Harada N, Okajima K, Liu W, Uchiba M
Department of Laboratory Medicine, Kumamoto University School of Medicine, Japan.
Dig Dis Sci. 2000 Jun;45(6):1210-6. doi: 10.1023/a:1005518523095.
Neutrophil elastase decreases production of PGI2 by cultured endothelial cells. Thus, neutrophil elastase may play an important role in gastric mucosal injury by decreasing the tissue level of PGI2, an important gastric cytoprotective substance. We examined whether activated neutrophils inhibit gastric PGI2 production in rats subjected to water-immersion restraint stress. Gastric 6-keto-PGF1alpha levels were determined by enzyme immunoassay. Gastric mucosal blood flow was determined by laser-Doppler flowmeter. Gastric microvascular permeability was determined by Evans blue leakage. Gastric levels of 6-keto-PGF1alpha were transiently increased 0.5 hr after the stress, followed by a decrease to below baseline at 6 hr, when mucosal blood flow fell to 60% of baseline. Gastric levels of 6-keto-PGF1alpha were significantly higher in animals with nitrogen mustard-induced leukocytopenia than in controls 1 and 6 hr after the stress. In leukocytopenic animals, levels 6 hr after stress were not lower than those preceding stress. Leukocytopenia markedly limited both the decrease in mucosal blood flow and the increase in gastric microvascular permeability. The level of gastric mucosal injury observed 6 hr after the stress was markedly attenuated by leukocytopenia. Pretreatment with neutrophil elastase inhibitors (ONO-5046 and Eglin C) or an anti-P-selectin monoclonal antibody produced effects similar to leukocytopenia. Neutrophil elastase is involved in the stress-induced gastric mucosal injury by decreasing gastric production of PGI2. Thus, pharmacologic inhibition of neutrophil elastase should help to prevent stress-induced gastric mucosal injury.
中性粒细胞弹性蛋白酶可降低培养的内皮细胞中前列环素（PGI2）的生成。因此，中性粒细胞弹性蛋白酶可能通过降低重要的胃细胞保护物质PGI2的组织水平，在胃黏膜损伤中发挥重要作用。我们研究了在水浸束缚应激的大鼠中，活化的中性粒细胞是否会抑制胃PGI2的生成。采用酶免疫测定法测定胃6-酮-前列腺素F1α（6-keto-PGF1α）水平。用激光多普勒血流仪测定胃黏膜血流量。通过伊文思蓝渗漏测定胃微血管通透性。应激后0.5小时，胃6-keto-PGF1α水平短暂升高，随后在6小时时降至基线以下，此时黏膜血流量降至基线的60%。在氮芥诱导的白细胞减少的动物中，应激后1小时和6小时，胃6-keto-PGF1α水平显著高于对照组。在白细胞减少的动物中，应激后6小时的水平不低于应激前。白细胞减少显著限制了黏膜血流量的减少和胃微血管通透性的增加。应激后6小时观察到的胃黏膜损伤程度因白细胞减少而明显减轻。用中性粒细胞弹性蛋白酶抑制剂（ONO-5046和依吉林C）或抗P-选择素单克隆抗体预处理产生了与白细胞减少相似的效果。中性粒细胞弹性蛋白酶通过降低胃PGI2的生成参与应激诱导的胃黏膜损伤。因此，中性粒细胞弹性蛋白酶的药理抑制作用应有助于预防应激诱导的胃黏膜损伤。
