GASTRIC-ULCERATION INDUCED BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS IS A NEUTROPHIL-DEPENDENT PROCESS
GASTRIC-ULCERATION INDUCED BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS IS A NEUTROPHIL-DEPENDENT PROCESS
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DOI：
10.1152/ajpgi.1990.259.3.g462
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发表时间：
1990-09-01
影响因子：
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通讯作者：
GRANGER, DN
中科院分区：
文献类型：
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作者：
WALLACE, JL;KEENAN, CM;GRANGER, DN
在大鼠实验中验证了中性粒细胞在非甾体抗炎药（NSAIDs）致胃溃疡发病机制中起重要作用的假设。用山羊培养的大鼠中性粒细胞抗体治疗的中性粒细胞减少的大鼠对吲哚美辛或萘普生的胃损伤作用的抵抗力明显高于对照大鼠或用正常山羊血清预处理的大鼠。中性粒细胞减少大鼠损伤的减轻不是由于抗中性粒细胞血清对胃酸分泌的影响，也不是由于吲哚美辛或萘普生抑制前列腺素合成的能力。吲哚美辛或萘普生对正常大鼠和中性粒细胞减少大鼠的胃环氧化酶活性均有95%的抑制作用。甲氨蝶呤治疗大鼠产生循环中性粒细胞数量也导致对吲哚美辛引起的胃损伤的易感性显著降低。由于循环中性粒细胞的激活在给药后胃糜烂的发展中似乎很重要，并且在给药后15分钟内观察到血管内皮完整性的显着变化（Monastral Blue染色），我们研究了白三烯（lt）和血小板活化因子（PAF）可能参与吲哚美辛诱导的溃疡发病机制的可能性。吲哚美辛给药后胃LTB4合成未见变化。用LTD4拮抗剂或PAF拮抗剂预处理对吲哚美辛引起的胃损伤程度无显著影响。这些结果提示中性粒细胞在非甾体抗炎药诱导的胃溃疡的发病机制中起重要作用。中性粒细胞可能在给药后早期发生的血管损伤中起重要作用。
The hypothesis that neutrophils play an important role in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs) was tested in rats. Rats made neutropenic by prior treatment with an antibody to rat neutrophils raised in goat were found to be significantly more resistant to the gastric-damaging actions of indomethacin or naproxen than were control rats or rats pretreated with normal goat serum. The reduction of damage in neutropenic rats was not due to effects of the antineutrophil serum on either gastric acid secretion or the ability of indomethacin or naproxen to inhibit prostaglandin synthesis. Gastric cyclooxygenase activity was inhibited by >95% in both normal and neutropenic rats that received indomethacin or naproxen. Production of circulating neutrophil number by treating rats with methotrexate also resulted in a significant reduction in the susceptibility to gastric damage induced by indomethacin. Since activation of circulating neutrophils appeared to be important in the development of gastric erosions after administration of indomethacin, and in the significant changes in vascular endothelial integrity (Monastral Blue staining) observed within 15 min of indomethacin administration, we investigated the possibility that leukotrienes (LTs) and platelet-activating factor (PAF) might be involved in the pathogenesis of indomethacin-induced ulceration. Changes in gastric LTB4 synthesis were not observed after indomethacin administration. Pretreatment with either an LTD4 antagonist or a PAF antagonist was without significant effect on the extent of gastric damage induced indomethacin. These results suggest an important role for neutrophils in the pathogeneisis of NSAID-induced gastric ulceration. Neutrophils may be important in the vascular injury that occurs early after administration of these compounds.