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 (TNFα) 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.

Key Words: sepsis, liver damage, cyclooxygenase-2, NS-398, cytokines, T cells