肥大细胞在变态反应性炎症发病机制中的核心作用

变态反应性炎症包括支气管哮喘、变应性鼻炎、变应性皮炎、食物及药物过敏等 ,发病率约占全球人口的 30 % - 4 0 %。由于对人类的危害极大 ,所以于 2 0 0 0年末被世界卫生组织定为四大非传染性疾病项目之一。虽然人类对于此类疾病的认识可追溯到 4 80 0年前 ,但对它们本质的认识直到最近 2 0年才逐渐清楚。这主要得益于生命科学各学科的迅猛发展。例如 ,纤支镜应用于哮喘研究使人们认识到哮喘是一种气道的慢性炎症过程。今天 ,通过对各种炎症性细胞及其介质 ,包括上皮细胞、内皮细胞、成纤维细胞和平滑肌细胞在内的传统“结构”细胞及其分泌…     

肥大细胞在类风湿关节炎中作用的研究进展

类风湿关节炎(rheumatoid arthritis, RA)是早期症状以慢性滑膜炎为主的自身免疫性疾病,会导致一系列的关节病变及关节畸形。进行性的残疾和多系统并发症使RA患者的生活质量严重下降。肥大细胞属于固有免疫细胞,可分泌多种生物活性物质,同时也参与固有免疫和适应性免疫应答。肥大细胞在RA发病时会发生特征性增殖,并在其病理生理机制中发挥重要作用。文章归纳总结了肥大细胞在RA发生发展中的作用及其研究进展,为该病发病机制的研究和治疗策略的制定提供一定思路。     

Cyclopamine在佐剂性关节炎大鼠肾脏损伤中的保护作用及机制研究

目的：观察佐剂性关节炎(AA) 大鼠Hedgehog信号通路活化,并探讨Cyclopamine对大鼠关节炎症及肾脏损伤的影响。方法：将40只大鼠随机分为空白组、Cyclopamine组、AA+Cyclopamine组、AA模型组。采用弗氏完全佐剂建立AA大鼠模型,使用Cyclopamine腹腔注射,并通过测量足爪肿胀、全身炎症反应及关节炎症评分的方法进行半定量评价。HE染色检测各组大鼠肾脏病理改变,Western blot检测各组大鼠肾脏Gli1蛋白表达水平,免疫组织化学法染色检测各组大鼠肾脏TNF-α、IFN-γ、IL-6表达。结果：使用Cyclopamine后,能够明显降低AA大鼠足爪肿胀度和改善AA大鼠的关节炎指。与对照组相比,AA模型组大鼠Cr、BUN和脏器系数出现明显升高改变,差异有统计学意义,同时肾脏电镜病理检测发现AA模型组大鼠出现明显的病理改变,AA大鼠使用抑制剂Cyclopamine后能够明显降低肌酐（Cr）、尿素氮（BUN）和脏器系数改变。Western blot检测各组肾脏组织中Gli1的蛋白表达,发现对照组与Cyclopamine组相比Gli1蛋白表达无明显差异,AA模型组及AA+Cyclopamine组Gli1蛋白表达量明显高于对照组,差异有统计学意义,AA+Cyclopamine组与AA模型组相比,Gli1蛋白表达水平明显有下降趋势,差异有统计学意义;免疫组化法检测肾脏组织中促炎因子TNF-α、IFN-γ、IL-6表达改变情况并进行半定量评分,与空白组相比,AA模型组及AA+Cyclopamine组肾脏TN-α、IFN-γ表达明显升高,且使用Cyclopamine后,AA大鼠肾脏TNF-α、IFN-γ表达显著降低,AA模型组肾脏IL-6表达较对照组明显升高。结论：Cyclopamine能够明显改善AA大鼠的关节炎症和肾脏损伤程度,在此过程中Hh通路处于活化状态,并诱导炎性因子表达改变。     

