Back to Search
Start Over
Inhibition of endothelin-1-mediated up-regulation of iNOS by bosentan ameliorates endotoxin-induced liver injury in cirrhosis.
- Source :
-
Shock (Augusta, Ga.) [Shock] 2006 Mar; Vol. 25 (3), pp. 306-13. - Publication Year :
- 2006
-
Abstract
- Endothelin-1 (ET-1) has been shown to regulate the expression of various genes in addition to its vasoconstrictor role in the liver. Elevated levels of ET-1 during cirrhosis play an important role in the observed microcirculatory dysfunction; however, its role as a transcription regulator remains unclear. This study aimed to determine the role of ET-1 in the hepatic gene expression of vasomediators after cirrhosis in response to LPS. Cirrhosis was induced by bile duct ligation (BDL) for 1 or 3 weeks in male Sprague-Dawley rats. Following 1 or 3 weeks of BDL or sham operation (sham), rats received an intravenous (i.v.) injection of bosentan, a dual-selective ETA/B receptor antagonist (30 mg/kg bw) or saline, and an intraperitoneal (i.p.) injection of LPS (1 mg/kg bw). Plasma alanine aminotransferase (ALT) levels were significantly elevated in 1- and 3-week BDL animals. Six hours following LPS, the elevated ALT levels were markedly exacerbated in 3-week BDL animals, which were significantly ameliorated with bosentan treatment. LPS resulted in increased ET-1, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 mRNA expressions in both sham and BDL rats. Bosentan significantly inhibited the up-regulations of ET-1, iNOS, and COX-2 mRNA. Our data strongly suggest that ET-1 plays an important role in up-regulating the expression of iNOS, COX-2, and ET-1 itself in hepatic tissue following LPS challenge, which may contribute to the observed hepatocellular injury during endotoxemia in cirrhosis. Thus, due to significant increases in ET-1 levels during cirrhosis, ET-1 receptor blockade may prove to be of great therapeutic value in the treatment of cirrhotic patients exposed to secondary injuries such as endotoxemia.
- Subjects :
- Alanine Transaminase blood
Animals
Antihypertensive Agents therapeutic use
Bosentan
Cyclooxygenase 2 genetics
DNA Primers
Disease Models, Animal
Endothelins antagonists & inhibitors
Gene Expression Regulation, Enzymologic drug effects
Liver drug effects
Liver pathology
Liver Cirrhosis, Experimental chemically induced
Male
RNA, Messenger genetics
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Endothelins physiology
Endotoxins toxicity
Lipopolysaccharides toxicity
Liver injuries
Liver Cirrhosis, Experimental drug therapy
Nitric Oxide Synthase Type II genetics
Sulfonamides therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1073-2322
- Volume :
- 25
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Shock (Augusta, Ga.)
- Publication Type :
- Academic Journal
- Accession number :
- 16552365
- Full Text :
- https://doi.org/10.1097/01.shk.0000196549.18258.6a