The role of oral fluvastatin on postoperative peritoneal adhesion formation in an experimental rat model

Background: Postoperative peritoneal adhesions are a momentousness complication after abdominal surgery. Although varied means have been used to prevent and treat adhesions, the effects have not been satisfactory. Fluvastatin, a HMG-CoA reductase inhibitors, exhibits a variety of pharmacological effects. Aim of this study was to evaluate the effect of fluvastatin on postoperative peritoneal adhesion formation.

Methods: Seventy-five male Wistar rats weighting 220–250g were randomly assigned equally to three groups. Group A was given sham operation without treatment, Group B was the model group in which postoperative peritoneal adhesion model was created without medication, and Group C was given oral fluvastatin treatment after postoperative peritoneal adhesion model created. After laparotomy on day 7, macroscopic and pathological assessment were evaluated, IL-1β and t-PA in plasma were performed to measure, and tissue samples were taken to measure MMP-9 protein.

Results: There were significant differences between the groups on adhesion grade (p?p?Conclusion: Oral fluvastatin application could reduce formation of intra-abdominal adhesion by promoting expression of MMP-9 level, lowering the levels of IL-1β and increasing the activity of t-PA after abdominal surgery.     

P物质及其受体在胰腺癌细胞中的表达

目的 了解P物质(SP)、神经激肽-1受体(NK-1R)及中性肽链内切酶(NEP)在胰腺癌细胞中表达。方法应用实时定量逆转录-聚合酶链反应(RQ-RT-PCR)技术,检测正常胰腺、胰腺癌组织和7株胰腺癌细胞中前速激肽原A(PPT-A)、NK-1R和NEP的mRNA表达,应用Westernblot检测NK-1R和NEP的蛋白水平。结果正常胰腺组织PPT-A的mRNA表达水平为0.430 0±0.464 7,胰腺癌组织中为1.790 0±1.833 1(P<0.05);正常胰腺NK-1R的mRNA表达水平为0.088 2±0.086 8,胰腺癌组织中为2.154 5±2.103 1(P<0.01);正常胰腺组织NEP的mRNA表达水平为3.234 7±6.301 0,胰腺癌为8.606 9±8.703 2(P>0.05)。Western Blot结果发现,胰腺癌组织中NK-1R蛋白也过度表达,而NEP的蛋白水平未相应上调。结论 胰腺癌组织中SP和NK-1R都明显上调,而SP的降解酶——NEP未相应上调,这表明胰腺癌组织中SP的产生与灭活的平衡被打破,产生过多的SP,发挥过度的生物学效应。     

黄体酮对雄性切口痛大鼠机械缩足反射阈值、脊髓神经激肽-1受体及血浆P物质表达的影响

目的:观察黄体酮对切口痛大鼠机械缩足反射阈值（paw mechanical withdraw threshold, PMWT）、脊髓神经激肽-1受体（neurokinin-1 receptor, NK-1R）、血浆P物质表达的影响,探讨黄体酮对疼痛影响的可能机制。方法:采用随机数字表法将24只健康成年雄性Wistar大...     

An FDA Approved Neurokinin-1 Receptor Antagonist is Effective in Reducing Intraabdominal Adhesions when Administered Intraperitoneally,But Not Orally

Introduction  Postoperative adhesions pose a continued healthcare problem. We previously demonstrated that intraperitoneal (IP) administration of a neurokinin-1 receptor antagonist (NK-1RA) at surgery reduces intraabdominal adhesions in rats. The NK-1RA aprepitant (Emend™, Merck) is clinically approved for preventing postoperative nausea and vomiting; however, its effects on adhesion formation are unknown. Thus, we determined the effects of IP and oral administration of aprepitant on adhesion formation in a rat model. Methods  Adhesions were surgically induced in rats that were randomized to receive either one or five oral preoperative doses or a single intraoperative IP dose of aprepitant (50 mg/kg). Adhesions were scored at 7 days. In similar experiments using IP dosing, animals were sacrificed at 24 h and peritoneal fluid, and tissue were collected to assess fibrinolytic activity and tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels, respectively. Results  IP aprepitant reduced adhesion formation by 33% (p < 0.05) compared with controls while oral aprepitant had no effect. Compared to controls IP aprepitant reduced tPA activity by 55% (p < 0.05), increased PAI-1 mRNA levels by 140% (p < 0.05), and had no affect on tPA mRNA levels. Conclusion  These data suggest that aprepitant maybe a useful pharmacologic agent for reducing adhesion formation clinically. This work was supported in part, by Merck, Rahway, NJ, USA and by the Smithwick Endowment Fund to the Department of Surgery at Boston University School of Medicine. Presented, in part, at the third Annual Academic Surgical Congress Feb 12–15th, 2008, Huntington Beach, CA, USA An erratum to this article can be found at     

