血小板活化因子拮抗剂与急性胰腺炎

血小板活化因子（PAF）是细胞膜表面分泌的生物活性脂质，它通过与细胞膜表面的受体结合而产生生理和病理作用，实验证明PAF参与急性胰腺炎的发生和发展过程，采用PAF拮抗剂在急性胰腺炎的治疗中可发挥重要作用。     

血小板活化因子与急性胰腺炎

血小板活化因子(PAF)是多种细胞产生的生物活化因子,在急性胰腺炎的炎症反应中,起到微循环障碍,氧自由基活化,细胞内领导转导异常,增强其他细胞因子的作用,介导胰腺形态和机能的改变,并在急性胰腺炎并发多器官功能衰竭中起关键作用。血小板活化因子拮抗剂有潜在治疗急性胰腺炎的作用。     

血小板活化因子与急性胰腺炎的发生和治疗

0 引言急性胰腺炎(acute pancreatitis,AP)的发病机制至今仍未完全阐明.自1988年 Rindernecht 提出 AP 的“白细胞系统过度激活学说”后,大量的实验和临床研究证实细胞因子及炎性递质在 AP 的发生发展中起重要作用,其中炎性递质血小板活化因子(platelet-activating factor,PAF)被认为是 AP 时的关键性炎性递质.PAF 是一种以前体形式储于细胞膜内的磷脂分子,为膜脂的结构成分,是强力的脂质炎性递质,其化学结构为1-O-烷基-2-乙酰基-Sn-甘油-3磷脂酰胆碱,M_(?)约为500.PAF 受体(PAF-R)属于 G 蛋白偶联受体家族,主要分布在大多数细胞膜上,包括血小板、白细胞和内皮细胞等,最近又证实细胞内微粒体上也存在 PAF-R,一般均有两个特异性结合位点.通过对 PAF-R 的 cDNA 克隆及表达的研究表明该受体含有342个氨基酸,有7个疏水的跨膜片段,且存在多种亚型.目前应用 RT-PCR 和 Northern Blot 技术可研究各种状态下 PAF-R 的表达及调控.PAF 是通过 PAF-R 发挥其生理和病理作用的,PAF-R 与细胞内信号转导途径相连,激活磷脂酰肌醇、钙信使系统及相关蛋白激酶,使某些蛋白质发生磷酸化并产生相应的生物学效应.     

血小板活化因子与急性胰腺炎

血小板活化因子（PAF）是多种细胞产生的生物活化因子，在急性胰腺炎的炎症反应中，起到微循环障碍，氧自由基活化，细胞内领导转导异常，增强其他细胞因子的作用。介导胰腺形态和机能的改变，并在急性胰腺炎并发多器官功能衰竭中起关键作用。血小板活化因子拮抗剂有潜在治疗急性胰腺炎的作用。     

血小板活化因子与急性胰腺炎

血小板活化因子为一作用广泛磷脂类内源性介质,参与体内多种病理生理反应过程。本文着重讨论血小板活化因子的生物学特性及代谢,并在此基础上阐述其与急性胰腺炎发病的关系,及其介导急性胰腺炎发生与发展的病理生理机制,指出血小板活化因子拮抗剂可望成为治疗急性胰腺炎的一类新型药物。     

血小板活化因子拮抗剂与急性胰腺炎

血小板活化因子(PAF)是细胞膜表面分泌的生物活性脂质,它通过与细胞膜表面的受体结合而产生生理和病理作用。实验证明PAF参与急性胰腺炎的发生和发展过程,采用PAF拮抗剂在急性胰腺炎的治疗中可发挥重要作用。     

重症急性胰腺炎外科治疗有关的认识进展

近年来。随着对于急性胰腺炎研究的深入,外科治疗有关的许多认识取得了极大的进展,治疗方法得以改进,从而使得重症急性胰腺炎的病死率大大降低。现就一些认识进展综述如下。 1 影响外科治疗决策的因素重症胰腺炎病情危重,病程漫长和复杂,并发症多和死亡率高,外科治疗决策受病情的严重程度、病因、病程阶段和先行治疗的影响。 1.1病情严重程度是影响外科治疗决策的最重要因素。急性胰腺炎的病变特点是既有局部病变如胰腺水肿、坏死和胰周浸润、腹水以及坏死组织的感染和局部并发症如胰瘘、胃肠瘘、坏死组织内血管溃破大出血等;又有全身病变如单一或多个器官、系统(心、肺、肾、肝、胃肠等器官和神经、血液、代谢等系统)     

