阿奇霉素对哮喘致敏大鼠气道炎症及Th1/Th2失衡的调节作用

目的:探讨阿奇霉素对哮喘(OVA)致敏大鼠气道炎症及Th1/Th2失衡的调节作用。方法:SD大鼠40只,随机分为生理盐水组、哮喘模型组、地塞米松组以及阿奇霉素组,每组10只。利用卵白蛋白(Ovalbumin,OVA)/Al(OH)3致敏与OVA雾化吸入激发建立大鼠过敏性气道炎症模型,收集肺泡灌洗液(BALF)进行白细胞分类计数。采用ELISA法测定肺泡灌洗液中IL-2、IL-4、TNF-α与ET-1的表达情况。光镜观察肺组织病理结构变化。结果:OVA模型大鼠肺泡灌洗液中的中性粒细胞、淋巴细胞以及嗜酸性粒细胞含量明显增加;HE染色观察肺组织病理结构出现明显的支气管上皮脱落、杯状细胞增生,支气管周围嗜酸性粒细胞明显浸润现象;BALF中IL-2、IL-4、TNF-α与ET-1的表达均明显高于生理盐水对照组(P<0.05)。阿奇霉素则显著降低肺泡灌洗液中中性粒细胞、淋巴细胞以及嗜酸性粒细胞含量;明显改善支气管上皮脱落、杯状细胞增生,支气管周围嗜酸性粒细胞浸润现象;BALF中IL-2、IL-4、TNF-α与ET-1的表达也明显低于OVA模型大鼠(P<0.05)。结论:阿奇霉素通过调节Th1/Th2失衡对过敏性哮喘的气道炎症具有明显的治疗作用。     

罗格列酮对大鼠肺纤维化的作用

目的探讨过氧化物酶体增殖物激活受体γ(PPARγ)激动剂罗格列酮对博莱霉素致大鼠肺纤维化的影响。方法将24只雄性SD大鼠随机分为4组,即生理盐水对照组、罗格列酮对照组、博莱霉素组、罗格列酮干预组,经气管内注射博莱霉素建立肺纤维化模型。HE染色及Masson染色观察肺组织形态学变化;检测支气管肺泡灌洗液(BALF)中细胞总数、中性粒细胞数、巨噬细胞数及乳酸脱氢酶(LDH)浓度;测定肺组织中羟脯氨酸含量。结果博莱霉素气管内注入后大鼠肺Ash-croft评分,胶原沉积、羟脯氨酸含量及BALF中LDH水平与生理盐水对照组比较明显增加(P均<0.05);给予罗格列酮干预后,上述指标均下降(P均<0.05)。生理盐水对照组和罗格列酮对照组的差异无统计学意义(P>0.05)。结论在博莱霉素诱导大鼠肺纤维化过程中,罗格列酮可减少胶原沉积,抑制肺纤维化。     

低分子肝素减轻大鼠肺纤维化机制探讨

目的探讨低分子肝素减轻大鼠肺纤维化的可能作用机制。方法54只雄性SD大鼠,随机分成正常对照组(A组)、模型组(B组)、低分子肝素组(C组)。B组、C组经气管内一次性注入博莱霉素A5(5mg·kg-1·ml-1)制作大鼠肺纤维化模型,A组气管内一次性注入等量生理盐水;C组皮下注射低分子肝素1000U/d,A、B组给予每天0.2ml生理盐水皮下注射。3组大鼠分别于造模后7d、14d、28d留取肺组织、血清、血浆、肺泡灌洗液。取肺组织做HE、Masson染色,并取肺组织测定肺组织胶原含量,取血清和肺泡灌洗液测定转化生长因子β1(TGF-β1)含量。结果C组较B组肺纤维化程度明显减轻,C组肺组织、血清及肺泡灌洗液中TGF-β1含量、胶原含量较B组明显减少。结论低分子肝素可能是通过影响TGF-β1的含量,从而减轻大鼠纤维化程度。     

吸入糖皮质激素对实验性肺纤维化的干预作用

为观察吸人糖皮质激素对博莱霉素诱导大鼠肺纤维化的干预作用，并探讨其作用机制，通过气管内注入博莱霉素复制肺纤维化模型，随机分为对照组(C组)、模型对照组(M组)和模型干预组(B组)，每组10只。B组给予每天雾化吸入布地奈德(0．5mg／kg体重)进行干预。ELISA方法测定血及支气管肺泡灌洗液(BALF)中转化生长因子β1(TCF-β1)、单核细胞趋化蛋白1(MCP-1)水平，同时观察病理、血气分析等变化。结果表明，第1周M组、B组均有肺泡炎，肺系数、BALF中性粒细胞高于对照组；第4周，B组肺纤维化程度较M组减轻(P&;lt;0．05)。血气分析与病理结果相符，第1周M组、B组氧分压均低于对照组(P&;lt;0．05)，第4周B组升高。第4周B组BALF中TCF-β1水平低于M组(37．70&;#177;5．05vs68．14&;#177;13．89，P&;lt;0．01)。M组BALF中MCP-1水平高于其他组。结论：吸入布地奈德可减轻博莱霉素诱导的肺纤维化，抗纤维化作用的机制与降低TGF-β1和MCP-1水平或阻止其升高有关。     

