Harada Naoaki, Okajima Kenji, Isobe Hirotaka
Department of Translational Medical Science Research, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
Shock. 2008 Oct;30(4):379-87. doi: 10.1097/SHK.0b013e3181673e2c.
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 F1alpha 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.
前列环素可通过抑制内毒素处理大鼠肺组织中肿瘤坏死因子（TNF）水平的升高来预防肺血管损伤和休克。我们之前报道过，内皮型一氧化氮合酶（eNOS）产生的一氧化氮（NO）可增加内皮细胞前列环素的生成。由于中性粒细胞弹性蛋白酶已被证明可通过抑制一氧化氮合酶（NOS）活性来降低内皮细胞前列环素的生成，因此我们研究了中性粒细胞弹性蛋白酶抑制剂是否可通过抑制内毒素处理大鼠肺内皮细胞前列环素生成的减少来减轻肺血管损伤和低血压。在内毒素给药前，用西维来司他或L-658,758（中性粒细胞弹性蛋白酶抑制剂）对动物进行预处理。内毒素给药后，肺组织中6-酮-前列腺素F1α水平显著升高，随后迅速降至基线水平。西维来司他和L-658,758抑制了这些降低，同时也抑制了内毒素处理动物肺组织中TNF水平的升高以及肺湿重与干重比值的增加。这些抑制剂还减轻了低血压，并抑制了内毒素处理动物肺组织中诱导型NOS mRNA水平的升高。用NOS抑制剂硝基-L-精氨酸甲酯或非特异性环氧化酶抑制剂吲哚美辛预处理可完全逆转中性粒细胞弹性蛋白酶抑制剂的作用。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细胞NO生成来降低肺内皮细胞前列环素的生成，从而通过增加内毒素处理大鼠肺组织中TNF水平导致肺血管损伤和休克的发生。