急性重症胰腺炎的心脑肺损伤的诊治

目的 为了解急性重症胰腺炎(SAP)的心脑肺损伤的情况与SAP病死率的关系.方法通过对18年我院肝胆外科收治的96例SAP回顾调查,了解SAP并发休克、ARDS和胰性脑病的发生及治疗情况和SAP死亡的主要因素.结果1982-10/2000-08我科共收治SAP 96例,手术治疗69例(72%),非手术治疗27例(28%),治愈77例(80%),死亡19例(20%),发生各种并发症68例(71%).SAP合并心脑肺损伤33例(34%),死亡16例(17%),SAP无心脑肺损伤63例(66%),死亡3例(3%),两者差异有统计学意义(P＜0.05).SAP伴ARDS 14例(15%),8例ARDS治愈(57%),6例ARDS死亡(43%).SAP伴休克13例(14%),5例休克治愈(38%),8例休克病人死亡(62%).SAP伴胰性脑病13例(14%),6例胰性脑病死亡(46%),7例治愈(54%).7例(7%)同时有两种心脑肺损伤,其中4例SAP同时有休克和ARDS,2例SAP病人有胰性脑病和ARDS,2例SAP合并休克和胰性脑病,死亡5例.结论SAP心肺脑损伤治疗困难,其病死率明显高于无心脑肺损伤的SAP,ARDS、休克和胰性脑病是导致SAP死亡的主要并发症和主要致命因素.     

急性胰腺炎血循环障碍的意义

急性胰腺炎血循环障碍的意义王兴鹏１王国良１巫协宁１袁耀宗２徐家裕２ＳｕｂｊｅｃｔｈｅａｄｉｎｇｓＰａｎｃｒｅａｓ／ｂｌｏｏｄｓｕｐｐｌｙＰａｎｃｒｅａｔｉｔｉｓ／ｅｔｉｏｌｏｇｙ主题词胰腺／血液供给胰腺炎／病因学中国图书资料分类号Ｒ５７６近年研究显...     

The effect of platelet activating factor antagonist (BN 52021) on cerulein-induced acute pancreatitis with reference to oxygen radicals

Acute edematous pancreatitis was induced in Wistar male rats by iv infusion of cerulein (CR) in the dose of 5.10(-6)g.kg-1.h-1 during 3 or 6 h. The effect of BN 52021--platelet activating factor (PAF) receptor antagonist, against this model of disease was examined. BN 52021 was applied iv as a bolus injection in the dose of 5.10(-3)g.kg-1 at 0 time. Treatment with this agent significantly ameliorates cerulein-induced acute pancreatitis in rats. The effect of BN 52021 was expressed by significant reduction of pancreas edema, diminution of hyperamylasemia, lack of superoxide dismutase activity depletion, and inhibition of lipid peroxidation in pancreatic tissue. These changes were accompanied by significant reduction of acinar cells vacuolization and remarkable inhibition of infiltration with inflammatory cells in the interacinar space. We suppose that beneficial effect of BN 52021 against cerulein-induced acute pancreatitis in rats depends on the prevention of inflammatory cells activation and subsequent generation of oxygen radicals within pancreatic tissue.     

The effect of platelet activating factor antagonist (BN 52021) on cerulein-induced acute pancreatitis with reference to oxygen radicals

Acute edematous pancreatitis was induced in Wistar male rats by iv infusion of cerulein (CR) in the dose of 5.10^-6g.kg^-1.h^-1 during 3 or 6 h. The effect of BN 52021—platelet activating factor (PAF) receptor antagonist, against this model of disease was examined. BN 52021 was applied iv as a bolus injection in the dose of 5.10^-3g.kg^-1 at 0 time. Treatment with this agent significantly ameliorates cerulein-induced acute pancreatitis in rats. The effect of BN 52021 was expressed by significant reduction of pancreas edema, diminution of hyperamylasemia, lack of superoxide dismutase activity depletion, and inhibition of lipid peroxidation in pancreatic tissue. These changes were accompanied by significant reduction of acinar cells vacuolization and remarkable inhibition of infiltration with inflammatory cells in the interacinar space. We suppose that beneficial effect of BN 52021 against cerulein-induced acute pancreatitis in rats depends on the prevention of inflammatory cells activation and subsequent generation of oxygen radicals within pancreatic tissue.     

