Neutrophil elastase contributes to the development of ischemia/reperfusion-induced liver injury by decreasing the production of insulin-like growth factor-I in rats.
Neutrophil elastase (NE) decreases the endothelial production of prostacyclin (PGI(2)) through the inhibition of endothelial nitric oxide synthase (NOS) activation and thereby contributes to the development of ischemia/reperfusion (I/R)-induced liver injury. We previously demonstrated that calcitonin gene-related peptide (CGRP) released from sensory neurons increases the insulin-like growth factor- I (IGF-I) production and thereby reduces I/R-induced liver injury. Because PGI(2) is capable of stimulating sensory neurons, we hypothesized that NE contributes to the development of I/R-induced liver injury by decreasing IGF-I production. In the present study, we examined this hypothesis in rats subjected to hepatic I/R. Ischemia/reperfusion-induced decreases of hepatic tissue levels of CGRP and IGF-I were prevented significantly by NE inhibitors, sivelestat, and L-658, 758, and these effects of NE inhibitors were reversed completely by the nonselective cyclooxygenase inhibitor indomethacin (IM) and the nonselective NOS inhibitor L-NAME but not by the selective inducible NOS inhibitor 1400W. I/R-induced increases of hepatic tissue levels of caspase-3, myeloperoxidase and the number of apoptotic cells were inhibited by NE inhibitors, and these effects of NE inhibitors were reversed by IM and L-NAME but not by 1400W. Administration of iloprost, a stable PGI(2) analog, produced effects similar to those induced by NE inhibitors. Taken together, these observations strongly suggest that NE may play a critical role in the development of I/R-induced liver injury by decreasing the IGF-I production through the inhibition of sensory neuron stimulation, which may lead to an increase of neutrophil accumulation and hepatic apoptosis through activation of caspase-3 in rats.
Kawai
Miho
M
Department of Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Harada
Naoaki
N
Takeyama
Hiromitsu
H
Okajima
Kenji
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002511:Cephalosporins / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006499:Hepatic Artery / Q000502:physiology; D016285:Iloprost / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000293:injuries* / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011169:Portal Vein / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D002511:Cephalosporins; D010975:Platelet Aggregation Inhibitors; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C065332:L 658758; D007334:Insulin-Like Growth Factor I; C069195:sivelestat; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019272:Leukocyte Elastase; D016285:Iloprost; D015740:Calcitonin Gene-Related Peptide; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin