Hepatocyte-derived cysteinyl leukotrienes modulate vascular tone in experimental cirrhosis

Background & Aims: The leukotrienes C-4/D-4/E-4 (cysteinyl-LTs) are 5-lipox ygenase (5-LO)-derived eicosanoids with potent vasoconstrictor, proliferati ve, and profibrogenic properties that may participate in key pathophysiolog ic events in liver cirrhosis. We examined the cysteinyl-LT biosynthetic pat hway in liver tissue and purified liver cells isolated from rats with carbo n tetrachloride-induced cirrhosis, and assessed the vasoactive properties o f LTD4 in hepatic stellate cells (HSCs) and anesthetized rats. Methods & Re sults: Liver homogenates from cirrhotic rats had increased 5-LO mRNA and cy steinyl-LT content, as determined by Northern blot and enzyme immunoassay, respectively. In isolated rat liver cells, 5-LO mRNA expression was found t o be restricted to Kupffer cells. However, among the fiver cells (i.e., hep atocytes, Kupffer cells, HSCs, and sinusoidal endothelial cells), hepatocyt es exhibited the highest ability to generate cysteinyl-LTs from the unstabl e intermediate LTA(4). Hepatocytes from cirrhotic rats showed an enhanced b aseline generation of cysteinyl-LTs, but their ability to synthesize cystei nyl-LTs from exogenous LTA(4) was found to be similar to that of hepatocyte s from normal animals. Both LTD4 and hepatocyte-conditioned medium increase d intracellular Ca2+ concentration and induced contraction in HSCs, suggest ing that hepatocyte-derived cysteinyl-LTs could act in a paracrine fashion on nearby nonparenchymal liver cells. The relevance of these in vitro findi ngs was further established in vivo by the observation that LTD4 significan tly increased portal pressure in anesthetized rats, Conclusions: These data suggest a role for hepatocyte-derived cysteinyl-LTs in mediating hepatic v ascular tone abnormalities in cirrhosis.