银杏苦内酯B对急性坏死性胰腺炎大鼠肺组织PAF-R表达的影响

目的 观测银杏苦内酯B(BN52021)干预前后ANP大鼠肺组织血小板活化因子受体(PAF-R)mRNA和蛋白质表达的变化,探讨其作用机制.方法 180只大鼠随机分为对照组(NC组)、ANP组和BN52021治疗组(BN组),每组再分为制模后1 h、2 h、3 h、6 h、12 h、24 h 6个亚组.逆行胰胆管内注射牛磺胆酸钠诱导ANP.BN组于制模后15 min股静脉注入BN52021(0.5 mg/100 g体重).各时间点取血检测血清淀粉酶,取胰腺和肺组织行病理学检查,采用RT-PCR和Western blot检测肺组织PAF-R mRNA和蛋白质表达.结果 ANP组和BN组各时点血清淀粉酶均高于NC组(P＜0.05),BN组1 h、2 h、3 h、6 h、24 h时点均低于ANP组(P＜0.05).ANP组和BN组胰腺和肺的病理分值均高于NC组,BN组在3 h、6 h、12 h显著低于ANP组(P＜0.05).ANP组和BN组PAF-R mRNA和蛋白质水平分别在3 h和1 h显著高于NC组,BN组与ANP组相比无显著差异.结论 PAF-R在ANP早期急性肺损伤中起重要作用,BN52021对其表达无显著影响.     

Significance of platelet activating factor receptor expression in pancreatic tissues of rats with severe acute pancreatitis and effects of BN52021

AIM:To investigate the dynamic changes and significance of platelet activating factor receptor (PAF-R) mRNA and protein in pancreatic tissues of rats with severe acute pancreatitis (SAP) and effects of BN52021 (Ginkgolide B). METHODS:Wistar male rats were randomly assigned to the negative control group (NC group),SAP model group (SAP group),and BN52051-remedy group (BN group),and each of the groups was divided into 6 subgroups at different time points after operation (1 h,2 h,3 h,6 h,12 h,and 24 h) (n=10 in each). PT-PCR and Western blot methods were used to detect PAF-RmRNA and protein expression in pancreatic tissues of rats respectively. Pathological examination of pancreatic tissues was performed and the serum amylase change was detected. RESULTS:Serum amylase and pathological results showed the that SAP model was successfully prepared,BN52021 was able to decrease serum amylase,and the pathological ratings in BN group at 3 h,6 h,and 12 h significantly decreased compared with those in the SAP group (8.85 ± 0.39 vs 5.95 ± 0.19,9.15 ± 0.55 vs 5.55 ± 0.36,10.10 ± 0.65 vs 6.72 ± 0.30,P < 0.05). The result of PAF-mRNA showed dynamic changes in SAP and BN groups,which increased gradually in early stage,reached a peak at 3 h (0.71 ± 0.14 vs 0.54 ± 0.14,0.69 ± 0.13 vs 0.59 ± 0.04,P < 0.05),and decreased gradually later. There were significant differences at each time point except 1 h and 2 h,when compared with those in the NC group (0.71 ± 0.14 or 0.69 ± 0.13 vs 0.47 ± 0.10,0.38 ± 0.08 or 0.59 ± 0.04 vs 0.47 ± 0.09,0.25 ± 0.07 or 0.29 ± 0.05 vs 0.46 ± 0.10,0.20 ± 0.06 or 0.20± 0.04 vs 0.43 ± 0.09,P < 0.05),whereas there was no significant difference between BN and SAP groups at each time point. The result of PAF-R protein showed that the change of PAF-R protein in the SAP group and the BN group was consistent with that of PAF-R mRNA. There were significant differences at each time point except 1 h,when compared with those in the NC group (0.90 ± 0.02 or 0.80 ± 0.05 vs 0.48 ± 0.02,1.69 ± 0.06 or 1.58 ± 0.02 vs 0.48 ± 0.03,1.12 ± 0.10 or 0.98 ± 0.03 vs 0.49 ± 0.09,1.04 ± 0.14 or 0.87 ± 0.02 vs 0.52 ± 0.08,0.97 ± 0.16 or 0.90 ± 0.05 vs 0.49 ± 0.10,P < 0.05),whereas there was no significant difference between the BN group and the SAP group. CONCLUSION:PAF-R plays an important role in occurrence and development of SAP. BN52021 exerts biological effects through competitively inhibiting the binding of increased both PAF and PAF-R expression rather than through decreasing PAF-R expression in pancreatic tissues.     

Role of platelet activating factor in pathogenesis of acute pancreatitis in rats.

