Neutrophil elastase contributes to the development of ischemia/reperfusion-induced liver injury by decreasing the production of insulin-like growth factor-I in rats

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 155; no. 6; pp. 294 - 304
• Main Authors: Kawai, Miho, Harada, Naoaki, Takeyama, Hiromitsu, Okajima, Kenji
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.06.2010; Elsevier
• Subjects: Alanine Transaminase - blood; Animals; Aspartate Aminotransferases - blood; Biological and medical sciences; Calcitonin Gene-Related Peptide - metabolism; Cardiology. Vascular system; Cephalosporins - pharmacology; General aspects; Glycine - analogs & derivatives; Glycine - pharmacology; Hepatic Artery - physiology; Iloprost - pharmacology; Indomethacin - pharmacology; Insulin-Like Growth Factor I - drug effects; Insulin-Like Growth Factor I - metabolism; Internal Medicine; Investigative techniques, diagnostic techniques (general aspects); Leukocyte Elastase - metabolism; Liver - blood supply; Liver - enzymology; Liver - injuries; Liver - metabolism; Male; Medical sciences; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Synthase Type II - antagonists & inhibitors; Peroxidase - metabolism; Platelet Aggregation Inhibitors - pharmacology; Portal Vein - physiology; Rats; Rats, Wistar; Reperfusion Injury - enzymology; Serine Proteinase Inhibitors - pharmacology; Sulfonamides - pharmacology; NO; IGF-I; alanine aminotransferase; ALT; inducible NOS; I/R; MPO; indomethacin; ischemia/reperfusion; TUNEL; insulin-like growth factor- I; iNOS; nitirc oxide; nitric oxide synthase; endothelial monocyte-activating polypeptide-II; AST; terminal deoxynucleotidyl transferase mediated dUTP nick end labelling; IM; PGI2; prostacyclin; calcitonin gene-related peptide; cyclooxygenase; myeloperoxidase; COX; aspartate aminotransferase; NOS; neutrophil elastase; NE; EMAP-II; CGRP; Leukocyte elastase; Serine endopeptidases; Rat; Digestive system; Enzyme; Liver; Ischemia reperfusion; Rodentia; Biosynthesis; Insulin like growth factor 1; Medicine; Peptidases; Vertebrata; Mammalia; Animal; Clinical biology; Production; Development; Hydrolases; Lesion
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2010.02.003

Neutrophil elastase (NE) decreases the endothelial production of prostacyclin (PGI2 ) 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 PGI2 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 PGI2 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.