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Platelet-activating factor (PAF)-induced cardiopulmonary dysfunctions and their reversal with a PAF antagonist (BN 52021) in strain 13 guinea pigs. 13株豚鼠血小板活化因子(PAF)诱导的心肺功能障碍及其与PAF拮抗剂(BN 52021)的逆转
Pub Date : 1993-07-01
C Qian, Z M Guo, C J Peters, C T Liu

Cardiovascular and respiratory responses to a 2 h intravenous constant infusion of PAF (5 and 10 ng/kg per min) were studied in strain 13 guinea pigs. PAF decreased arterial blood pressure, left systolic ventricular pressure, and cardiac output (CO). These cardiovascular changes were dose-dependent. The PAF-induced hypotension returned to a pre-infusion level spontaneously with increased total peripheral resistance despite continuous infusion of PAF. The decreased CO was most striking, and did not recover to pre-infusion levels due to depressed cardiac contractility and impaired ventricular relaxation. Respiratory responses to PAF infusion at these doses were mild and only occurred after serious cardiovascular dysfunctions developed. A higher dose of PAF (20 ng/kg per min) produced drastically decreased CO and dynamic lung compliance (Cdyn), increased pulmonary airway resistance, hypoventilation and apnea within 10-40 min. BN 52021, a PAF receptor antagonist, administered as a single i.v. dose (6 mg/kg) 15 min after PAF infusion, reversed most of cardiopulmonary dysfunctions and prevented death by increasing cardiac contractility, CO, and minute volume from extremely low values. The data suggest that marked cardiopulmonary disturbances induced by intravenous PAF infusion reflects certain pathophysiological mechanisms of diseases that may involve the cellular release of PAF. The administration of BN 52021 or other potent PAF antagonists may be beneficial under these circumstances.

研究了13株豚鼠对2小时静脉持续输注PAF(5和10 ng/kg / min)的心血管和呼吸反应。PAF降低动脉血压、左心室收缩压和心输出量(CO)。这些心血管变化是剂量依赖性的。PAF诱导的低血压自发恢复到输注前水平,尽管持续输注PAF,但总外周阻力增加。CO的降低是最显著的,由于心脏收缩力下降和心室舒张受损,并没有恢复到输液前的水平。这些剂量的PAF输注的呼吸反应是轻微的,仅在发生严重心血管功能障碍后发生。较高剂量的PAF (20 ng/kg / min)会显著降低CO和动态肺顺应性(Cdyn),在10-40分钟内增加肺气道阻力、通气不足和呼吸暂停。PAF受体拮抗剂BN 52021在PAF灌注15分钟后单次静脉注射(6 mg/kg),逆转了大多数心肺功能障碍,并通过增加心脏收缩力、CO和极低的分气量来预防死亡。这些数据提示,静脉输注PAF引起的明显的心肺功能紊乱反映了疾病的某些病理生理机制,这些机制可能与PAF的细胞释放有关。在这种情况下,BN 52021或其他有效的PAF拮抗剂可能是有益的。
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引用次数: 0
The effect of heparin and related proteoglycans on allergen and PAF-induced eosinophil infiltration. 肝素及相关蛋白聚糖对变应原和paf诱导的嗜酸性粒细胞浸润的影响。
Pub Date : 1993-07-01
E A Seeds, J Hanss, C P Page

Exposure of normal guinea pigs to an aerosol of PAF induced a selective increase in the percentage of eosinophils in bronchoalveolar lavage (BAL) fluid 24 h after challenge. Challenge of actively sensitised guinea pigs with an aerosol of ovalbumin also induced a selective increase in the percentage of eosinophils recovered in BAL fluid 24 h post challenge. Pretreatment of actively sensitised guinea pigs or normal guinea pigs with unfractionated heparin significantly reduced such eosinophil infiltration induced by allergen or PAF challenge respectively, although higher amounts of heparin were required to inhibit antigen induced eosinophil infiltration. Similar effects were also observed following treatment with the low molecular weight heparin-like material ORG 10172 but not the anionic molecule polyglutamic acid or high molecular weight dextrans. These results suggest that proteoglycans may possess anti-allergic activity that is not necessarily related to either such molecules being anionic in nature nor to anti-coagulant activity.