Initiation of a fibrinolytic system in hepatic resection: The roles of tissue-type plasminogen activator and plasminogen activator inhibitor-1

The factors related to the initiation of fibrinolysis, especially with regard to the tissue-type plasminogen activator (tPA) and the plasminogen activator inhibitor-1 (PAI-1), were investigated in 15 patients who underwent hepatic resection, and the findings were compared between those with normal livers and those with diseased livers. It was found that tPA increased before hepatic division, whereas PAI-1 increased after hepatic division and reached a peak immediately following the operation. Plasminogen decreased during hepatectomy, reaching its lowest point on postoperative day 1, and increasing later. Decreased levels of both plasminogen and the ₂-plasmin inhibitor were considered to be partly due to plasmin formation in the blood. Patients with a diseased liver tended to have higher intraoperative values of euglobulin lysis activity and higher postoperative values of plasminogen activator, but significantly lower postoperative values of ₂-plasmin inhibitor than those with a normal liver. The results of this study suggest that activation of the fibrinolytic system occurs both during hepatectomy and in the early postoperative period, and that patients with a diseased liver are prone to develop hyperfibrinolysis during hepatectomy. Moreover, the increased levels of both tPA and PAI-1 can serve as one of the most sensitive markers for the vital reaction against surgical stress.     

In vivo expression of thrombospondin-1 suppresses the formation of peritoneal adhesion in rats

BACKGROUND Formation of intraperitoneal adhesions is one of the major complications after abdominal surgery, which may lead to bowel obstruction. Thrombospondin 1(TSP-1) is an extracellular matrix modulating glycoprotein during tissue regeneration and collagen deposition.AIM To evaluated the therapeutic potential of overexpressed TSP-1 in suppressing pelvic adhesion formations in rat models.METHODS Pelvic adhesion was induced in anesthetized rats by laparotomy cecal abrasion.The animals were randomly assigned to treatment of local application with Seprafilm(an antiadhesive bioresorbable membrane) or adenoviral vectors encoding mouse TSP-1(AdTSP-1) on the surfaces of the injured cecum. The severity of the peritoneal adhesions was evaluated by blinded observers 14 d later.RESULTS Compared with control(no treatment) group, the application of Sperafilm significantly reduced the formation of adhesion band, and local administration of AdTSP-1 on the injured cecum the also attenuated the severity of peritoneal adhesion score. However, systemic delivery of AdTSP-1 did not affect the formation of adhesion.CONCLUSION We conclude that therapeutic approaches in inducing regional overexpression of TSP-1 may serve as alternative treatment strategies for preventing postoperative peritoneal adhesion.     

Heating of carbon dioxide during insufflation alters the peritoneal fibrinolytic response to laparoscopic surgery