环孢素A对实验大鼠肺纤维化的干预作用

目的 研究环孢素A(CsA)对大鼠肺纤维化的干预作用.方法 平阳霉素(BLM)气管内注入建立大鼠肺纤维化模型,观察CsA对支气管肺泡灌洗液(BALF)中细胞成分和转化生长因子-β(TGF-β)的含量、肺组织学变化,应用SABC法检测肺组织中纤维连接蛋白(FN)和血小板衍化生长因子(PDGF)表达的作用.结果 应用BLM后第7天即有严重肺泡炎性改变,第28天有严重的肺纤维化,而CsA组,早期只有轻度炎性改变,BALF中细胞计数及TGF-β含量较BLM组低(P＜0.05),FN及PDGF表达显著弱于BLM组(P＜0.01).结论 CsA可能通过抑制FN、PDGF的表达及TGF-β的生成干预BLM致肺纤维化.     

1,8-桉油精对卵白蛋白致哮喘豚鼠的气道高反应性和炎症的抑制作用

目的探讨1,8-桉油精(1,8-cineol)对哮喘豚鼠肺功能的改善作用及其机制。方法豚鼠第0天和第7天ip给予0.5ml含卵白蛋白(OVA)20μg的氢氧化铝凝胶致敏,28d后OVA攻击制备哮喘模型。观察豚鼠OVA攻击后1h,1,8-桉油精10,30和100mg.kg-1对豚鼠吸入OVA后1,2,3,4,10,20和30min时气道阻力(Raw)和肺顺应性(Cdyn)变化及支气管肺泡灌洗液(BALF)中白细胞数和细胞分类的影响,并测量豚鼠肺组织中嗜酸细胞阳离子蛋白(ECP)、白细胞介素4(IL-4)、IL-8和肿瘤坏死因子α(TNF-α)的含量。观察豚鼠OVA攻击后17h再吸入乙酰甲胆碱(MCh)后,1,8-桉油精10,30和100mg.kg-1对Raw和Cdyn及BALF中白细胞数和细胞分类的影响,并测量豚鼠肺组织中ECP,IL-4,IL-8和TNF-α的含量。结果与正常对照组比较,豚鼠OVA攻击后1h,在4min时模型组Raw达到高峰;与模型组比较,1,8-桉油精30和100mg.kg-1明显抑制Raw增加(P<0.05);在3min时模型组Cdyn达到高峰,与模型组比较,1,8-桉油精10,30和100mg.kg-1均能明显抑制Cdyn降低(P<0.05);模型组豚鼠肺组织ECP,IL-4和TNF-α含量明显高于正常对照组(P<0.05);1,8-桉油精100mg.kg-1组ECP,IL-4和TNF-α含量均明显低于模型组(P<0.05),模型组与正常对照组豚鼠肺组织IL-8含量无明显差异。与模型组比较,1,8-桉油精100mg.kg-1能明显减少BALF中白细胞数和嗜酸性粒细胞比例(P<0.05)。致敏豚鼠OVA攻击17h后,模型组豚鼠Raw与正常对照组比较显著升高(P<0.05),模型组豚鼠Cdyn与正常对照组比较有显著性差异(P<0.01),1,8-桉油精100mg.kg-1对MCh引起的Raw的增加有明显的抑制作用,1,8-桉油精10,30和100mg.kg-1对MCh引起的Cdyn降低有明显的改善作用;与模型组相比,1,8-桉油精100mg.kg-1能明显减少BALF中白细胞数和中性粒细胞比例,降低肺组织ECP,IL-8和TNF-α含量(P<0.01);模型组与正常对照组豚鼠肺组织IL-4含量无明显差异;1,8-桉油精30mg.kg-1也能降低哮喘豚鼠肺组织中ECP和TNF-α含量(P<0.01)。结论在哮喘急性发作时,1,8-桉油精通过减少嗜酸性粒细胞,下调嗜酸性粒细胞的活性,从而抑制了哮喘的急性发作。在哮喘迟发相阶段,1,8-桉油精可通过下调IL-8水平,降低TNF-α活性,从而抑制或改善由IL-8水平升高导致的中性粒细胞聚集于支气管肺泡而直接引起的哮喘加重和持续状态。     