正常豚鼠暴露于PAF气溶胶后24小时,支气管肺泡灌洗液(BAL)中嗜酸性粒细胞百分比选择性增加。用卵清蛋白气溶胶刺激主动致敏豚鼠,24小时后BAL液中恢复的嗜酸性粒细胞百分比也有选择性增加。主动致敏豚鼠和正常豚鼠分别用未分离肝素进行预处理,可显著减少由过敏原或PAF刺激引起的嗜酸性粒细胞浸润,但抑制抗原诱导的嗜酸性粒细胞浸润需要更高剂量的肝素。用低分子量肝素样物质ORG 10172治疗后也观察到类似的效果,而阴离子分子聚谷氨酸或高分子量右旋糖酐治疗后则没有。这些结果表明,蛋白多糖可能具有抗过敏活性,而这种活性不一定与这些分子的阴离子性质或抗凝血活性有关。
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引用次数: 0
Labeling of the mitochondrial membrane D-3-hydroxybutyrate dehydrogenase (BDH) with new bifunctional phospholipid analogues. 新的双功能磷脂类似物标记线粒体膜d -3-羟基丁酸脱氢酶(BDH)。
Pub Date : 1993-06-01
B Nasser, C Morpain, J Zirkel, M Seiter, B Laude, W E Trommer, N Latruffe

D-3-Hydroxybutyrate dehydrogenase (BDH), an inner mitochondrial protein, is a well-known phospholipid dependent enzyme. It is a primary dehydrogenase of the oxidative phosphorylation system and is involved in the redox balance of the NAD+/NADH pool. The preparation of fluorescent phospholipids and newly synthesized bifunctional phospholipid analogues (fluorescent and photoactivatable) allowed us to study the structural requirement for lipid activation of the purified enzyme. This paper reports the chemical synthesis protocols to prepare these new phospholipids and their characterization. Illumination experiments of complexes between bifunctional phospholipids and BDH which lead to a cross-linked polypeptide indicate that both the polar head and the hydrophobic moiety of phospholipids interact with BDH. The bifunctional phospholipids were also tested on other lipid-binding proteins, i.e., horse cytochrome c and bovine serum albumin, and demonstrated the promising potential of this new type of photoactivatable molecules which can be followed merely by fluorescence without radioactive labeling.

d -3-羟基丁酸脱氢酶(BDH)是一种线粒体内蛋白,是一种众所周知的磷脂依赖性酶。它是氧化磷酸化系统的初级脱氢酶,参与NAD+/NADH池的氧化还原平衡。荧光磷脂的制备和新合成的双功能磷脂类似物(荧光和光活化)使我们能够研究纯化酶对脂质活化的结构要求。本文报道了这些新型磷脂的化学合成方法及其表征。双功能磷脂与BDH之间形成交联多肽的配合物的照明实验表明,磷脂的极性头和疏水部分都与BDH相互作用。双功能磷脂还在其他脂质结合蛋白(即马细胞色素c和牛血清白蛋白)上进行了测试,并证明了这种新型光活化分子的潜力,它可以仅用荧光跟踪而不需要放射性标记。
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引用次数: 0
MK 287: a potent, specific, and orally active receptor antagonist of platelet-activating factor. MK 287:一种有效的,特异性的,口服活性的血小板活化因子受体拮抗剂。
Pub Date : 1993-06-01
S B Hwang, M H Lam, D M Szalkowski, D E MacIntyre, T J Bach, S Luell, R Meuer, S P Sahoo, A W Alberts, J C Chabala

MK 287 (L-680,573), a tetrahydrofuran analog, potently inhibited [3H]C18-PAF binding to human platelet, polymorphonuclear leukocyte (PMN) and lung membranes with K1 values of 6.1 +/- 1.5, 3.2 +/- 0.7, and 5.49 +/- 2.3 nM, respectively. The inhibitory effects are stereospecific and competitive. The racemate, L-668,750 is less potent and the enantiomer, L-680,574 is 20-fold less potent than MK 287. Inhibition of the binding of [3H]C18-PAF to human PMN membranes by MK 287 was associated with the reduction of the affinity of the radioligand but not the number of the receptor sites. Binding of other radioligands (e.g., LTB4, LTC4, C5a, FMLP) to their specific receptors was unaltered at 1-10 microM MK 287. [3H]MK 287 bound to membranes from human platelets and PMNs: KD = 2.1 +/- 0.6 and 2.9 +/- 1.2 nM, respectively. When examined on isolated human cells, MK 287 potently and selectively inhibited PAF-induced aggregation of platelets in plasma (ED50 = 56 +/- 38 nM) or gel-filtered platelets (ED50 = 1.5 +/- 0.5 nM) and elastase release from PMNs (ED50 = 4.4 +/- 2.6 nM). In studies in vivo, MK 287 inhibited PAF-induced lethality in mice (ED50 = 0.8 mg/kg orally) and PAF-induced bronchoconstriction in guinea pigs (ED50 = 0.18 mg/kg intraduodenally and 0.19 mg/kg intravenously). Inhibition of PAF-induced bronchoconstriction was accompanied by parallel rightward shifts in concentration-response curves for PAF-induced platelet aggregation measured ex vivo.

