘内给药。同时,分别在造模前以及造模后d 1、3、5、7检测4组小鼠机械刺激缩足阈值(mechanical withdraw threshold, MWT)和辐射热刺激缩爪潜伏期(PWL)的变化。以逆转录聚合酶链反应检测IL-36Ra对CFA小鼠脊髓A1、A2型星形胶质细胞标志物表达水平的影响。以免疫组化法检测各组小鼠脊髓背角A1型星形胶质细胞标志物C3与GFAP共表达水平的变化。结果炎性痛小鼠造模后患侧MWT、PWL均明显下降,IL-36Ra(100、200 ng)可显著改善小鼠的机械性痛觉超敏与热痛觉过敏;且在治疗7 d后,IL-36Ra可降低CFA小鼠脊髓星形胶质细胞激活标志物GFAP、Lcn2的表达水平,抑制星形胶质细胞激活;同时,IL-36Ra(100、200 ng)可下调CFA小鼠脊髓A1型星形胶质细胞标志物Serping1、 H2-T23的mRNA水平,但IL-36Ra各个剂量对A2型星形胶质细胞标志物表达没有明显作用;此外,IL-36Ra还可抑制脊髓背角A1型星形胶质细胞标志物C3表达。结论 IL-36Ra可能通过抑制CFA小鼠脊髓A1型星形胶质细胞极化,进而改善小鼠炎性痛痛行为。     

鞘内注射氟代柠檬酸对炎性痛敏大鼠的镇痛作用

目的研究鞘内注射氟代柠檬酸(fluorocitrate,Fc)对致炎大鼠痛觉过敏的影响。方法采用大鼠右后爪踝关节外侧皮下注射完全弗氏佐剂(complete freunds adjuvant,CFA)50μl致炎模型。测定给予CFA或Fc前后大鼠机械性缩爪阈值(MWT)和热刺激缩爪潜伏期(TWL)。免疫组化分析脊髓背角星形胶质细胞标记物(GFAP)和小胶质细胞标记物(OX-42)的表达。结果大鼠皮下注射CFA24h后出现明显的炎性痛敏,鞘内注射Fc后4,6,8,10,12h,与CFA组大鼠比较,大鼠MWT明显提高(P<0.01),TWL明显延长(P<0.01)。鞘内注射Fc6h后,降低脊髓背角GFAP和OX-42表达。结论脊髓胶质细胞可能参与炎性痛敏的发生和维持,氟代柠檬酸可能通过抑制其生物活性而发挥镇痛作用。     

星形胶质细胞在完全弗氏佐剂诱导的炎性痛中的作用

目的 探讨脊髓背角星形胶质细胞在完全弗氏佐剂(complete Freund's adjuvant,CFA)诱导的炎性痛中的作用.方法 雄性SD大鼠随机分为3组(6只/组):CFA组(大鼠左后肢足底注射CFA诱导炎性痛,同时行鞘内置管术,术后6 d鞘内给予生理盐水);L-α-aminoadipate(LAA)组(处理方式同CFA组,但术后6 d鞘内给予LAA);对照组(处理方式同CFA组,但足底注射生理盐水).术前2 d及术后7 d检测各组机械痛和热痛阈值,术后7 d以Real-time PCR法检测脊髓背角GFAP mRNA变化.结果 术前2 d各组大鼠左后肢足底机械痛及热痛阈值无明显差异(P> 0.05).术后7 d,CFA组大鼠脊髓背角GFAP mRNA较对照组明显增高(P<0.01),左后肢足底机械痛及热痛阈值较对照组明显降低(P<0.01);与CFA组相比,LAA组大鼠脊髓背角GFAP mRNA明显降低(P<0.01),左后肢足底机械痛及热痛阈值均明显增高(P<0.01).结论 LAA特异性抑制脊髓背角星形胶质细胞活性,缓解了CFA大鼠炎性痛,提示脊髓背角星形胶质细胞活化是CFA诱导炎性痛的重要机制.     