鬼针草总黄酮对大鼠佐剂性关节炎的治疗作用及机制

目的 探讨鬼针草总黄酮(TFB)对大鼠佐剂性关节炎(AA)关节肿胀指数、炎症因子水平、toll样受体4（TLR4）信号转导通路及病理评分的影响。方法 选取50只雄性SD大鼠,随机分为空白组、模型组、TFB(40 mg/kg、80 mg/kg、160 mg/kg)组,每组各10只。比较各组大鼠关节肿胀指数;采用放射免疫法检测血清白细胞介素1β（IL-1β）、肿瘤坏死因子α（TNF-α）的水平;Western blotting检测巨噬细胞中TLR4、核因子κB（NF-κB）的表达水平;HE染色进行大鼠关节病理评分。结果 模型组关节肿胀指数、炎症因子水平、TLR4及NF-κB表达均明显高于空白组,不同剂量的TFB组（40 mg/kg、80 mg/kg、160 mg/kg）关节肿胀指数、炎症因子水平、TLR4、NF-κB表达及病理评分均显著低于模型组(P<0.05),且TFB剂量越大,所有指标表达水平越低(P<0.05)。结论 TFB对AA大鼠具有治疗作用,其作用机制可能与降低关节肿胀指数及炎症因子水平、抑制TLR4和NF-κB表达、阻碍血管翳形成有关。     

佐剂性关节炎大鼠滑膜巨噬细胞在关节破坏中的作用

目的:了解佐剂性关节炎(AA)大鼠滑膜巨噬细胞在关节破坏中的作用。方法:采用大鼠尾部皮内注射完全福氏佐剂建立AA模型,不同时点处死后后肢关节X线照片并进行放射学指数(RI)评分,膝关节滑膜石蜡切片HE染色和ED₁免疫组化染色及计数,分析RI与滑膜衬里层细胞层数及ED⁺₁细胞数的相关性。结果:AA大鼠滑膜衬里层细胞层数、衬里层及衬里下层ED⁺₁细胞数与RI水平呈显著正相关。结论:滑膜巨噬细胞在AA大鼠关节破坏中起重要作用。     

静脉注射丙种球蛋白对佐剂关节炎的作用

观察静脉注射丙种球蛋白 (IVIG)对佐剂关节炎的作用及其机制。建立佐剂关节炎模型 ,分别在接种完全弗氏佐剂 (CFA)后第 8天 (IVIG1组 )或第 15天 (IVIG2组 )尾静脉注射IVIG ,10mL/ (kg·d) ,疗程均为 14d。第 6周末处死大鼠 ,观察关节病理改变 ,免疫组化检测滑膜组织中TNF α和血管内皮生长因子 (VEGF)的表达。结果显示TNF α、VEGF阳性细胞数均与关节病理积分呈正相关 ,接种CFA后IVIG1组和IVIG2组尾静脉注射IVIG均可抑制TNF α和VEGF的表达 ,减轻滑膜炎症。表明IVIG可通过抑制滑膜组织中的TNF α和VEGF蛋白表达 ,减轻滑膜炎症。     

TNF-α在骨质疏松性疼痛中的作用

目的:探讨肿瘤坏死因子α(TNF-α)在骨质疏松性疼痛中的作用。方法:40只5月龄Sparague-Dawley(SD)雌性大鼠随机分为假手术组(sham组,16只)和去卵巢组(Ovx组,24只)。Ovx术后第5周开始应用上下法(up-down method)和撤尾法(tail withdrawtest)对2组大鼠进行疼痛行为测量,每周1次。术后第8周每组分别杀死8只大鼠,取腰5背根神经节,用免疫荧光方法检测腰5背根神经节中TNF-α的表达。Ovx组剩余的16只大鼠再随机分成Ovx-1组和Ovx-2组,其中Ovx-2组予腹腔注射TNF-α合成抑制剂沙利度胺(50mg/kg,每天1次);Ovx-1组和sham组则分别注射等量的生理盐水。继续应用上下法和撤尾法对sham、Ovx-1、Ovx-2组进行疼痛行为测量至术后10周结束。结果:(1)术后第5、6、7、8周,Ovx组机械刺激疼痛阈值及热刺激的撤尾潜伏期均显著低于sham组(P0.01);术后第9、10周,注射沙利度胺的Ovx-2组其机械刺激疼痛阈值和热刺激的撤尾潜伏期与sham组无显著差别(P0.05),而显著高于Ovx-1组(P0.05)。(2)Ovx组腰5背根神经节中TNF-α的表达显著高于sham组,差别显著(P0.01)。结论:TNF-α可能在绝经后骨质疏松性疼痛中发挥重要作用,并可能通过作用于背根神经节引起痛觉敏感,抑制TNF-α的合成可缓解绝经后骨质疏松性疼痛。     