mk287 (L-680,573)是一种四氢呋喃类似物,可有效抑制[3H]C18-PAF与人血小板、多形核白细胞(PMN)和肺膜的结合,其K1值分别为6.1 +/- 1.5、3.2 +/- 0.7和5.49 +/- 2.3 nM。抑制作用具有立体特异性和竞争性。外消旋体L-668,750的效力较低,对映体L-680,574的效力比MK 287低20倍。MK 287抑制[3H]C18-PAF与人PMN膜的结合与放射性配体的亲和力降低有关,但与受体位点的数量无关。其他放射性配体(如LTB4、LTC4、C5a、FMLP)在1-10微米MK 287下与其特异性受体的结合没有改变。[3H]MK 287与人血小板和PMNs膜结合:KD分别为2.1 +/- 0.6和2.9 +/- 1.2 nM。在分离的人类细胞中,MK 287有效且选择性地抑制了paf诱导的血小板在血浆(ED50 = 56 +/- 38 nM)或凝胶过滤血小板(ED50 = 1.5 +/- 0.5 nM)中的聚集,以及PMNs (ED50 = 4.4 +/- 2.6 nM)中弹性蛋白酶的释放。在体内研究中,mk287抑制paf诱导的小鼠死亡(ED50 = 0.8 mg/kg口服)和paf诱导的豚鼠支气管收缩(ED50 = 0.18 mg/kg十二指肠注射和0.19 mg/kg静脉注射)。对paf诱导的支气管收缩的抑制伴随着paf诱导的血小板聚集的浓度-反应曲线的平行右移。
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引用次数: 0
Lack of increase or reduction in circulating platelet factor 4 and heparin-releasable platelet factor 4 in symptomatic patients with asthma. 有症状哮喘患者循环血小板因子4和肝素释放血小板因子4缺乏升高或降低。
Pub Date : 1993-06-01
G Luzzatto, G Cella, P Boschetto, L Fabbri

We measured circulating platelet factor 4 (PF4) and heparin-releasable platelet factor 4 (HR-PF4) in 13 symptomatic patients suffering from bronchial asthma and in 10 matched normal controls. Neither a difference between patients and controls, nor a correlation between platelet count and HR-PF4 was found (PF4: controls 2.1 +/- 2.9; patients 3.6 +/- 4.4 ng/ml (n.s.); HR-PF4: controls 127 +/- 49, patients 101 +/- 34 ng/ml (n.s.). Therefore, the pathogenetic role of PF4 in the mechanism of bronchial asthma, elsewhere hypothesized, cannot definitely be established.

我们测量了13例支气管哮喘症状患者和10例正常对照者的循环血小板因子4 (PF4)和肝素释放血小板因子4 (HR-PF4)。患者与对照组之间没有差异,血小板计数与HR-PF4之间也没有相关性(PF4:对照组2.1 +/- 2.9;患者3.6 +/- 4.4 ng/ml (n.s);HR-PF4:对照组127 +/- 49,患者101 +/- 34 ng/ml (n.s)。因此,在支气管哮喘的发病机制中,PF4的致病作用,其他地方的假设,不能确定。
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引用次数: 0
Occupancy of platelet receptors for platelet-activating factor in asthmatic patients during an allergen-induced bronchoconstrictive reaction. 哮喘患者在过敏原诱导的支气管收缩反应中血小板活化因子受体的占用。
Pub Date : 1993-06-01
J A Burgers, P L Bruynzeel, H J Mengelers, J Kreukniet, J W Akkerman