Background Laparoscopic surgery is evolving rapidly. It involves the creation of a pneumoperitoneum, mostly using carbon dioxide. Cooling of the peritoneum, due to insufflation, might traumatize the peritoneum and disturb peritoneal fibrinolysis, important in peritoneal healing processes. The current study was performed to elucidate the effects of the temperature of insufflation gas on the peritoneal fibrinolytic response to laparoscopic surgery. Methods Thirty patients scheduled for laparoscopic cholecystectomy were randomized in two groups: one group in which the pneumoperitoneum was created with carbon dioxide at room temperature, and one wherein carbon dioxide at body temperature was used. Peritoneal biopsies were taken at the start and at the end of surgery. Tissue concentrations of tPA antigen, tPA activity, uPA antigen, and PAI-1 antigen were measured using ELISA techniques. Results Peritoneal PAI-1 antigen levels were significantly higher at the end of the procedure in patients operated with carbon dioxide at room temperature (p < .05). A slight, but not significant, decrease in tPA antigen and activity was observed in both groups during the procedure. Peritoneal concentrations of uPa antigen did not change during the procedure. Conclusions The temperature of carbon dioxide used for insufflation of the abdominal cavity affects peritoneal biology. Cooling of the peritoneum by unheated carbon dioxide causes increased peritoneal PAI-1 levels, important in peritoneal healing processes.     

肾病综合征患者血浆中t-PA/PAI-1的变化及糖皮质激素治疗的影响

目的:探讨肾病综合征患者糖皮质激素治疗前后不同阶段组织型纤溶酶原激活物(t-PA)与纤溶酶原激活物抑制物-1(PA1-1)的变化.方法:分为健康对照组、肾病综合征组,采用酶联免疫吸附(ELISA)方法检测血浆中t-PA和PAI-1水平的变化.结果:t-PA的血浆水平在各组之间无统计学差异(P>0.05);PAI-1的水平在肾病综合征组较正常明显升高(P<0.05),激素治疗1周后进一步升高(P<0.05),治疗4周后比1周组有显著下降(P<0.05),但较正常仍高(P<0.05).结论:t-PA/PAI-1平衡的紊乱,可能参与了肾病综合征的损伤机制,经糖皮质激素治疗后高凝状态短期内无明显改善.     

尿激酶型纤溶酶原激活因子及其受体在神经母细胞瘤中的表达及其意义

目的：研究尿激酶型纤溶酶原活因子（uPA)及其受体（uPAR）在神经母细胞瘤（NB）中的表达和意义。方法：应用免疫组织化学方法研究uPA及uPAR在42例神经母细胞瘤中的表达，并应用逆转录-聚合酶链式反应（RT－PCR）方法检测患儿骨髓和外周血中的神经蛋白基因产物9．5（PGP9．5）。结果：uPA及uPAR阳性表达主在进展期肿瘤（均为85．7％）高于局灶期肿瘤（42．9％，28．6％）；预后不良型患儿（91．7％，83．3％）高于预后良好型患儿（均为44．4％），且差异均具有非常显著性（P＜0．01）。患儿骨髓和外周血中PGP9．5阳性检出率在uPA阳性患儿组（60．0％）显著高于uPA阴性患儿组（8．3％，P＜0．01）；uPAR阳性组（57．1％）高于uPAR阴性组（21．4％，P＜0．05）。uPA和uPAR同时阳性的10例患儿，骨髓和外周血中均有PGP9．5阳性表达，而同时阴性的5例患儿中，均未检测到PGP9．5。结论：uPA和uPAR在NB的浸润转移过程中发挥重要的作用。     

PAI－1、t-PA、u—PA、u—PAR在支气管哮喘患者诱导痰中的表达及意义

目的探讨纤维蛋白溶解酶原激活物抑制剂（PAI）－1、组织型纤维蛋白溶解酶原激活物（t—PA）、尿激酶型纤维蛋白溶解酶原激活物（u－PA）及其受体（u－PAR）在支气管哮喘（简称哮喘）患者诱导痰中的表达及意义。方法用ELISA法分别检测29例哮喘急性发作者（发作组）、26例缓解者（缓解组）及15例健康对照者（对照组）诱导痰中PAI－1、t-PA、u—PA和u－PAR的含量,同期测定肺功能（第1秒用力呼气容积占预计值百分比,FEV,％pred）,并进行比较。结果发作组和缓解组诱导痰PAI－1、u—PAR含量[分别为（23．32±2t．64）、（0．766±0．272）μg／L和（17．23±9．40）、（0．700±0．271）μg／L]较对照组[（5．99±5．04）、（O．516±0．197）μg／L3均明显升高（P〈0．05）。而三组诱导痰u—PA、t-PA含量[分别为（O．287±0．235）、（7．68±3．46）μg／L,（0．251±0．276）、（9．88±4．68）μg／L,（0．239±0．322）、（10．35±7．47）μg／L]比较差异均无统计学意义（P〉0．05）。缓解组诱导痰PAI-1与FEV1 % pred呈负相关（r=-0．756,P〈0．01）。缓解组诱导痰PAI-1与病程呈正相关（r=0．454,P〈0．05）。结论PAI-1、u-PAR参与了哮喘气道慢性炎性反应的病理生理过程。     

