OBJECTIVE: To evaluate cyclooxygenase-2 (
COX-2) inhibition by NS-398 in septic rats
with respect to immunologic derangements and
hepatic damage. METHODS: Six sham rats (Sham), 24 rats that underwent experimentally induced
sepsis using
cecal ligation and puncture (CLP), and 24 rats that underwent induced
sepsis after treatment with NS-398 (NS-398), were compared. Sham rats were immediately sacrificed. Six each of CLP and NS-398 animals were sacrificed at 3, 6, 12, and 24 h after induction of
sepsis. From each rat was obtained
liver for
COX-2 mRNA copy number determination and
blood for quantification of
alanine transaminase (ALT),
aspartate aminotransferase (AST),
interleukin 10 (IL-10),
interleukin 6 (IL-6), and
tumor necrosis factor alpha (TNFalpha) levels, and
CD4:
CD8 ratios. RESULT: Sham rats had a lower
COX-2 mRNA copy number than NS-398 rats, which had a lower
copy number than CLP rats. CLP and NS-938 rats had IL-10 and IL-6 levels above Sham levels. NS-938 rat IL-10 levels were greater and IL-6 levels less than those of CLP rats. For CLP rats,
TNF production sharply declined and then increased above Sham levels; NS-398 rat
TNF production was consistently mildly elevated above Sham levels.
CD4:
CD8 ratios sharply dropped over time; NS-398 showed a more modest decline. CLP rats showed unrelenting climbs in AST and ALT values; NS-398 rat levels peaked at 6 h and returned to normal after 12 h; the biochemical evidence of protection against septic
liver damage was also seen morphologically, with ultrastructural and
histologic normalization of nuclear appearances 12 h after
sepsis induction with NS-398 pretreatment. CONCLUSION: Septic rats given the
COX-2 inhibitor NS-398 showed amelioration of
cytokine and cellular immunologic imbalances and decreased
liver injury.
