NLRP3炎性小体与慢性疼痛

慢性疼痛是一类机制复杂的疾病,神经炎症被广泛认为是一种重要的促进机制.而NLRP3炎性小体是模式识别受体激活后形成的一种多蛋白复合体,在接收到外源性和内源性信号后,能促进炎性细胞因子的产生,继而引发神经炎症.众多证据表明,NLRP3炎性小体介导的神经炎症在慢性疼痛的发生发展中起着重要作用,靶向NLRP3可能是一种新颖而...     

IL—10与全身炎症反应综合征

白细胞介素10（IL－10）是一种作用广泛的抗炎细胞因子，在体内炎症反应的调控上发挥着重要的作用。全面深入研究IL－10的功能、产生、调控、抗炎和免疫抑制作用机制，可为最终解决全身炎症反应综合征这一临床难题的探索提供新思路。     

体外循环触发炎症反应的病理生理机制

体外循环诱发的全身炎症反应涉及一系列复杂的急性过程,最终导致白细胞和内皮细胞激活,使不同器官的细胞功能发生障碍。补体系统激活、内毒素血症、缺血再灌注损伤和手术创伤都是体外循环后炎症反应的诱发因素。细胞因子、内毒素、一氧化氮、粘附分子参与了这一过程,其释放和作用的发挥是由细胞内转录因子(核因子κB)介导的。     

炎症因子与椎间盘退变

椎间盘退变是导致腰背痛的主要原因之一。研究证明,肿瘤坏死因子-α、白细胞介素-1β、前列腺素E2、环氧化酶-2、一氧化氮等炎症因子在椎间盘退变进程中起重要作用。它们主要通过引起炎症反应、诱导细胞凋亡等途径促进椎间盘退变,同时各种炎症因子之间还可相互影响。针对性地阻断退变椎间盘中炎症因子的作用途径,抑制其引起的炎症反应,减少椎间盘细胞凋亡,对于延缓椎间盘退变进程,减轻患者临床症状具有重要意义。     

炎症因子与椎间盘退变

椎间盘退变是导致腰背痛的主要原因之一.研究证明,肿瘤坏死因子-α、白细胞介素-1β、前列腺素E2、环氧化酶-2、一氧化氮等炎症因子在椎间盘退变进程中起重要作用.它们主要通过引起炎症反应、诱导细胞凋亡等途径促进椎间盘退变,同时各种炎症因子之间还可相互影响.针对性地阻断退变椎间盘中炎症因子的作用途径,抑制其引起的炎症反应,减少椎间盘细胞凋亡,对于延缓椎间盘退变进程,减轻患者临床症状具有重要意义.     

胆汁白细胞介素6和干扰素γ基因表达在大鼠肝移植急性排斥反应诊断中的意义

目的　探讨肝移植术后急性排斥反应的早期诊断方法。方法　应用RT PCR技术检测大鼠肝移植术后胆汁中的IL 6和IFN γ基因表达 ,以组织病理学作为急性排斥反应的诊断标准 ,将肝移植大鼠分为急性排斥组 (Rt组 )和非急性排斥组 (Rf组 ) ,观察胆汁中IL 6和IFN γ基因表达与急性排斥反应的关系。结果　胆汁中IL 6基因表达在Rt组和Rf组无显著性差异 (P >0 0 5 ) ,而IFN γ基因表达在Rt组和Rf组有显著性差异 (P <0 0 1)。结论　检测胆汁中IFN γ基因表达可能是早期诊断肝移植术后急性排斥反应的一个有效指标 ,而IL 6基因表达则无助于急性排斥反应的诊断。     

抗内毒素Fab'对严重烧伤早期炎症细胞因子的影响

目的 观察抗内毒素Fab'对严重烧伤早期肠源性内毒素血症小鼠肠道损伤的保护作用.方法 采用严重烧伤早期肠源性内毒素血症小鼠模型,分为烧伤组、治疗组及对照组,分别于6、12、24、48 h四个时相点测定血清肿瘤坏死因子(TNF)-α、白细胞介素(IL)-lβ、IL-10的浓度.结果 与正常对照组比较,烧伤后血清TNF-α、IL-1β、IL-10水平增高,差异有统计学意义(P<0.01);治疗组血清TNF-α、IL-1β、IL-10水平较烧伤组显著降低(P<0.01).病理检查结果提示治疗组较烧伤组肠黏膜损伤明显减轻.结论 抗内毒素Fab'能抑制内毒素所诱导的TNF-α、IL-1β产生,同时调节血清中的IL-10水平,减轻内毒素对机体的损害,从而起到对严重烧伤后肠源性脓毒症的防治作用.     