Comparative Effects of Pulsatile and Nonpulsatile Flow on Plasma Fibrinolytic Balance in Pediatric Patients Undergoing Cardiopulmonary Bypass

In the brain, the components of the fibrinolytic system, tissue plasminogen activator (tPA) and its endogenous inhibitor plasminogen activator inhibitor‐1 (PAI‐1), regulate various neurophysiological and pathological responses. Fibrinolytic balance depends on PAI‐1 and tPA concentrations. The objective of this study is to compare the effects of pulsatile and nonpulsatile perfusion on fibrinolytic balance in children undergoing pediatric cardiopulmonary bypass (CPB). Plasma PAI‐1 antigen and tPA antigen were measured in 40 children (n = 20 pulsatile and n = 20 nonpulsatile group). Plasma samples (1.5 mL) were collected (i) prior to incision, (ii) 1 h after CPB, and (iii) 24 h after CPB. PAI‐1 and tPA levels were measured at each time point. PAI‐1 and tPA levels were significantly increased at 1 h after CPB, followed by a decrease at 24 h. Nonpulsatile but not pulsatile CPB lowered PAI‐1 : tPA ratio significantly at 24 h (median PAI‐1 : tPA ratio 4.63 ± 0.83:1.98 ± 0.48, P = 0.03, for the nonpulsatile group and 4.50 ± 0.92:3.56 ± 1.28, P = 0.2, for the pulsatile group). These results suggest that pulsatile flow maintains endogenous fibrinolytic balance after pediatric cardiopulmonary bypass. Further studies are needed to define the clinical significance of these differences.     

神经激肽 1受体在溃疡性结肠炎组织的表达和临床意义

目的 了解P物质受体-神经激肽1受体（NK-1R）在正常肠管和溃疡性结肠炎组织中的表达，探讨该受体在溃疡性结肠炎的病理生理过程中所起的作用。方法 21个溃疡性结肠炎标本取自因该病并发症而手术的患。正常肠管组织取自24个器官捐献，应用逆转录聚合酶链反应（RT-PCR）技术检测正常肠管和溃疡性结肠炎组织NK-1R的信使核糖核酸（mRNA)水平，应用Western blot技术检测NK-1R的蛋白水平，应用免疫组织化学方法（免疫组化）进行NK-1R的组织学定位。结果 与正常肠管相比，溃疡性结肠炎组织中NK-1RmRNA和蛋白都过度表达，免疫组化检查显示，NK-1R的表达主要位于溃疡性结肠炎组织的肠黏膜表面，黏膜固有层的单核细胞，黏膜下层的动，静脉和纵形与环形肌层等处。结论 溃疡性结肠炎组织中NK-1R的表达水平明显上调，扰乱了神经激肽的作用环节，加剧肠管的病理改变。     

An evaluation of normal saline and taurolidine on intra-abdominal adhesion formation and peritoneal fibrinolysis

BACKGROUND: Intraoperative lavage with normal saline or taurolidine solutions is commonly used in abdominal surgery. For this purpose, normal saline and taurolidine, which may modify the intrinsic fibrinolytic activity of the peritoneum by breaking the peritoneal adhesions, are frequently used. We aimed to evaluate how normal saline and taurolidine affect peritoneal fibrinolysis and adhesion formation. METHODS: A rat model of peritoneal adhesion was used. Control animals received no medication, while normal saline or taurolidine solutions were administered intraperitoneally to the remaining two groups (n = 20 for each group). At postoperative day 10 adhesions were graded, and cardinal parameters of peritoneal fibrinolysis (activities and concentrations of tissue plasminogen activator [tPA], plasminogen activator inhibitor type 1 [PAI-1], and tPA/PAI-1 complex), and hydroxyproline contents were determined in peritoneal tissue samples. RESULTS: Total adhesion scores were decreased in both of the treated groups. Median tissue levels of tPA and tPA activity were higher in the treated groups versus controls. The PAI-1 levels were similar among the three groups. tPA/PAI-1 complex levels were higher in animals that received normal saline and in those treated with taurolidine solution compared with control animals. Peritoneal hydroxyproline levels were similar across the three groups. CONCLUSIONS: Our results suggest that normal saline and taurolidine solution administrations might reduce peritoneal adhesion formation, probably by altering peritoneal fibrinolytic activity.     