下丘脑室旁核ATP敏感性钾离子通道参与大鼠炎性痛调节的作用研究

目的探讨下丘脑室旁核ATP敏感性钾离子通道(KATP通道)在大鼠炎性痛中的作用。方法♂SD大鼠(250²80 g),采用随机数字法分为5组(每组6只):正常组(Normal组)、完全弗氏佐剂致炎性痛组(CFA组)、生理盐水组(Saline组)、KATP通道特异性激动剂组(Diaoxide组)和激动剂溶媒组(Vehicle组)。以热痛敏刺激仪检测各组大鼠热缩足潜伏期(TWL),观察痛行为学变化;以免疫荧光技术观察室旁核KATP通道和脊髓背角c-Fos阳性细胞数的变化。并观察KATP通道激动剂对大鼠痛行为和脊髓背角c-Fos表达的影响。结果 1与术前和Saline组相比,CFA组大鼠炎症侧后足术后d 1、d 3和d 7的TWL降低(P<0.05),CFA组术后d 3、d 7的KATP阳性细胞数减少(P<0.01),脊髓背角c-Fos阳性细胞数增加(P<0.01);2与Vehicle组相比,激动剂组大鼠热痛觉过敏减轻(P<0.01),脊髓背角c-Fos阳性细胞数减少(P<0.01)。结论下丘脑室旁核KATP通道可能与CFA所致炎性痛的发生机制相关。     

小胶质细胞抑制剂对佐剂性关节炎大鼠脊髓促炎性细胞因子的影响

目的:观察小胶质细胞抑制剂对佐剂性关节炎大鼠脊髓促炎性细胞因子的影响。方法:蛛网膜下腔置管成功的雄性SD大鼠分别脊髓蛛网膜下腔注射(it)生理盐水(NS)和米诺环素50μg,30 min后右踝关节皮内注射完全氟氏佐剂(CFA),it,qd,连续7 d,观察CFA后0,2,6,13 d后爪热刺激回缩潜伏期(PWTL)的变化及CFA致炎后0,2,6 d给药后4 h和13 d脊髓IL-1β,IL-6,TNF-α含量变化,这些促炎性细胞因子的表达水平通过ELISA方法检测。结果:米诺环素能抑制PTWL缩短;CFA致炎后脊髓IL-1β,IL-6,TNF-α表达明显增加,米诺环素可减少相应时间点脊髓IL-1β,IL-6,TNF-α的表达水平。结论:蛛网膜下腔注射米诺环素可以减少外周炎症诱导的脊髓促炎性细胞因子的分泌;脊髓小胶质细胞可能通过促炎性细胞因子介导炎性痛觉过敏。     

复方甘草酸苷对佐剂性关节炎大鼠血清中TNF-α、IL-1和IL-6表达水平的影响

目的:研究复方甘草酸苷对佐剂性关节炎大鼠血清中TNF-αIL-1和IL-6表达水平的影响,以探讨复方甘草酸苷对佐剂性关节炎的治疗作用.方法:通过给大鼠右后足跖部皮下注射完全弗氏佐剂(CFA)建立类风湿性关节炎的动物模型(AA),在致炎后第14d,大鼠继发性关节炎出现.开始在治疗组AA大鼠腹腔注射复方甘草酸苷注射液2mg/kg,连续10d,直至第28d处死全部大鼠,断头取血后用酶免法洲大鼠血清中TNF-α、IL-1、IL-6的表达水平.结果:治疗组大鼠血清中的TNF-α、IL-l、IL-6水平均低于模型组,复方甘草酸苷对佐剂性关节炎大鼠血清中TNF-α、IL-1、IL-6表达均成抑制作用.结论:复方甘草酸苷可降低佐剂性关节炎大鼠血清中TNF-α、IL-1、IL-6的表达,对类风湿性关节炎的治疗具有一定的作用.     

复方甘草酸苷对佐剂性关节炎大鼠血清中TNF-α、IL-1和IL-6表达水平的影响

目的:研究复方甘草酸苷对佐剂性关节炎大鼠血清中TNF-αIL-1和IL-6表达水平的影响,以探讨复方甘草酸苷对佐剂性关节炎的治疗作用.方法:通过给大鼠右后足跖部皮下注射完全弗氏佐剂(CFA)建立类风湿性关节炎的动物模型(AA),在致炎后第14d,大鼠继发性关节炎出现.开始在治疗组AA大鼠腹腔注射复方甘草酸苷注射液2mg...     