IL-1α和IL-1β在胃癌组织中的表达及其临床意义

目的:通过检测胃癌组织和癌旁组织中白细胞介素-1α(interleukin-1α,IL-1α)和IL-1β的表达水平并分析其与临床病理特征的关系,探讨IL-1α和IL-1β在胃癌发生、发展中的作用。方法:取73例原发性胃癌新鲜的肿瘤和对应远离肿瘤切缘(≥5 cm)的癌旁组织。用RIPA裂解液提取组织中的总蛋白,BCA法测定各组织的蛋白浓度,酶联免疫吸附实验检测组织中IL-1α和IL-1β的含量,细胞因子含量与蛋白浓度的比值为相对细胞因子含量,分析相对细胞因子含量与临床病理资料的关系。结果:胃癌组织中IL-1α的含量较癌旁组织明显升高[(3.450比2.665)ng/g,P<0.05]。结论:炎性因子IL-1α和IL-1β在胃癌的发生发展中有重要作用。     

冠心病患者围手术期炎症反应的研究

目的　探讨体外循环或非体外循环下冠状动脉搭桥和激光心肌打孔治疗冠心病时围手术期炎症因子变化的特点 ,为冠心病围手术期的临床治疗提供参考。　方法　测定 37例冠心病患者及 10例瓣膜病患者术前 ,搭桥或打孔前 ,主动脉开放时 (搭桥结束时或打孔后 )及术后 3、6、2 4h的血浆肿瘤坏死因子 (TNF α)、白介素 6 (IL 6 )、C反应蛋白 (CRP)的水平。　结果　术后患者血浆TNF α、IL 6、CRP水平均有一定程度升高 ,使用体外循环患者TNF α为 (4 10± 0 71)pg/ml,显著高于不使用者的 (1 34± 0 2 9)pg/ml,差异有显著性意义 (P <0 0 5 ) ;两者IL 6差异无显著性意义 (P >0 0 5 )。冠状动脉搭桥患者术后CRP为 (12 89± 0 2 9) μg/ml,高于瓣膜病患者的 (12 0± 0 31) μg/ml,差异有显著性意义 (P <0 0 5 )。　结论　冠心病患者 ,冠状动脉搭桥、激光打孔手术后 ,围手术期均有一定程度的炎症反应 ,体外循环者反应较重     

前炎症因子在脊髓型颈椎病发病早期的表达

目的探讨前炎症因子在脊髓型颈椎病发病的早期变化,探讨前炎症因子与颈椎间盘早期退变的关系。方法收集从2004年5月~2005年1月之间我科收治的20例发病时间<1个月的早期脊髓型颈椎病患者术中取出的32个部分椎间盘髓核组织,与同时期取自死亡时间<24h的新鲜尸体中15个颈部椎间盘组织,分别作为实验组和对照组。采用免疫组化的方法检测其中TNF-α、IL-1β、IL-6的表达阳性例数,采用小鼠抗人TNF-α、IL-1β、IL-6单克隆抗体来检测早期脊髓型颈椎病患者椎间盘组织中的前炎症因子的含量。结果实验组32个颈部突出椎间盘组织中,TNF-α、IL-1β、IL-6表达阳性分别为27例、21例、18例,其中12例为4种细胞因子均表达阳性。对照组15个正常椎间盘组织中表达的阳性细胞较少。应用SPSS11.5统计学软件对实验数据进行统计学分析结果有差异性(P<0.05)。结论突出的颈椎间盘可产生TNF-α、IL-1β、IL-6,阳性细胞主要以成纤维细胞、软骨细胞及淋巴细胞为主,这些细胞因子可能在颈椎椎间盘早期退变中发挥作用。     

The concept of the inflammasome and its rheumatologic implications

The inflammasome is a proteolytic complex that regulates IL1β and IL-18 secretion in macrophages and dendritic cells. Its plays a vital role in the control of the inflammatory and cellular responses to infectious and danger signals and is an essential part of the innate immune system. Four different inflammasomes have been identified so far, and the NLRP3-inflammasome has been the best-studied in relation to human disease. Activation of the NLRP3-inflammasome by microcrystals, such as monosodium urate (MSU) and basic calcium phosphate (BCP) crystals, leads to IL1β release, which in turn triggers local inflammation. Dysfunction of the NLRP3-inflammasome due to mutations of the NLRP3 gene is the cause of the auto-inflammatory syndrome CAPS. The symptoms and signs of inflammation in both conditions respond to IL1 blockade. IL1 inhibitors have also been used successfully in other idiopathic inflammatory diseases, suggesting that dysregulated inflammasome activity contributes to the pathogenesis of multiple diseases, but the precise underlying mechanisms remain to be identified.     