精液中PAI-1含量与精液液化的关系

目的测定精液中纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor type-1,PAI-1)的含量,探讨精液的液化机制。方法分别检测门诊患者1h内不液化精液40例(A组)和1h内液化精液30例(B组)中PAI- 1的含量。结果A组PAI-1含量为(10．25±0．75)ng/ml,B组为(6．46±0．37)ng/ml,A组含量显著高于B组,P＜0．01,差异有统计学意义。精液中PAI-1含量与精液液化时间的相关性r=0．362,P＜0．01,呈正相关。结论精液中PAI-1含量升高,可导致精液液化时间延长,可作为检测精液粘稠度的一个相对指标。     

腹腔镜结直肠癌手术对腹膜微结构损伤和纤维溶解分子表达的影响

目的 探讨腹腔镜结直肠癌根治术对腹膜微结构损伤和腹膜纤维溶解分子表达的影响.方法 前瞻性纳入2011年6月至2012年2月间山西省人民医院收治的50例结直肠癌患者,根据患者意愿和医生决策分为腹腔镜组(27例)和开腹组(23例).分别在光镜和电镜下观察术后腹膜微结构损伤程度;采用ELISA法比较手术前后腹膜组织型纤溶酶原激活物t-PA和纤溶酶原激活物抑制因子1(PAI-1)水平的改变.结果 术后标本光镜和电镜观察显示,开腹组肠管浆膜完整性受损、系膜脂肪细胞与间皮细胞覆盖脱失、炎性细胞聚集程度较腹腔镜组严重,两组损伤评分比较的总平均秩次分别为38.22和14.67,差异有统计学意义(P＜0.01).术后网膜组织t-PA、肠管浆膜组织t-PA及PAI-1水平的差异均无统计学意义(均P＞0.05);但腹腔镜组网膜组织中PAI-1水平显著低于开腹组(P＜0.05).结论 相对于开腹手术,腹腔镜结直肠癌根治术腹膜损伤程度较轻,对腹膜纤溶功能的影响较小,有利于防止肠粘连的形成.     