亚油酸及其甲酯对大鼠佐剂性关节炎的治疗作用

目的观察亚油酸和亚油酸甲酯对大鼠佐剂性关节炎的治疗作用。方法用弗氏完全佐剂建立大鼠关节炎模型(AA),观察亚油酸及其甲酯对AA大鼠足肿胀的抑制作用和对血清中IL-1β和TNF-α表达水平的影响。结果亚油酸及其甲酯能显著减轻关节肿胀,并能显著降低血清中IL-1β和TNF-α的含量。结论亚油酸及其甲酯对佐剂性关节炎有一定的治疗作用。     

8-O-乙酰山栀子苷甲酸对慢性炎性痛模型大鼠的镇痛作用机制研究

目的:研究8-O-乙酰山栀子苷甲酸(8-OaS)对慢性炎性痛模型大鼠的镇痛作用机制。方法:将30只雄性SD大鼠分为假手术组(生理盐水)、模型组(生理盐水)和8-OaS低、中、高剂量组(3、10、30μg/kg),每组6只。除假手术组外,其余各组大鼠足底注射弗氏完全佐剂复制慢性炎性痛模型。造模成功后,各组大鼠鞘内给予相应药物,每天1次,连续给药7 d后,采用Von-Frey细丝检测各组大鼠足底疼痛阈值,计算各组大鼠疼痛阈值曲线下面积和8-OaS的半数有效剂量(ED50)。另取36只雄性SD大鼠分为假手术组(生理盐水)、模型组(生理盐水)和8-OaS组(给药剂量为ED50),同法造模及给药,然后采用免疫荧光组织染色法观察各组大鼠脊髓背角内离子钙结合衔接分子1(Iba-1)、磷酸化p38丝裂原激活的蛋白激酶(p-p38 MAPK)的阳性表达情况,采用Western blotting法检测各组大鼠脊髓背角内Iba-1、p-p38 MAPK、白细胞介素1β(IL-1β)、IL-6及肿瘤坏死因子α(TNF-α)的蛋白表达水平。结果:与假手术组比较,模型组大鼠足底疼痛阈值和曲线下面积均显著降低(P&...     

8-O-乙酰山栀子苷甲酸对慢性炎性痛模型大鼠脊髓背角内HDAC1～5表达的影响及与JAK_2-STAT_3信号通路的关系研究

目的:研究8-O-乙酰山栀子苷甲酸(8-OaS)对慢性炎性痛模型大鼠脊髓背角内组蛋白去乙酰化酶1～5(HDAC1～5)表达的影响及与Janus激酶2-信号转导与转录活化因子3(JAK_2-STAT3)信号通路的关系。方法:取SD大鼠随机分为正常对照组、假手术组(生理盐水)、完全弗氏佐剂(CFA)组(生理盐水)和8-OaS低、中、高剂量组(2、20、200μg/kg),每组6只,除正常对照组和假手术组外,其余各组大鼠左侧后足趾侧皮下注射CFA复制慢性炎性痛模型,建模后腹腔注射相应药物,每日1次,连续7 d。采用热辐射法检测首次给药第1、2、3、4、5、6、7、8、11、15天大鼠的缩足潜伏期。另取大鼠按上述后5组方法进行分组给药,采用Western blot法检测大鼠末次给药后腰膨大节段脊髓背角中HDAC1～5、磷酸化JAK_2(pJAK_2)、磷酸化STAT3(pSTAT3)蛋白表达情况。再另取大鼠随机分为假手术组(生理盐水)、CFA组(生理盐水)、8-OaS组(20μg/kg)和JAK_2-STAT_3的拮抗药α-氰基-(3,4-羟基)-N-苄苯乙烯胺(AG490)组(8 mg/kg),每组6只,同上法复制IP模型后腹腔注射相应药物,每日1次,连续7 d,采用免疫荧光组织化学染色观察各组大鼠HDAC5和胶质纤维酸性蛋白(GFAP)在脊髓背角的表达情况。结果:与正常对照组和假手术组比较,其余各组大鼠的缩足潜伏期均明显缩短(P<0.05);与CFA组比较,8-OaS低、中、高剂量组大鼠的缩足潜伏期均明显延长(P<0.05),且呈剂量依赖性。与假手术组比较,CFA组大鼠脊髓背角中HDAC1～5、pJAK_2、pSTAT3蛋白表达均明显增强(P<0.05);与CFA组比较,8-OaS低、中、高剂量组大鼠脊髓背角中HDAC5、pJAK_2、pSTAT3蛋白表达均明显降低(P<0.05),但HDAC1～4蛋白表达差异均无统计学意义(P>0.05)。HDAC5大量表达于星形胶质细胞上,与假手术组比较,CFA组大鼠脊髓背角中GFAP和HDAC5表达均明显增强(P<0.05);与CFA组比较,8-OaS组和AG490组大鼠脊髓背角中GFAP和HDAC5表达均明显降低(P<0.05)。结论:8-OaS可有效缓解由CFA诱导的慢性炎性痛,其机制可能与下调脊髓背角中HDAC5表达和JAK_2、STAT3的磷酸化水平有关。     