Role of inflammation and inflammasome activation in human bile cast nephropathy

Bile cast nephropathy (BCN) is an underdiagnosed cause of acute kidney injury (AKI). The precise pathogenesis of bilirubin tubular toxicity remains unknown. The aim of this study is to explore the cellular and molecular pathophysiology of human BCN. Paraffin‐embedded sections of renal biopsy tissue from a BCN patient were stained by immunohistochemistry (IHC) for oxidative stress (4‐hydroxynonenal), immune cell subpopulations, including dendritic cells (CD1c), macrophages (CD68) and T cells (CD3), and inflammasome activation by staining for active‐caspase‐1 and the inflammasome adaptor protein, ASC (apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain). Quantitative analyses of IHC staining were compared to healthy renal cortical tissue. We identified yellow to brown granular casts within the BCN case, consistent with the presence of bile pigment. The presence of bile pigment was associated with strong tubular 4‐hydroxynonenal staining intensity, a marker of oxidative stress. Diffuse tubulointerstitial inflammatory cell infiltrate was detected, with elevated CD1c, CD68 and CD3 staining. Foci of inflammasome activity were co‐localized with this intense immune cell infiltration, with increased active‐caspase‐1 and ASC staining. Our findings are the first to suggest that bile casts may lead to oxidative stress and trigger the inflammasome signalling cascade, leading to interstitial inflammation and driving AKI pathobiology. SUMMARY AT A GLANCE The report suggests that bile casts may lead to oxidative stress and trigger the inflammasome signalling cascade, leading to interstitial inflammation and driving bile cast nephropathy pathobiology.     

感染性胆汁中内毒素的变化及意义

目的 通过检测胆管结石病人胆汁中内毒素、内皮素（ET-1）和降钙素基因相关肽（CGRP）的浓度及血浆ALT、AST、TB含量，探讨内毒素在胆管结石胆道感染病人肝脏损伤中的作用。方法选择胆管结石病人50例，按临床感染程度分成择期手术组和急症手术组。另选择单纯性胆囊结石病人20例为对照组。术中采取胆总管胆汁，检测胆汁内毒素、ET-1、CGRP和血浆ALT、AST、TB的含量。结果急症手术组胆汁中内毒素、ET-1、CGRP含量和血浆ALT、AST、TB的含量明显高于择期手术组和对照组。伴随胆道感染程度加重，胆汁中内毒素含量升高，胆汁中ET-1、CGRP含量也升高，肝功能损害加重。结论胆道感染时，胆管结石病人胆汁中内毒素对肝胆系统合成和释放ET-1、CGRP有强烈的刺激作用。胆汁中ET-1和CGRP的生理平衡失调，在胆管结石胆道感染病人肝脏损伤中可能起重要作用。     

高浓度胆汁改变肠上皮细胞氯通道蛋白－2和通透性

目的 观察胆汁对肠上皮细胞氯离子通道和通透性的影响.方法 鼠肠上皮细胞株IEC-6分别与5.0％、1.0％、0.1％胆汁及氯通道激动剂接触.20h后检测跨膜电阻,Western blot分析氯离子通道蛋白-2(CLC-2)和紧密连接闭锁小带－1(ZO-1)表达的变化及各条带的相对灰度值.结果 5.0％浓度组降低跨膜电阻作用最强.5.0％和1.0％组的CLC-2蛋白相对灰度值(0.30±0.05和0.37±0.08)低于对照组(P均＜0.05).5.0％组的ZO-1相对表达量下降.添加氯通道激动剂后,5.0％浓度组的跨膜电阻(451.3±60.5)Ω.cm2及ZO-1相对表达量(0.32±0.04)较对照组上升明显(P均＜0.05).结论 高浓度胆汁破坏肠上皮细胞氯离子通道和紧密连接蛋白,增加上皮细胞通透性.     

