Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats
Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats
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DOI：
10.1152/ajpgi.00061.2004
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发表时间：
2004-12-01
影响因子：
4.5
通讯作者：
Mori, M
中科院分区：
文献类型：
--
作者：
Okajima, K;Harada, N;Mori, M
我们以前曾报道过内皮型一氧化氮合酶（NOS）产生的一氧化氮（NO）可增加肝缺血再灌注（I/R）大鼠内皮型前列环素（PGI（2））的产生。本研究旨在确定中性粒细胞弹性蛋白酶（NE）是否会减少PGI（2）的内皮生成，从而通过减少大鼠肝组织血流量促进I/R诱导的肝损伤的发展。肝组织中6-keto-PGF（1 α）（PGI（2）的稳定代谢物）水平短暂升高，并在再灌注后1小时达到峰值，随后逐渐下降，直至再灌注后3小时。西维来司钠盐酸盐和L-658，758，两种NE抑制剂，减少I/R诱导的肝损伤。这些物质在再灌注后2和3小时抑制肝组织6-keto-PGF（1 α）水平的下降，但在再灌注后1小时不影响水平。这些NE抑制剂显着增加肝组织血流量从1至3小时后再灌注。这两个NE抑制剂抑制肝I/R诱导的中性粒细胞的积累和微血管通透性的增加。两种NE抑制剂诱导的保护作用可被NOS抑制剂硝基-L-精氨酸甲酯或吲哚美辛完全逆转。伊洛前列素是PGI的一种稳定衍生物（2），给药后产生的效应与NE抑制剂类似。这些观察结果强烈表明，NE可能通过减少NO和PGI的内皮产生，导致肝组织血流量减少（抑制血管舒张和诱导活化的嗜酸性粒细胞诱导的微血管损伤），在I/R诱导的肝损伤的发展中发挥关键作用（2）。
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.