Bacterial
endotoxin (
lipopolysaccharide; LPS) augments the hepatotoxicity of a number of
xenobiotics including
allyl alcohol. The mechanism for this effect is known to involve the inflammatory response elicited by LPS. Upregulation of
cyclooxygenase-2 (COX-2) and production of
eicosanoids are important aspects of
inflammation, therefore studies were undertaken to investigate the role of COX-2 in LPS-induced enhancement of liver injury from
allyl alcohol. Rats were pretreated (iv) with a noninjurious dose of LPS or sterile saline vehicle and 2 h later were treated (ip) with a noninjurious dose of
allyl alcohol or saline vehicle. COX-2
mRNA was determined by semiquantitative
reverse transcriptase-polymerase chain reaction (RT-PCR), and liver injury was assessed from activities in serum of
alanine and
aspartate aminotransferases (ALT and AST, respectively) and from histology. Liver injury was observed only in rats cotreated with LPS and
allyl alcohol. Serum ALT activity was increased by 4 h after administration of LPS and continued to increase through 8 h. COX-2
mRNA was detectable at low levels in livers from rats receiving only the vehicles at any time up to 8 h. Expression of COX-2
mRNA was increased by 30 min after administration of LPS and remained elevated through 6 h.
Allyl alcohol treatment alone caused an increase in COX-2
mRNA at 4 h (2 h after
allyl alcohol) that lasted less than 2 h. In livers from rats cotreated with LPS and
allyl alcohol, levels of COX-2
mRNA were greater than levels seen with either LPS or
allyl alcohol alone. The increased expression of COX-2
mRNA was accompanied by an increase in the concentration of
prostaglandin (PG) D(2) in plasma. Plasma
PGD(2) concentration was increased to a greater extent in rats treated with LPS plus
allyl alcohol compared to
allyl alcohol or LPS alone. Pretreatment with the COX-2 selective inhibitor,
NS-398, abolished the increase in plasma
PGD(2) and reduced the increase in ALT and AST activities observed in rats cotreated with LPS and
allyl alcohol.
NS-398 did not affect liver injury from
allyl alcohol alone administered at a larger, hepatotoxic dose. In addition,
ibuprofen, a nonselective inhibitor of
cyclooxygenases, did not protect against liver injury from LPS plus
allyl alcohol. In isolated hepatocytes
PGD(2), but not
PGE(2), reduced the concentration of
allyl alcohol required to cause half-maximal cytotoxicity. These results suggest that products of COX-2 play a role in the augmentation of
allyl alcohol-induced liver injury by LPS.