甘草次酸衍生物TY501抗肺纤维化作用及机制研究

目的探索甘草次酸衍生物TY501对博莱霉素(BLM)诱导的肺纤维化模型大鼠的抗肺纤维化作用及初步机制。方法将40只大鼠随机分成5组:假手术组、模型组、吡非尼酮组、TY501高剂量组和低剂量组。经气道给予BLM制备大鼠肺纤维化模型,每天灌胃给予受试药。实验结束后,测定肺系数、氧分压(Pa O2),测定BALF中ALB、ALP、LDH以及肺组织中GSH、HYP含量,测定血清Ⅲ型前胶原(PCⅢ)、Ⅳ型胶原(COL4)含量。结果 1肺纤维化早期肺泡炎阶段相关指标:各治疗组与模型组相比,肺系数显著下降(P<0.05)、Pa O2明显升高(P<0.05);与模型组相比,各治疗组大鼠BALF中ALP、ALB以及LDH呈下降趋势(P<0.05);模型组肺组织匀浆中GSH含量反馈性增高,与假手术组相比存在明显差异(P<0.05),各治疗组较模型组含量降低(P<0.05);(2)肺纤维化晚期肺间质纤维化阶段:大鼠肺组织HYP、血清PCⅢ(TGF-β通路指标)、血清COL4(MMPs通路指标)含量,各治疗组较模型组呈下降趋势,差异有显著性(P<0.05)。结论 TY501对肺纤维化治疗存在价值,能够减轻BLM诱导的肺纤维化程度。TY501可能通过阻断TGF-β的作用、抑制MMPs等多途径抑制肺纤维化的发生,减轻肺纤维化症状。     

大鼠肺纤维化过程中转化生长因子-β1在不同肺组织中的表达变化及意义

目的 观察转化生长因子-β(TGF-β<,1>)在博莱霉素(BLM)所诱导的肺纤维化大鼠肺泡灌洗液中的动态变化及其意义.方法 BLM制成大鼠肺间质纤维化模型,观察组13只大鼠气管注入BLM 0.2～0.3ml,对照组5只大鼠气管注入等量生理盐水,并将各组动物处死后提取肺组织及支气管肺泡灌洗液(BALF)进行病理定量分析,检测BALF中TGF-<,1>的水平变化.结果 观察组TGF-β<,1>水平高于对照组,第7、14天比较差异有统计学意义(P<0.01).TGF-β<,1>在观察组成纤维细胞(Fb)和肺泡巨噬细胞(AM)中表达于实验第7天显著增强,于实验第14天达到高峰,至第28天有所降低,但明显高于对照组(P<0.05或P<0.01).结论 TGF-β<,1>在肺纤维化中及其病理发生发展过程中均发挥重要作用.     

天山堇菜提取物基于NLRP3/caspase-1/IL-1β信号通路改善哮喘小鼠气道炎症的作用及机制

目的 探究天山堇菜提取物(Viola tianshanica Maximextract, VTME)改善哮喘小鼠气道炎症的作用及机制。方法 BALB/c雌性小鼠,随机分为正常对照组、卵清白蛋白(OVA)模型组、VTME低、中、高剂量(80、160、320 mg·kg^-1)组、阳性对照药地塞米松组(Dex, 80 mg·kg^-1)组。采用OVA致敏、激发的方法诱导哮喘模型。收集小鼠肺泡灌洗液(BALF)并对炎症细胞进行分类计数;采用ELISA法检测BALF中调节活化的正常T细胞表达和分泌因子(RANTES)、IFN-γ及TNF-α含量,肺组织中TNF-α、MCP-1、IFN-γ、IL-17含量以及血清中IgE、嗜酸性粒细胞趋化因子(eotaxin)水平;采用HE染色观察肺组织病理改变;采用qRT-PCR法和Western blot法分别检测肺组织NLRP3 mRNA表达水平及GSDMD、caspase-1、IL-1β、NLRP3蛋白表达水平。结果 VTME能明显降低哮喘小鼠BALF中各类炎症细胞数量及TNF-α、IFN-γ、Rantes的含量,...     

黄芩总黄酮对博莱霉素致大鼠肺纤维化的干预作用

目的探讨黄芩总黄酮(total flavonoids of scutellariabaicalensis georgi,TFSB)对博莱霉素致大鼠肺纤维化的干预作用。方法气管内注入博莱霉素制备大鼠肺纤维化模型,给予TFSB灌服28 d,每天1次后,计算肺系数、测定肺组织和血清中肺纤维化部分相关生化指标,观察大鼠肺泡炎和肺纤维化程度,RT-PCR检测转化生长因子-β1(TGF-β1)、Smad2、Smad3 mRNA的表达水平,Western blot检测平滑肌肌动蛋白α(α-SMA)与过氧化物酶体增殖因子活化受体γ(PPAR-γ)的蛋白表达水平。结果与模型组相比,TFSB各剂量组大鼠肺组织羟脯氨酸(HYP)含量、血清与肺组织匀浆中丙二醛(MDA)含量降低(P<0.05,P<0.01),血清与肺组织匀浆中谷胱甘肽(GSH)含量、血清超氧化物歧化酶(SOD)活性、血清总抗氧化能力(T-AOC)升高(P<0.05,P<0.01),TFSB各剂量组大鼠肺泡炎和肺纤维化程度降低(P<0.01),RT-PCR和Western blot结果显示:TGFβ-1、Smad2、Smad3 mRNA的表达水平升高(P<0.05),α-SMA蛋白表达水平降低(P<0.05),PPAR-γ蛋白表达水平升高(P<0.05)。结论 TFSB对博莱霉素致大鼠肺纤维化有一定的防治作用,其机制可能与机体内的抗氧化和下调TGF-β1信号通路有关。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

---

Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.