肥大细胞在肺部感染性疾病中的作用

肺部肥大细胞主要分布于肺部血管周围,支气管以及粘膜组织。病原体入侵时,肥大细胞通过胞吞作用直接摄取病原体,同时通过激活自身受体促进下游细胞介质的释放,增强炎性细胞的募集,直接和间接杀伤病原体。此外,肺部肥大细胞参与病原体的抗原递呈,介导细胞和体液免疫。肥大细胞对肺部病原体感染具有重要的保护功能。     

薏苡仁及其组分对佐剂性关节炎大鼠抗炎镇痛的作用及其机制

背景：类风湿性关节炎是一种自身免疫性疾病,以关节炎症及疼痛为主要症状,属中医痹症范畴。以薏苡仁为主的方剂为除痹经典方,但起效组分及其机制尚不清楚。目的：探讨观薏苡仁及其组分对佐剂性关节炎大鼠的抗炎作用及其作用机制,寻找薏苡仁抗炎的关键组分。方法：64只SPF级Wistar大鼠随机分为正常组、模型组、地塞米松组、薏苡仁水煎液组、薏苡仁挥发油组、薏苡仁蛋白组、薏苡仁多糖组、薏苡仁淀粉组,除正常组外,其余各组大鼠右后足足跖皮下注射完全弗氏佐剂0.2 mL诱导佐剂性关节炎模型,造模后第14天开始灌胃给予相应药物;对照组、模型组给予同体积生理盐水,连续给药18 d。观察各组大鼠一般情况和体质量变化,周长法测量足肿胀度,检测胸腺和脾指数,酶联免疫吸附法检测外周血清白细胞介素1、白细胞介素6和肿瘤坏死因子α质量浓度,苏木精-伊红染色法观察大鼠膝关节病理改变。结果与结论：(1)与正常组相比,造模后各组大鼠的关节肿胀程度达到高峰期,且体质量显著升高(P <0.05);与模型组比较,薏苡仁水煎液组、薏苡仁挥发油组大鼠体质量显著降低(P <0.05);(2)与模型组比较,地塞米松组、薏苡仁挥发油...     

Mast cells: Versatile gatekeepers of pain

Mast cells are important first responders in protective pain responses that provoke withdrawal from intense, noxious environmental stimuli, in part because of their sentinel location in tissue–environment interfaces. In chronic pain disorders, the proximity of mast cells to nerves potentiates critical molecular cross-talk between these two cell types that results in their synergistic contribution to the initiation and propagation of long-term changes in pain responses via intricate signal networks of neurotransmitters, cytokines and adhesion molecules. Both in rodent models of inflammatory pain and chronic pain disorders, as well as in increasing evidence from the clinic, it is abundantly clear that understanding the mast cell-mediated mechanisms underlying protective and maladaptive pain cascades will lead to improved understanding of mast cell biology as well as the development of novel, targeted therapies for the treatment and management of debilitating pain conditions.     