Disruption of inflammatory signals by cytokine-targeted therapies for inflammatory bowel diseases

Gut inflammation occurring in patients with inflammatory bowel diseases (IBD) is associated with an excessive immune response that is directed against constituents of the normal bacterial flora and results in the production of large amounts of inflammatory cytokines. Anti-cytokine compounds, such as the neutralizing TNF antibodies, have been employed with clinical success in patients with IBD. However, nearly half of IBD patients are refractory to such treatments, response can wane with time, and anti-TNF treatment can associate with severe side effects and/or development/exacerbation of extra-intestinal immune-mediated pathologies. These observations, and the demonstration that, in IBD, the pathological process is also characterized by defects in the production and/or activity of counter-regulatory cytokines, have boosted further studies aimed at delineating novel strategies to combat the IBD-associated tissue-damaging immune response.     

炎性相关指标在小儿全身炎症反应综合征中的意义

目的探讨炎性相关指标在小儿全身炎症反应综合征中的意义。方法选取本院2009年7月～2010年6月收治的全身炎症反应综合征患儿2378例作为观察组,选取同期的健康儿童268例为对照组,比较两组人员检查时外周血白细胞、中性粒细胞、血沉、C反应蛋白、血小板计数等指标。结果观察组白细胞、中性粒细胞、血沉、C反应蛋白等炎性相关指标均明显高于对照组,观察组血小板计数明显低于对照组,差异均有统计学意义（P〈0.05）。观察组患儿平均住院（5.7±2.6）d。经治疗后,1861例患儿治愈,516例患儿好转,仅有1例患儿死亡。结论外周血白细胞、中性粒细胞、血沉、C反应蛋白、血小板计数等炎性相关指标在小儿全身炎症反应综合征的诊断中具有重要的临床意义。     

Evaluation of time course and inter-relationship of inflammatory mediators in experimental inflammatory reaction

Inflammatory signs, such as heat, redness, swelling and pain, have been described from the Greek era. In these phenomena various endogenous active substances, i.e., inflammatory mediators, could cause and manifest vascular dilatation, a vascular permeability increase and sensitization of pain receptors, etc. In order to evaluate the roles of inflammatory mediators, we have studied the time courses of inflammatory reaction along with detection of various active substances directly or indirectly in the experimental animal model of pleurisy, such as rat carrageenin-induced, and zymosan-induced pleurisy. These pleurisies showed almost similar time courses of pleural exudate accumulation and neutrophil migration. However, mediators detected in the exudates of such pleurisies were different; in carrageenin-induced pleurisy bradykinin and prostacyclin (PGI2) caused exudate formation, while zymosan-induced pleurisy showed early degradation of mast cells and activation of complements, followed by an increase in platelet activating factor (PAF). In both pleurisies TNF alpha, IL-1, IL-6 and CINC (cytokine-induced neutrophil chemoattractant) appeared similarly in the exudates to cause chemoattractant for neutrophils. TNF alpha and IL-1 could stimulate to produce IL-6 and IL-8. While prostaglandins may regulate cytokine production via a cellular cAMP-dependent mechanism. Thus one should consider the time for application of anti-inflammatory drugs, such as cyclooxygenase inhibitor, indomethacin, since it causes increases in TNF alpha and IL-1 production by reducing PGI2 and prostaglandin E2 (PGE2) levels. In conclusion, inflammatory reaction has its own automatic regulation mechanism through complex cross talks between inflammatory mediators.     