The administration of platelet-activating factor (PAF) to human subjects triggers asthma-like responses. We investigated whether a bronchoconstrictive reaction was accompanied by the release of PAF in the circulation of allergic asthmatics. The appearance of PAF was assessed by measuring the number of freely accessible PAF-receptors on platelets in vitro, assuming that the contact between platelets and PAF in vivo would reduce the receptor binding of [3H]PAF in vitro. 16 asthmatics were challenged twice, first with buffer and the next day with allergen. A comparison between receptor binding after provocation with the data of the same patients after allergen challenge revealed a significant difference in PAF binding (P = 0.034), with an average decrease of 14% immediately after allergen challenge followed by a return to control values after about 4 h and a transient increase of 9% at 7 h after provocation. The decrease in accessible PAF receptors was accompanied by a slight decrease in platelet count in peripheral blood between 30 min and 4 h after allergen challenge. The platelet counts recovered to the original values afterwards. These data support the concept that in patients with allergic asthma PAF is secreted in the circulation. The contact between PAF and the platelets may trigger the transient sequestration of platelets, possibly in the lung. Thus, PAF and platelets may contribute to the pathogenesis of allergic asthma.

给人服用血小板活化因子(PAF)会引发类似哮喘的反应。我们研究了过敏性哮喘患者的支气管收缩反应是否伴随着PAF的释放。通过测定体外血小板上可自由接近的PAF受体的数量来评估PAF的出现,假设体内血小板与PAF的接触会减少体外[3H]PAF的受体结合。16例哮喘患者接受两次挑战,第一次用缓冲液,第二天用过敏原。将激射后的受体结合与同一患者激射后的数据进行比较,发现PAF结合有显著差异(P = 0.034),激射后立即平均下降14%,约4小时后恢复到对照值,激射后7小时短暂增加9%。在过敏原攻击后30分钟至4小时内,可达PAF受体的减少伴随着外周血血小板计数的轻微减少。术后血小板计数恢复到原来的水平。这些数据支持了过敏性哮喘患者在循环中分泌PAF的概念。PAF与血小板之间的接触可能触发血小板的短暂隔离,可能在肺中。因此,PAF和血小板可能参与过敏性哮喘的发病机制。
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引用次数: 0
Protective effects of PF-10040 in experimental NSAID-gastritis: role of leukocytes, leukotrienes and PAF. PF-10040对实验性nsaid -胃炎的保护作用:白细胞、白三烯和PAF的作用。
Pub Date : 1993-06-01
J L Wallace, G W McKnight, D Donigi-Gale, T S Shoupe, D N Granger

The effects and mechanism of action of PF-10040, a quinoline derivative, were examined in an experimental model of NSAID-gastritis. Oral pretreatment with PF-10040 dose-dependently reduced the severity of indomethacin-induced gastric damage, with a significant protective effect being observed with doses of 10 mg/kg or greater. The protective effects of this compound persisted for as long as 6 h after administration. PF-10040 also significantly reduced the severity of aspirin- or naproxen-induced gastric damage. At protective doses, PF-10040 did not significantly affect gastric LTB4 synthesis, LTB4-induced granulocyte recruitment to intradermal injection sites, or LTD4-induced changes in gastric blood flow. The free radical scavenging effects of PF-10040 were examined using an in vitro assay, in which it failed to exert significant effects at concentrations of up to 10 mM. PF-10040 had no significant effect on gastric acid secretion. In rat mesenteric venules, PF-10040 inhibited PAF-, but not LTB4-induced leukocyte adherence and emigration. These results suggest that the protective effects of PF-10040 are not attributable to scavenging of free radicals, inhibition of leukotriene synthesis, blockade of LTB4 or LTD4 receptors or inhibition of LTB4-mediated leukocyte endothelial cell adhesion.