Role of mast cells in experimental anti-glomerular basement membrane glomerulonephritis

Recently, divergent reports on the role of mast cells (MC) in different glomerular diseases have brought our attention to their role in an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Genetically MC-deficient Kit(W)/Kit(W-v) mice, MC-reconstituted Kit(W)/Kit(W-v) mice and Kit+/+ control mice were subjected to anti-GBM GN. Kit(+/+) mice developed moderate proteinuria and glomerular damage following the induction of anti-GBM nephritis. In contrast, proteinuria and glomerular damage were dramatically increased in MC-deficient Kit(W)/Kit(W-v) mice. MC-reconstituted Kit(W)/Kit(W-v) mice showed proteinuria and glomerular damage comparable to Kit+/+ mice. A significant increase in infiltrating T cells and macrophages was detected in MC-deficient Kit(W)/Kit(W-v) mice as compared to Kit+/+ control mice and MC-reconstituted Kit(W)/Kit(W-v) mice. Accordingly, we observed an increase of TGF-beta1 mRNA in kidneys from Kit(W)/Kit(W-v) mice. Interestingly, we did not detect MC in the kidney using either Giemsa staining or RT-real-time PCR, but MC were found in the regional lymph nodes. Finally, mortality of Kit(W)/Kit(W-v) mice was significantly increased after the induction of anti-GBM GN due to uremia. Our report provides the first direct evidence that MC are protective in anti-GBM GN, possibly by modulating the influx of effector T cells and macrophages to inflammatory sites in the kidney.     

大鼠舌组织中肥大细胞与肽能神经纤维的分布

目的探讨舌组织内肥大细胞与肽能神经的关系及其功能意义。方法采用甲苯胺蓝染色和免疫组织化学ABC染色法对10只Wistar大鼠舌组织进行SP、VIP和NPY染色。结果经与甲苯胺蓝邻片对比观察,舌组织内肥大细胞分别呈SP、VIP和NPY免疫反应性;在舌组织固有层及肌间结缔组织中还分布有丰富的SP、VIP和NPY免疫反应阳性纤维;在肽能神经纤维附近或周围可见有免疫反应阳性的肥大细胞,这些肥大细胞与神经纤维紧密相靠或接触。结论 大鼠舌组织内肥大细胞和神经纤维分别呈SP、VIP和NPY免疫反应性,提示肥大细胞与周围神经无论是在形态还是在功能上有着密切的联系。     

Role of nitric oxide in mast cells

Mast cells (MC) are important effector cells in allergic disorders. Recenty, the role of MC in innate and adaptive immunity is gaining prominence. Nitric oxide is an important signaling molecule and its production in mast cell has been reported widely. However, controversy exists about whether MC produce NO. This review addresses the role of NO in MC biology and the reasons behind the controversy and discusses effects of NO in regulation of MC phenotype and function.     

肥大细胞在支气管哮喘中的研究进展

支气管哮喘(哮喘)是呼吸系统的常见病和多发病,肥大细胞是其主要的反应细胞,目前关于肥大细胞在哮喘中作用的研究取得了新的进展,特别是肥大细胞蛋白酶及其抑制剂的深入研究和哮喘患者气道平滑肌束中肥大细胞数量明显增加并呈脱颗粒状态的发现,引起学者们极大的关注,本文将就肥大细胞在哮喘中的研究进展进行综述。     

Long-term study of TNBS-induced colitis in rats: Focus on mast cells

Objective and design To investigate the severity and duration of colitis induced by two different doses of 2,4,6-trinitrobenzenesulfonic acid (TNBS) and the changes in mast cell number in acute inflammation and in the recovery process of colitis. Methods Colitis was induced in rats by an enema of TNBS (10 or 30 mg) in 25% ethanol. Macroscopic and histologic changes of the colon, colon weight and mast cell counts were examined at various times (7, 30 and 60 days) after colitis induction. Results TNBS induced a colonic damage which was dose-related for both severity and time necessary to complete recovery. On day 7 after colitis induction 10 mg TNBS induced macroscopic and microscopic alterations of colonic architecture that completely resolved at day 60. By contrast, 30 mg TNBS induced massive necrosis, thickening of the colon, severe histologic changes that were only partially reversed after two months. Mast cell number in the submucosa and muscularis propria decreased significantly in the acute phase of inflammation (7 days) and slowly increased thereafter, reaching a maximum level (up to about 5-fold) at day 60 after both doses of TNBS. Conclusions Present data confirm the ability of TNBS to induce in rats damage to the colon that was dose-dependent for severity and duration. Moreover, these data unravel a different role of mast cells in TNBS-induced colitis: an early degranulation in the acute phase of inflammation and a subsequent accumulation of mast cells in the late phase of the disease, associated with tissue repair. Received 31 January 2006; returned for revision 29 April 2006; accepted by A. Falus 3 May 2006     