Treatment of pelvic inflammatory disease

The pathogenesis, risk factors, microbiology, sequelae, diagnosis, and treatment of pelvic inflammatory disease (PID) are reviewed, and factors associated with the selection of effective, safe, and economical drug therapy are discussed. PID is an acute clinical syndrome not related to surgery or pregnancy that is caused by the spread of microorganisms from the vagina and cervix to the endometrium, fallopian tubes, and other adnexal structures. Primary PID, the most common form of the disease, is the result of the ascent of sexually acquired or endogenous lower genital tract microorganisms to the upper genital tract. Presence of a sexually transmitted disease is the most common risk factor for PID, but a previous episode of PID, multiple sexual partners, intrauterine device use, and young age are also risk factors. PID is classified as gonococcal or nongonococcal (i.e., caused by anaerobic and aerobic pelvic organisms). The long-term consequences of PID are the most devastating aspects of the disease; infertility remains the most common sequela. Therapy of PID is aimed at preserving fertility, preventing long-term consequences, and relieving acute clinical symptoms. In areas in which penicillinase-producing Neisseria gonorrhoeae is endemic, therapy that is effective against penicillinase-producing N. gonorrhoeae is necessary. Gonococcal PID that is not penicillin resistant may be treated with a single intramuscular or oral dose of a penicillin; penicillin-resistant infection may be treated with a cephalosporin or ciprofloxacin. If chlamydia is a diagnostic consideration, a one- to two-week course of oral tetracycline or doxycycline (injectable-drug therapy is an alternative) should be added to the regimen. Single-agent therapy is a cost-effective alternative to combination regimens. Ampicillin-sulbactam is a cost-effective alternative to the more costly injectable cephalosporins or the combination regimens of an aminoglycoside plus clindamycin or metronidazole. With the increasing prevalence of PID in the United States, the selection of cost-effective antimicrobial therapy has important implications for the hospital pharmacist and the pharmacy and therapeutics committee.     

Local control of inflammatory pain

The mechanism of the local hyperalgesic action of prostaglandin E2 has been studied using rat paw oedema. Prostaglandin E2 is a metabotropic transmitter, activating adenylate cyclase, either directly or through the release of a stimulatory protein factor. This activation of adenylate-cyclase is blocked, locally, by opiates. Hyperalgesia results from the alteration of the cAMP/Ca2+ balance after chemical or mechanical initiation of generator potentials at the nociceptor.     

Antibody treatments of inflammatory arthritis

Inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis are extremely common in the community, with a prevalence of up to 5%, and they cause substantial morbidity. The development of anti-TNF agents for use initially in rheumatoid arthritis, and subsequently more broadly in inflammatory arthritis, represents the biggest advance in management of these conditions since the introduction of corticosteroid agents, and is a major vindication of public funded arthritis research. However, there are limitations of even these highly effective agents. A significant minority of patients with inflammatory arthritis do not respond to these anti-TNF agents, they are associated with substantial risk of toxicity, require parenteral administration, and are extremely expensive. New antibody treatments in development can be divided into anti-cytokine agents, cell-targeted therapies, co-stimulation inhibitors, and treatments aimed at preventing joint erosion consequent on inflammation. This review discusses the state of the art in the development of these agents for management of this common group of diseases.     

炎症性肠病的生物治疗

<正> 对慢性炎症生物学的深入了解,促进了针对炎性通路上各个靶位的特殊生物治疗的发展。生物治疗(biological therapy)是指伴随着现代生物技术进步产生的、应用一系列生物小分子物质进行靶向治疗疾病的新型治疗方法。其主要内容包括:①各种天然生物制剂和分离物,如血液制品及各类疫苗;②重组的肽类和蛋白质,如生长激素与促红细胞生成素;③