High glucose induces toll-like receptor expression in human monocytes: mechanism of activation

OBJECTIVE—Hyperglycemia-induced inflammation is central in diabetes complications, and monocytes are important in orchestrating these effects. Toll-like receptors (TLRs) play a key role in innate immune responses and inflammation. However, there is a paucity of data examining the expression and activity of TLRs in hyperglycemic conditions. Thus, in the present study, we examined TLR2 and TLR4 mRNA and protein expression and mechanism of their induction in monocytic cells under high-glucose conditions.RESEARCH DESIGN AND METHODS—High glucose (15 mmol/l) significantly induced TLR2 and TLR4 expression in THP-1 cells in a time- and dose-dependent manner (P < 0.05). High glucose increased TLR expression, myeloid differentiation factor 88, interleukin-1 receptor–associated kinase-1, and nuclear factor-κB (NF-κB) p65-dependent activation in THP-1 cells. THP-1 cell data were further confirmed using freshly isolated monocytes from healthy human volunteers (n = 10).RESULTS—Pharmacological inhibition of protein kinase C (PKC) activity and NADPH oxidase significantly decreased TLR2 and TLR4 mRNA and protein (P < 0.05). Knocking down both TLR2 and TLR4 in the cells resulted in a 76% (P < 0.05) decrease in high-glucose–induced NF-κB activity, suggesting an additive effect. Furthermore, PKC-α knockdown decreased TLR2 by 61% (P < 0.05), whereas inhibition of PKC-δ decreased TLR4 under high glucose by 63% (P < 0.05). Small inhibitory RNA to p47Phox in THP-1 cells abrogated high-glucose–induced TLR2 and TLR4 expression. Additional studies revealed that PKC-α, PKC-δ, and p47Phox knockdown significantly abrogated high-glucose–induced NF-κB activation and inflammatory cytokine secretion.CONCLUSIONS—Collectively, these data suggest that high glucose induces TLR2 and -4 expression via PKC-α and PKC-δ, respectively, by stimulating NADPH oxidase in human monocytes.The major cause of death in type 1 and type 2 diabetic patients is atherosclerosis (1–3). The pathogenesis of the accelerated atherosclerosis is multifactorial. Inflammation is pivotal in the development of atherosclerosis. Recent studies have shown that diabetes is a proinflammatory state (4–6). We and others have shown that the proinflammatory phenotype in diabetes is characterized by elevated plasma C-reactive protein (CRP), cytokines, chemokines, adhesion molecules, monocytic activity, etc. (4–6). Hyperglycemia contributes to vascular complications of diabetes. High glucose has been shown to induce inflammatory cytokines, chemokines, p38 mitogen-activated protein kinase, reactive oxygen species (ROS), protein kinase C (PKC), and nuclear factor-κB (NF-κB) activity in both clinical and experimental systems (7–12). Several lines of evidence support a role for oxidative stress in the development of diabetes complications (13,14). Diabetic patients have increased O₂⁻ production in monocytes and neutrophils (8,13,15); however, the mechanism of the interactions among these mediators remain unclear.Toll-like receptors (TLRs) recognize conserved pathogen-associated molecular patterns and induce innate immune responses that are essential for host defenses (16). TLRs are activated by both endogenous and exogenous agonists of microbial and nonmicrobial origin. TLR activation by their agonists triggers a signaling cascade, leading to cytokine production and initiation of an adaptive immune response (17). TLR expression is increased in a plethora of inflammatory disorders, including atherosclerosis and diabetes (18–20). Some of the endogenous ligands for TLR2 and TLR4 include high-mobility group B1, biglycan, hyaluronic acid fragments, necrotic cells, serum amyloid A, advanced glycation end products, and extracellular matrix components (18). Among the TLRs, TLR2 and TLR4 play an important role in atherosclerosis. TLR2 and TLR4 bind to components of the Gram-positive and -negative bacteria, respectively (17). They are expressed in multiple cells and tissues, primarily in monocytes. TLR2 and TLR4 expression is increased in atherosclerotic plaque macrophages and in animal models of atherosclerosis (21–25). Plaques of TLR4 knockout mice on a high-fat diet show reduced lesion size, lipid content, and macrophage infiltration (22). TLR2/LDLR^−/− and TLR2/ApoE^−/− double knockout mice are protected from the development of atherosclerosis (24). In addition, total loss of myeloid differentiation factor 88 (MyD88), a common adapter molecule of TLR2 and TLR4 in the cell, results in reduced plaque size, lipid content, inflammation, and plasma interleukin (IL)-1 and tumor necrosis factor-α (TNF-α) (25).The interactions among inflammation, hyperglycemia, and diabetes have clear implications for the immune system. Mohammad et al. (26) reported increased TLR2 and TLR4 expression in type 1 diabetic NOD mice, correlating with increased NF-κB activation in response to endotoxin, and increased proinflammatory cytokines. Kim et al. (27) using TLR2^−/−, TLR4^−/− knockouts, and NOD mice have demonstrated that TLR2 senses β-cell death and contributes to the instigation of autoimmune diabetes. Devaraj et al. (20) showed increased TLR2 and TLR4 expression, intracellular signaling, and TLR-mediated inflammation in monocytes with significant correlation to A1C levels in type 1 diabetic patients. Also, Song et al. (28) reported increased TLR4 mRNA expression in differentiating adipose tissue of db/db mice. Creely et al. (29) showed increased TLR2 expression in the adipose tissue of type 2 diabetic patients with strong correlates to endotoxin levels. These observations taken together suggest a potential role for TLR2 and TLR4 in the pathology of diabetes with limited mechanistic details.However, data examining the mechanism of increased TLR2 and TLR4 expression in diabetes are unknown. Therefore, this study aimed to test the ability of high glucose, one of the key abnormalities of the diabetic condition, to induce TLR expression in human monocytes.     