采用非甾体抗炎药-胃炎实验模型研究喹啉衍生物PF-10040的作用及机制。口服PF-10040剂量依赖性地降低了吲哚美辛引起的胃损伤的严重程度,当剂量为10 mg/kg或更大时,观察到显著的保护作用。该化合物的保护作用在给药后持续长达6小时。PF-10040还能显著降低阿司匹林或萘普生引起的胃损伤的严重程度。在保护剂量下,PF-10040对胃LTB4合成、LTB4诱导的粒细胞向皮内注射部位募集或ltd4诱导的胃血流变化没有显著影响。通过体外实验检测了PF-10040对自由基的清除作用,结果表明,在高达10 mM的浓度下,PF-10040对胃酸分泌没有显著影响。在大鼠肠系膜小静脉中,PF-10040抑制PAF-,但不抑制ltb4诱导的白细胞粘附和迁移。这些结果表明,PF-10040的保护作用不是由于清除自由基、抑制白三烯合成、阻断LTB4或LTD4受体或抑制LTB4介导的白细胞内皮细胞粘附。
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引用次数: 0
Regulation of phospholipid metabolism by K+ channel blockers and inhibitors of choline transport in the Jurkat T cell line. Relationships with cell proliferation and interleukin-2 production. K+通道阻滞剂和胆碱转运抑制剂对Jurkat T细胞系磷脂代谢的调节。与细胞增殖和白细胞介素-2产生的关系。
Pub Date : 1993-06-01
C Aussel, N Cattan, C Pelassy, B Rossi

In the human T cell line Jurkat, three drugs generally used as effectors of K+ channels, i.e., quinine, 4-aminopyridine and tetraethylammonium, modify phospholipid metabolism. The drugs inhibited the synthesis of both phosphatidylcholine and phosphatidylethanolamine. The mechanism of such inhibition involves a decreased uptake of choline and ethanolamine by the cells, since the three K+ channel blockers were found to be able to competitively inhibit the high-affinity choline/ethanolamine transport system at the membrane level. In contrast, choline transport-inhibitors such as hemicholinium-3, decamethonium and dodecyltrimethylammonium do not inhibit interleukin-2 synthesis and proliferation of the Jurkat T cell line. This indicates that the inhibition of either phosphatidylcholine and/or phosphatidylethanolamine synthesis is not directly implicated in these processes. The inhibition of interleukin-2 synthesis appeared to be mediated through the inhibition of diacylglycerol production induced by T cell activators. A major role for phosphatidylserine in the regulation of T cell activation emerged, since we demonstrated that a panel of K+ channel blockers enhanced the synthesis of this phospholipid mimicking the previously described effect of exogenously added phosphatidylserine in Jurkat cells, i.e., a blockade of interleukin-2 synthesis probably due to a defect in diacylglycerol production.

在人T细胞系Jurkat中,常用的三种K+通道效应器药物奎宁、4-氨基吡啶和四乙基铵可以改变磷脂代谢。药物抑制磷脂酰胆碱和磷脂酰乙醇胺的合成。这种抑制的机制涉及细胞对胆碱和乙醇胺的摄取减少,因为发现三种K+通道阻滞剂能够在膜水平上竞争性地抑制高亲和力的胆碱/乙醇胺运输系统。相比之下,胆碱转运抑制剂如钬-3、十甲基铵和十二烷基三甲基铵不会抑制白细胞介素-2的合成和Jurkat T细胞系的增殖。这表明抑制磷脂酰胆碱和/或磷脂酰乙醇胺合成与这些过程没有直接关系。白细胞介素-2合成的抑制似乎是通过T细胞激活剂诱导的二酰基甘油生成的抑制介导的。磷脂酰丝氨酸在调节T细胞活化中的主要作用出现了,因为我们证明了一组K+通道阻滞剂增强了这种磷脂的合成,模拟了先前描述的Jurkat细胞中外源添加磷脂酰丝氨酸的效果,即可能由于二酰基甘油产生缺陷而阻断白细胞介素-2合成。
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引用次数: 0
Isolation and identification of lysophosphatidylcholines as endogenous modulators of thromboxane receptors. 溶磷脂酰胆碱作为内源性血栓素受体调节剂的分离与鉴定。
Pub Date : 1993-06-01
D W Phillipson, A A Tymiak, J G Tuttle, K S Hartl, T W Harper, M S Bolgar, G T Allen, M L Ogletree

