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首页> 外文期刊>American Journal of Physiology >Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats.
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Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats.

机译：中性粒细胞弹性蛋白酶通过减少大鼠前列环素的内皮产生，促进缺血再灌注诱导的肝损伤的发展。

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摘要

We previously reported that nitric oxide (NO) derived from endothelial NO synthase (NOS) increased endothelial prostacyclin (PGI(2)) production in rats subjected to hepatic ischemia-reperfusion (I/R). The present study was undertaken to determine whether neutrophil elastase (NE) decreases endothelial production of PGI(2), thereby contributing to the development of I/R-induced liver injury by decreasing hepatic tissue blood flow in rats. Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of PGI(2), were transiently increased and peaked at 1 h after reperfusion, followed by a gradual decrease until 3 h after reperfusion. Sivelestat sodium hydrochloride and L-658,758, two NE inhibitors, reduced I/R-induced liver injury. These substances inhibited the decreases in hepatic tissue levels of 6-keto-PGF(1alpha) at 2 and 3 h after reperfusion but did not affect the levels at 1 h after reperfusion. These NE inhibitors significantly increased hepatic tissue blood flow from 1 to 3 h after reperfusion. Both hepatic I/R-induced increases in the accumulation of neutrophils and the microvascular permeability were inhibited by these two NE inhibitors. Protective effects induced by the two NE inhibitors were completely reversed by pretreatment with nitro-l-arginine methyl ester, an inhibitor of NOS, or indomethacin. Administration of iloprost, a stable derivative of PGI(2), produced effects similar to those induced by NE inhibitors. These observations strongly suggest that NE might play a critical role in the development of I/R-induced liver injury by decreasing endothelial production of NO and PGI(2), leading to a decrease in hepatic tissue blood flow resulting from inhibition of vasodilation and induction of activated neutrophil-induced microvascular injury.
机译：我们先前曾报道过，源自内皮一氧化氮合酶（NOS）的一氧化氮（NO）增加了大鼠肝缺血再灌注（I / R）的内皮前列环素（PGI（2））的产生。本研究旨在确定中性粒细胞弹性蛋白酶（NE）是否会降低PGI（2）的内皮生成，从而通过减少大鼠肝组织血流量来促进I / R诱导的肝损伤的发展。肝组织中6-酮-PGF（1α）（一种稳定的PGI（2）代谢产物）的水平在再灌注后1 h短暂升高并达到峰值，然后逐渐降低直至再灌注后3 h。 Sivelestat盐酸钠和L-658,758（两种NE抑制剂）减少了I / R引起的肝损伤。这些物质在再灌注后2和3小时抑制了6-酮-PGF（1alpha）肝组织水平的降低，但在再灌注后1 h却没有影响肝组织水平的降低。这些NE抑制剂在再灌注后1至3小时显着增加肝组织血流量。这两种NE抑制剂均抑制了肝I / R诱导的中性粒细胞积聚增加和微血管通透性。两种NE抑制剂诱导的保护作用通过用硝基-1-精氨酸甲酯（NOS抑制剂）或消炎痛进行预处理而完全逆转。伊洛前列素（一种稳定的PGI（2）衍生物）的给药产生的效果类似于NE抑制剂诱导的效果。这些观察结果强烈表明，NE可能通过减少内皮细胞中NO和PGI的产生而在I / R诱导的肝损伤的发展中发挥关键作用（2），从而导致由于抑制血管扩张和诱导而导致的肝组织血流量减少。激活的中性粒细胞诱导的微血管损伤。

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