ROLE OF NEUTROPHIL ELASTASE IN DEVELOPMENT OF PULMONARY VASCULAR INJURY AND SEPTIC SHOCK IN RATS
ROLE OF NEUTROPHIL ELASTASE IN DEVELOPMENT OF PULMONARY VASCULAR INJURY AND SEPTIC SHOCK IN RATS
复制标题
DOI：
10.1097/shk.0b013e3181673e2c
复制
发表时间：
2008-10
期刊：
影响因子：
3.1
通讯作者：
N. Harada;K. Okajima;H. Isobe
中科院分区：
文献类型：
--
作者：
N. Harada;K. Okajima;H. Isobe
前列环素通过抑制给予内毒素的大鼠肺组织TNF水平的增加来预防肺血管损伤和休克。我们以前报道，NO来源于eNOS增加前列环素的内皮生产。由于中性粒细胞弹性蛋白酶已被证明通过抑制NOS活性减少前列环素的内皮产生，我们研究了中性粒细胞弹性蛋白酶抑制剂是否通过抑制给予内毒素的大鼠肺内皮产生前列环素的减少来减少肺血管损伤和低血压。内毒素给药前，用西维来司他或L-658，758（中性粒细胞弹性蛋白酶抑制剂）预处理动物。内毒素给药后，肺组织6-酮-前列腺素F1水平显著升高，随后迅速降至基线水平。西维来司和L-658，758抑制了这些降低，并抑制了给予内毒素的动物的肺组织TNF水平和肺湿干重比的增加。这些抑制剂也减少低血压和抑制肺组织中诱导型NOS的mRNA水平的增加，在动物管理内毒素。中性粒细胞弹性蛋白酶抑制剂的作用完全逆转预处理硝基-L-精氨酸甲酯，NOS的抑制剂，或吲哚美辛，非特异性环氧合酶抑制剂。这些观察结果表明，中性粒细胞弹性蛋白酶可能通过抑制内皮NO的产生来减少肺内皮前列环素的产生，从而通过增加给予内毒素的大鼠肺组织TNF水平来促进肺血管损伤和休克的发展。
Prostacyclin prevents pulmonary vascular injury and shock by inhibiting increases in lung tissue levels of TNF in rats administered endotoxin. We previously reported that NO derived from eNOS increases endothelial production of prostacyclin. Because neutrophil elastase has been shown to decrease endothelial production of prostacyclin by inhibiting NOS activity, we examined whether neutrophil elastase inhibitors reduce pulmonary vascular injury and hypotension by inhibiting the decrease in pulmonary endothelial production of prostacyclin in rats administered endotoxin. Animals were pretreated with sivelestat or L-658,758, neutrophil elastase inhibitors, before endotoxin administration. Lung tissue levels of 6-keto-prostaglandin F1 were markedly increased after endotoxin administration, followed by a rapid decrease to baseline levels. Sivelestat and L-658,758 inhibited these decreases as well as inhibiting increases in lung tissue levels of TNF and lung wet-to-dry weight ratios in animals administered endotoxin. These inhibitors also reduced hypotension and inhibited increases in lung tissue levels of mRNA of the inducible form of NOS in animals administered endotoxin. The effects of neutrophil elastase inhibitors were completely reversed by pretreatment with nitro-l-arginine methyl ester, an inhibitor of NOS, or indomethacin, a nonspecific cyclooxygenase inhibitor. These observations suggested that neutrophil elastase might decrease the pulmonary endothelial production of prostacyclin by inhibiting endothelial NO production, thereby contributing to the development of pulmonary vascular injury and shock through increases in lung tissue levels of TNF in rats administered endotoxin.