Activation of sensory nerves participates in stress-induced histamine release from mast cells in rats

To elucidate the mechanism by which stress induces rapid histamine release from mast cells, Wistar rats, pretreated as neonates with capsaicin, were subjected to immobilization stress for 2 h, and histamine release was measured in paws of anesthetized rats by using in vivo microdialysis after activation of sensory nerves by electrical or chemical stimulation. Immobilization stress studies indicated that in control rats stress induced a 2.7-fold increase in the level of plasma histamine compared to that in freely moving rats. Whereas pretreatment with capsaicin significantly decreased stress-induced elevation of plasma histamine. Microdialysis studies showed that electrical stimulation of the sciatic nerve resulted in a 4-fold increase of histamine release in rat paws. However, this increase was significantly inhibited in rats pretreated with capsaicin. Furthermore, injection of capsaicin into rat paw significantly increased histamine release in a dose-dependent manner. These results suggest that activation of sensory nerves participates in stress-induced histamine release from mast cells.     

A crucial role for macrophages in the pathology of K/B x N serum-induced arthritis

Autoantibodies in the form of immune complexes are known to be crucial mediators in initiating inflammation in a variety of autoimmune diseases. This has been well documented in the anti-collagen II antibody-induced arthritis animal model for a long time now. Recently, in the K/B x N mouse model (the F1 of the TCR-transgenic KRN and the diabetic NOD mice), anti-glucose-6-phosphate isomerase (GPI) autoantibodies have been shown to induce arthritis. Experimental work in the K/B x N model demonstrated key roles of autoantigenic immune complexes activating the alternative pathway of complement, the subsequent association with C5aR and Fc gammaRIII-mediated cell activation and production of the inflammatory cytokines IL-1 and TNF-alpha, finally leading to joint destruction. The presence of high amounts of inflammatory cytokines and matrix-degrading proteases at sites of inflammation obviously put the cytokine-producing macrophages as the next target for investigation in this model. Here, we show that mice depleted of macrophages by clodronate liposome treatment are completely resistant to K/B x N serum-induced arthritis. Reconstituting clodronate liposome-treated mice with macrophages from naive animals could reverse this resistance. Also, we found that deficiencies in the Wiskott-Aldrich syndrome protein and CD40, which are both implicated in macrophage activation, chemotaxis and phagocytosis, are not essential in serum-induced arthritis. Mast cell degranulation was seen in arthritogenic serum-treated mice even in the absence of macrophages, possibly suggesting that mast cell degranulation/activation acts hierarchically before macrophages in the inflammatory cascade of anti-GPI antibody-induced arthritis.     

巨噬细胞对小鼠骨髓肥大细胞增殖的调节作用

本文应用体外细胞共培养和免疫细胞化学技术观察小鼠腹腔巨噬细胞对小鼠骨髓来源的肥大细胞生长增殖的影响。结果表明小鼠腹腔巨噬细胞对肥大细胞的生长增殖具有一定的促进作用，不仅表现在肥大细胞数量的增加，而且也能促使肥大细胞进入Ｓ期的比例增加（二者数值均为对照值的２－３倍）；还发现上述促增殖作用与巨噬细胞和肥大细胞的浓度有关。文中提出了巨噬细胞促使肥大细胞增殖的最适浓度范围以及两种细胞浓度比值的最佳范围，并