Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats.
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.
Okajima
Kenji
K
Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860, Japan. whynot@kaiju.medic.kumamoto-u.ac.jp
Harada
Naoaki
N
Uchiba
Mitsuhiro
M
Mori
Masakazu
M
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002511:Cephalosporins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019743:Chemokines, CXC / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis* / Q000235:genetics; D005998:Glycine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016285:Iloprost / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000503:physiopathology*; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology*; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000637:Transaminases / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D002511:Cephalosporins; D019743:Chemokines, CXC; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D013449:Sulfonamides; D014665:Vasodilator Agents; C065332:L 658758; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; C069195:sivelestat; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000637:Transaminases; D019272:Leukocyte Elastase; D016285:Iloprost; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin