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Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats.
Am J Physiol Gastrointest Liver Physiol. 2004 Dec; 287(6):G1116-23.AJ

Abstract

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.

Authors+Show Affiliations

Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Kumamoto 860, Japan. whynot@kaiju.medic.kumamoto-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15246960

Citation

Okajima, Kenji, et al. "Neutrophil Elastase Contributes to the Development of Ischemia-reperfusion-induced Liver Injury By Decreasing Endothelial Production of Prostacyclin in Rats." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 287, no. 6, 2004, pp. G1116-23.
Okajima K, Harada N, Uchiba M, et al. Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats. Am J Physiol Gastrointest Liver Physiol. 2004;287(6):G1116-23.
Okajima, K., Harada, N., Uchiba, M., & Mori, M. (2004). Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats. American Journal of Physiology. Gastrointestinal and Liver Physiology, 287(6), G1116-23.
Okajima K, et al. Neutrophil Elastase Contributes to the Development of Ischemia-reperfusion-induced Liver Injury By Decreasing Endothelial Production of Prostacyclin in Rats. Am J Physiol Gastrointest Liver Physiol. 2004;287(6):G1116-23. PubMed PMID: 15246960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats. AU - Okajima,Kenji, AU - Harada,Naoaki, AU - Uchiba,Mitsuhiro, AU - Mori,Masakazu, Y1 - 2004/07/08/ PY - 2004/7/13/pubmed PY - 2004/12/21/medline PY - 2004/7/13/entrez SP - G1116 EP - 23 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 287 IS - 6 N2 - 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. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/15246960/Neutrophil_elastase_contributes_to_the_development_of_ischemia_reperfusion_induced_liver_injury_by_decreasing_endothelial_production_of_prostacyclin_in_rats_ DB - PRIME DP - Unbound Medicine ER -