The importance of platelet activating factor in acute pancreatitis was examined by determining the tissue content of endogenous platelet activating factor and the protective effects of TCV-309, a highly selective platelet activating factor blocker, against caerulein induced pancreatitis in rats. Infusion of caerulein (10 micrograms/kg/h) for five hours resulted in about 70% increase in pancreatic weight, 22% rise in protein content, 50% reduction in tissue blood flow, nine fold increase in tissue level of platelet activating factor and 165% rise in plasma amylase as well as histological evidence of acute pancreatitis. Such infusion of caerulein in chronic pancreatic fistula rats caused a marked increase in protein output from basal secretion of 10 mg/30 minutes to 40 mg/30 minutes in the first hour of infusion followed by a decline in protein output to 15-20 mg/30 minutes in the following hours of the experiment. Exogenous platelet activating factor (50 micrograms/kg) injected ip produced similar alterations in weight, protein content, blood flow, and histology of the pancreas but the increment in serum amylase was significantly smaller and pancreatic secretion was reduced below the basal level. TCV-309 (50 micrograms/kg) given ip before caerulein or platelet activating factor administration significantly reduced the biochemical and morphological alterations caused by caerulein and abolished those induced by exogenous platelet activating factor. These results indicate that platelet activating factor plays an important role in the pathogenesis of acute pancreatitis probably by reducing the blood flow and increasing vascular permeability in the pancreas.     

The effect of platelet activating factor antagonist (BN 52021) on acute experimental pancreatitis with reference to multiorgan oxidative stress

Summary Acute hemorrhagic pancreatitis was induced in Wistar rats using a retrograde intraductal injection of 5% Na-taurocholate. Rats were treated with platelet-activating factor receptor (PAF) antagonist—BN 52021 (5 mg/kg) and sacrificed at 1 and 3 h after induction of acute pancreatitis. Malondialdehyde and sulfhydryl groups concentration were measured in pancreatic, lung, and liver tissue as a parameters of oxidant-antioxidant balance. We have shown that BN 52021 exerts only partial protecting effect against Na-TC-induced AP in rats. The positive effects of BN 52021 were expressed by: (1) Significant reduction of hyperamylasemia accompanied by lower malondialdehyde accumulation in pancreatic tissue; (2) Prevention of sulfl hydryl groups depletion in lung tissue; (3) Diminution of necrotic and inflammatory changes in pancreatic tissue; and (4) Improvement of survival rate. We suggest that these effects may depend on the inhibition of PAF-mediated activation and oxidant generation by phagocytes.     

银杏苦内酯B对急性坏死性胰腺炎大鼠肺组织PAF—R表达的影响

目的观测银杏苦内酯B（BN52021）干预前后ANP大鼠肺组织血小板活化因子受体（PAF-R）mRNA和蛋白质表达的变化,探讨其作用机制。方法180只大鼠随机分为对照组（NC组）、ANP组和BN52021治疗组（BN组）,每组再分为制模后1h、2h、3h、6h、12h、24h6个亚组。逆行胰胆管内注射牛磺胆酸钠诱导ANP。BN组于制模后15min股静脉注入BN52021（0.5mg/100g体重）。各时间点取血检测血清淀粉酶,取胰腺和肺组织行病理学检查,采用RT-PCR和Western blot检测肺组织PAF-R mRNA和蛋白质表达。结果ANP组和BN组各时点血清淀粉酶均高于NC组（P〈0.05）,BN组1h、2h、3h、6h、24h时点均低于ANP组（P〈0.05）。ANP组和BN组胰腺和肺的病理分值均高于NC组,BN组在3h、6h、12h显著低于ANP组（P〈0.05）。ANP组和BN组PAF-R mRNA和蛋白质水平分别在3h和1h显著高于NC组,BN组与ANP组相比无显著差异。结论PAF-R在ANP早期急性肺损伤中起重要作用,BN52021对其表达无显著影响。     

Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis

BACKGROUND: Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. METHODS: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. FINDINGS: Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups. INTERPRETATION: The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis     

重症急性胰腺炎的外科干预策略

重症急性胰腺炎病程中的"2次死亡高峰"是临床治疗中的一大挑战.早期为炎症反应期,应进行以维护器官功能为核心的多学科综合救治;后期以感染性并发症为主,外科医师对于外科干预指征、时机及方式的掌控尤为重要.重症急性胰腺炎的治疗已逐步形成为一个由多学科参与、个体化的综合治疗模式,临床中应建立以疾病为核心的综合救治平台.文章就近...     

重症急性胰腺炎肾功能障碍机制

重症急性胰腺炎 (SAP)是临床常见急腹症 ,常并发多器官功能障碍综合征 (MODS)。其胰外器官损伤中肾功能障碍发生率仅次于肺功能障碍 ,大约在 14 %～ 43 % ,且大多同时伴有其它器官系统的损害。发展至急性肾功能衰竭(ARF)后病死率高达 71%～ 84% ,出现ARF后其它脏器衰竭发生率也