Inhibition of thromboxane receptor radioligand binding to human platelet membranes has been employed as the basis for a radioreceptor assay designed to measure thromboxane receptor binding activity in samples of biological fluids. This method was used during phase 1 clinical evaluation of the thromboxane receptor antagonist SQ 30,741. Frequently, baseline plasma samples as well as plasma samples from placebo-treated subjects showed significant inhibition of radioligand binding in the radioreceptor assay, suggesting the presence of endogenous thromboxane receptor ligands. This receptor binding activity was stable and could be monitored in blood from normal volunteers using a modification of the radioreceptor assay. In order to identify the substance responsible for the observed activity, the activity present in pooled bovine blood was isolated and evaluated by a combination of FAB/MS, 1H-NMR, 13C-NMR and co-injection with reference standards on HPLC. Several endogenous thromboxane receptor ligands were identified as L-alpha-lysophosphatidylcholine (LPC) species. One major species, palmitoyl-LPC, contracted isolated rat aortic spirals, and these contractions could be delayed or prevented, but not reversed by the thromboxane receptor antagonist SQ 29,548. Palmitoyl-LPC slightly potentiated aortic contractions induced by the thromboxane receptor agonist, U-46,619, and diminished in a concentration-dependent manner the antagonism by SQ 29,548 of contractile responses to U-46,619. These findings are consistent with a potential for LPC species to bind and activate thromboxane receptors.

血栓素受体放射配体与人血小板膜结合的抑制作用已被用作放射受体测定的基础,该测定旨在测量生物液体样品中的血栓素受体结合活性。该方法用于血栓素受体拮抗剂SQ 30,741的一期临床评估。通常,基线血浆样本以及安慰剂治疗受试者的血浆样本在放射受体测定中显示出明显的放射性配体结合抑制,表明内源性血栓素受体配体的存在。这种受体结合活性是稳定的,可以在正常志愿者的血液中使用一种改进的放射性受体测定法进行监测。为了鉴定产生活性的物质,采用FAB/MS、1H-NMR、13C-NMR、HPLC联合进样的方法,对混合牛血液中的活性进行了分离和评价。几种内源性血栓素受体配体被鉴定为l - α -溶血磷脂酰胆碱(LPC)种。其中一个主要的物种棕榈酰lpc可以收缩离体大鼠主动脉螺旋,这些收缩可以延迟或阻止,但不能被血栓素受体拮抗剂SQ 29,548逆转。棕榈酰lpc轻微增强了血栓素受体激动剂u - 46619诱导的主动脉收缩,并以浓度依赖性的方式减弱了SQ 29548对u - 46619收缩反应的拮抗作用。这些发现与LPC物种结合和激活血栓素受体的潜力一致。
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引用次数: 0
Involvement of platelet-activating factor (PAF) in endotoxin- or ischaemia-induced intestinal hyperpermeability in the rat. 血小板活化因子(PAF)参与内毒素或缺血诱导的大鼠肠道高通透性。
Pub Date : 1993-05-01
J P Defaux, F Thonier, N Baroggi, A Etienne, P Braquet

We have investigated the influence of BN 50727, a PAF antagonist, and allopurinol, a free radical scavenger, on the damaging effects of ischaemia-reperfusion and endotoxin in the small intestinal mucosa. Using a rat experimental model, we determined the alterations in intestinal permeability and mucosal levels of PAF and lysoPAF following ischaemia or intravenous administration of endotoxin. Both of these treatments increased intestinal permeability and enhanced PAF levels in the mucosa. Preventive oral or intraduodenal administration of BN 50727 reduced both of these effects, by decreasing mucosal PAF formation, probably as a result of neutrophil infiltration and activation reduction. Pretreatment of the rats with allopurinol also resulted in similar protection except that the free radical scavenger was unable to inhibit the increase in PAF levels after ischaemia, suggesting that oxidative reagents are implicated in this pathology to a much greater extent than PAF.

我们研究了PAF拮抗剂bn50727和自由基清除剂别嘌呤醇对小肠黏膜缺血再灌注和内毒素损伤作用的影响。使用大鼠实验模型,我们测定了缺血或静脉注射内毒素后肠通透性和粘膜PAF和lysoPAF水平的变化。这两种治疗方法都增加了肠通透性和粘膜中PAF的水平。预防性口服或十二指肠内给药BN 50727通过减少粘膜PAF的形成来减少这两种作用,这可能是中性粒细胞浸润和活化减少的结果。用别嘌呤醇预处理大鼠也产生类似的保护作用,除了自由基清除剂不能抑制缺血后PAF水平的增加,这表明氧化试剂在这种病理中的作用要比PAF大得多。
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引用次数: 0
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Journal of lipid mediators
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