COX-2 Inhibition Improves Immune System Homeostasis and Decreases Liver Damage in Septic Rats

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.

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