腹腔镜联合胆道镜治疗胆管结石30例报告

目的:总结应用腹腔镜联合胆道镜治疗胆管结石的体会。方法:回顾分析2002年7月至2005年5月联合应用腹腔镜胆道镜治疗胆管结石的临床资料。结果:胆总管I期缝合11例,1例出现胆漏;T管引流19例,1例术后发生水肿性胰腺炎,经保守治疗均痊愈。结论:腹腔镜联合胆道镜治疗胆管结石患者创伤小,效果好,且安全可靠。     

腹腔镜联合胆道镜治疗胆管结石77例临床体会

目的探讨腹腔镜联合胆道镜治疗胆管结石的可行性及临床体会。方法回顾性分析2011年12月~2013年12月77例在我院腹腔镜联合胆道镜下行胆囊切除、胆总管切开取石+T管引流术的病人术中情况、术后临床恢复情况及疗效,对其手术成功率、手术时间、术中失血量、肠功能恢复时间、住院时间、术后胆漏例数及残石例数等指标进行分析。结果77例患者手术均获成功,无中转开腹,其中63例行T管引流,14例行胆总管一期缝合;手术时间75~170min;术中出血40~150ml;胃肠道功能恢复时间为1~3 d;住院时间4~14 d;术后胆漏1例;经腹腔引流治愈;术后胆道残石3例,术后经T管胆道镜下取尽结石。结论腹腔镜联合胆道镜治疗胆管结石安全有效、可靠,损伤小,恢复快,但术者需要掌握熟练的操作技能。     

EST联合LC治疗胆囊结石胆总管结石

目的：探讨EST联合LC联合治疗胆囊、胆总管结石的可行性及优越性。方法：先行EST（经内镜十二指肠乳头括约肌切开术）取出胆总管结石,再行LC（腹腔镜胆囊切除术）,EST失败或不宜行EST者置ENBD（鼻胆管）再行LC+腹腔镜下胆道探查、胆道镜取石,或开腹行胆道探查术。结果：全组99例,91例LC术前EST取石成功,3例LC术后EST取石成功,3例EST取石失败。2例年龄小于15岁者未行EST改行LC+腹腔镜下经胆囊管胆道镜胆道探查取石。3例EST取石失败,改行腹腔镜下胆道探查胆道镜取石、胆总管一期缝合或T管引流+LC,或开腹胆道探查一期缝合胆总管未置T管（已置ENBD）。无严重并发症,患者均治愈出院。结论：EST联合LC联合治疗胆囊结石胆总管结石是安全、可靠的方法,软硬镜联合充分体现了“微创”治疗的优势。     

腹腔镜联合内镜技术治疗胆囊结石合并胆管结石的临床研究

目的 探讨腹腔镜联合内镜技术在治疗胆囊结石合并胆管结石中的临床应用价值。方法 对2000-2005年应用腹腔镜联合十二指肠镜和纤雏胆道镜治疗的118例胆囊结石合并肝内外胆管结石病人行回顾性分析。其中胆囊结石合并胆总管结石102例，胆囊结石合并胆总管结石和左肝管结石16例。手术方式包括腹腔镜胆囊切除术（LC）联合经内镜括约肌切开术（EST）（49例）、LC联合胆道镜胆道棵查术（62例）、LC联合腹腔镜下左肝叶切除和胆道镜胆管棵壶术（7例）。结果96例病人术后得到随访和定期复查。影像学检查提示无残留结石。术后无严重并发症。4例接受LC结合胆道镜胆道棵查术的病人，中转开腹手术，其中2例由于存在离位胆管狭窄。1例由于肝门部严重粘连水肿，1例由于不易控制的动脉性出血。结论腹腔镜联合内镜治疗胆囊结石合并胆管结石安全、可行、疗效良好，应该在胆系结石病的治疗中得到推广应用。