膀胱移行细胞癌Mta-1表达及与ER、u-PA/PAI-1、MVD的相关性研究

目的 研究膀胱移行细胞癌（BTCC）中转移相关基因（Mta-1）表达，分析其与BTCC临床分期、病理分级、转移及复发的关系，探求其可能的分子作用机制。方法 免疫组化方法检测42例BTCC组织Mta-1、雌激素受体（ER）、尿激酶型纤溶酶原激活物（u-PA）、Ⅰ型纤溶酶原激活物抑制物（PAI-1）的表达；CD34标记血管内皮细胞，计数肿瘤组织微血管密度（MVD）；分析Mta-1与BTCC的侵袭转移、血管生成及复发间的关系及Mta-1表达与ER、u-PA、PAI-1表达及MVD的相关性。结果 BTCC Mta-1蛋白表达阳性率为73．8％（31／42），正常膀胱组织无一例阳性表达，P〈0．01；Mta-1蛋白表达阳性率随BTCC临床分期及病理分级的升高而增加，肿瘤复发组（100．0％，15／15）高于无复发组（59．3％，16／27），肿瘤转移组（100．0％，14，／14）高于无转移组（60．7％，17／28）（P〈0．05）。BTCC组织中ER表达阳性率随肿瘤临床分期和组织学分级的升高而降低；有转移者14例均无表达（0．0％），28例未转移者中13例有表达（53．6％）（P〈0．05）；复发组15例中仅1例表达（6．7％），未复发组27例中12例表达（44．4％）（P〈0．05）。BTCC中ER与Mta-1蛋白表达呈负相关（r=-0．739，P〈0．01）。BTCC组织和正常膀胱组织中u-PA表达阳性率分别为59．5％（25／42）和16．7％（2／12），BTCC组明显高于对照组（P〈0．05）。BTCC中u-PA蛋白表达与Mta-1蛋白表达呈正相关（r=0．875），而与PAI-1蛋白表达呈负相关（r=-0．535）。PAI-1表达阳性率对照组（50．0％，6／12）明显高于BTCC组（19．0％，8／42）（P〈0．05）。PAI-1蛋白表达与Mta-1蛋白表达呈负相关（r=-0．706）。BTCC中MVD与Mta-1蛋白表达呈正相关（r=0．683）。结论 Mta-1在BTCC中高度表达，并随肿瘤临床分期和病理分级的升高而增加，与肿瘤的转移及复发密切相关。Mta-1参与BTCC的侵袭、转移，可能与上调u-PA蛋白、下调PAI-1蛋白的表达，促进血管生成有关。Mta-1在BTCC侵袭和转移中的作用亦与ER的负调节机制有关。     

Intraperitoneal administration of methylene blue attenuates oxidative stress, increases peritoneal fibrinolysis, and inhibits intraabdominal adhesion formation

BACKGROUND: Mounting evidence indicates that postoperative oxidative stress may be linked to decreased fibrinolytic activity and, subsequently, the development of intraabdominal adhesions. The goal of this study was to determine if methylene blue, a highly redox active dye that has been shown to inhibit adhesion formation (1) acts as an antioxidant in the postoperative peritoneum, and (2) subsequently affects fibrinolytic activity. MATERIALS AND METHODS: Intraabdominal adhesions were surgically induced in rats receiving methylene blue (30 mg/kg) or vehicle (sterile water) intraperitoneally at surgery. At 24 h and 7 d following surgery, adhesion formation, oxidative stress, and peritoneal fibrinolytic activity were assessed. RESULTS: Methylene blue did not affect adhesion formation at 24 h, but did induce a >50% regression in adhesions after 7 d (P < 0.05). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase (MPO) activities, and 8-isoprostane and thiobarbituric acid-reactive substances were all significantly increased in peritoneal tissue samples (P < 0.05) by 24 h following surgery. Methylene blue inhibited NADPH oxidase by 98% and MPO activity by 78% in the 24 h tissue samples, and blunted the corresponding surgery-induced increases in tissue lipid and protein oxidation. Furthermore, methylene blue significantly increased (P < 0.05) fibrinolytic activity in peritoneal fluid at 24 h. CONCLUSIONS: Methylene blue acts as an antioxidant in this experimental system and may reduce intraabdominal adhesion formation by enhancing peritoneal fibrinolytic activity following surgery.     

白细胞介素1受体拮抗剂等位基因与紫癜性肾炎和IgA肾病的相关联系

目的 为了进一步阐明紫癜性肾炎(HSPN)及IgA肾病(IgAN)二者在发病机理上可能存在的联系。方法 用PCR方法对43例HSPN,97例IgAN患者和98名正常人IL-l受体拮抗剂(IL-lra)基因数目可变的串联重复(VNTR)多态性进行了分析。结果 HSPN患者白细胞介素l受体拮抗剂等位基因(IL IRN 2)的携带率明显高于正常人(P<0.02)和IgAN患者(P<0.05)。在IgAN患者中表现为反复发作性肉眼血尿者其IL IRN 2等位基因的携带率明显高于其它临床类型IgAN患者(P<0.o1),而与HSPN无显著性差异(P>0.05)。结论 HSPN患者IL-lra基因特定的遗传背景在其发病机理中可能起一定作用。IgAN患者中表现为反复发作性肉眼血尿者较其它临床类型IgAN患者与HSPN有更多的相似之处,而ILlRN 2等位基因高携带率可能是二者发病机理的共同点之一。