TUMOR NECROSIS FACTOR-INDUCED LUNG INJURY IS NOT MEDIATED BY PLATELET-ACTIVATING FACTOR
TUMOR NECROSIS FACTOR-INDUCED LUNG INJURY IS NOT MEDIATED BY PLATELET-ACTIVATING FACTOR
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DOI：
10.1152/ajplung.1989.257.4.l232
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发表时间：
1989-10-01
影响因子：
--
通讯作者：
VOELKEL, NF
中科院分区：
文献类型：
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作者：
CHANG, SW;OHARA, N;VOELKEL, NF
肿瘤坏死因子（TNF）和血小板活化因子（PAF）都被认为是内毒素休克的介质。由于TNF刺激PAF合成在体外，我们测试的假设，PAF介导TNF诱导的肺损伤在体内使用特定的PAF受体拮抗剂。静脉内输注纯化的人重组TNF导致外周嗜中性粒细胞增多、淋巴细胞减少和血液浓缩，引起盲肠出血性损伤，并增加血栓素B2和6-酮前列腺素F1 α的肺组织水平。此外，血浆谷胱甘肽二硫化物（GSSG），体内氧化应激指数，显着增加。在注射TNF后90分钟从大鼠体内取出的离体灌流肺中测量，TNF（0.01-1 mg/kg）导致肺渗透性-表面积积（PS）呈剂量依赖性增加。[Lung对照组和0.01、0.1和1.0 mg/kg TNF后的PS为0.022 ± 0.001。0.001，0.027。0.002，0.033。0.001和0.036 ±。0.005（对于TNF 0.1和lmg/kg，与对照相比P < 0.05）。预先给予大鼠PAF受体拮抗剂WEB 2086（10 mg/kg）和SRI 63-441（10 mg/kg），其剂量与先前预防内毒素诱导的肺损伤的剂量相同，但对TNF诱导的（0.1 mg/kg）红细胞压积、血浆GSSG或肺PS变化无显著影响。此外，WEB 2086（10 mg/kg）不抑制TNF诱导的（1 mg/kg）淋巴细胞减少症或肺组织类花生酸产物的增加。我们的结论是，TNF导致氧化应激，类花生酸激活，并在大鼠急性肺损伤的机制在很大程度上独立于PAF受体激活。
Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) have been incriminated as mediators of endotoxic shock. Since TNF stimulates PAF synthesis in vitro, we tested the hypothesis that PAF mediates TNF-induced lung injury in vivo using specific PAF receptor antagonists. Intravenous infusion of purified human recombinant TNF resulted in peripheral neutrophilia, lymphocytopenia,and hemoconcentration, caused hemorrhagic injury to the cecum, and increased lung tissue levels of thromboxane B2 and 6-ketoprostaglandin F1.alpha.. In addition, plasma glutathione disulfide (GSSG), an in vivo index of oxidative stress, was significantly increased. TNF (0.01-1 mg/kg) caused a dose-dependent increase in lung permeability-surface area product (PS) measured in isolated perfused lungs removed from rats 90 min after injection of TNF. [Lung PS in controls and after 0.01, 0.1, and 1.0 mg/kg of TNF were 0.022 .+-. 0.001, 0.027 .+-. 0.002, 0.033 .+-. 0.001, and 0.036 .+-. 0.005, respectively (P < 0.05 from control for TNF 0.1 and 1 mg/kg).] Pretreatment of the rats with the PAF receptor antagonists WEB 2086 (10 mg/kg) and SRI 63-441 (10 mg/kg), at doses that previously protected against endotoxin-induced lung injury, did not significantly affect TNF-induced (0.1 mg/kg) changes in hematocrit, plasma GSSG, or lung PS. Moreover, WEB 2086 (10 mg/kg) did not inhibit TNF-induced (1 mg/kg) lymphocytopenia or the increases in lung tissue eicosanoid products. We conclude that TNF causes oxidative stress, eicosanoid activation, and acute lung injury in rats by a mechanism largely independent of PAF receptor activation.