Inhibition of endothelin-1-mediated up-regulation of iNOS by bosentan ameliorates endotoxin-induced liver injury in cirrhosis.
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.
Department of Biology, University of North Carolina at Charlotte, charlotte, NC 28223, USA.
Steve
S
Keller
Amel
A
Karaa
Markus
M
Paxian
Mark G
MG
Clemens
Jian X
JX
Zhang
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000077300:Bosentan; D051546:Cyclooxygenase 2 / Q000235:genetics; D017931:DNA Primers; D004195:Disease Models, Animal; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004731:Endotoxins / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D017931:DNA Primers; D016232:Endothelins; D004731:Endotoxins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013449:Sulfonamides; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D000410:Alanine Transaminase; D000077300:Bosentan