PATTERN OF CYTOKINES AND PHARMACOMODULATION IN SEPSIS-INDUCED BY CECAL LIGATION AND PUNCTURE COMPARED WITH THAT INDUCED BY ENDOTOXIN

The production of tumor necrosis factor alpha (TNF-alpha), interleukin -1 beta (IL-1 beta), and IL-6 and their pharmacomodulation were evalua ted in a model of polymicrobial sepsis induced in mice by cecal ligati on and puncture (CLP) and were compared with the effects of endotoxin (lipopolysaccharide [LPS]) treatment. LPS levels rose as early as 1 h after CLP and increased further after 2 and 21 h. TNF-alpha was detect able in serum, spleen, liver, and lungs during the first 4 h, with a p eak 2 h after CLP. IL-1 beta was measurable in serum after 24 h, and l evels increased significantly in spleen and liver 4 and 8 h after CLP. IL-6 levels increased significantly in serum throughout the first 16 h after CLP. These cytokines were detectable after LPS injection, with kinetics similar to those after CLP but at a significantly higher lev el. To cast more light on the differences between these two animal mod els of septic shock, we studied the effects of different reference dru gs. Pretreatment with dexamethasone (DEX); ibuprofen (IBU), an inhibit or of cyclooxygenase; and N-G-nitro-L-arginine, an inhibitor of nitric oxide synthase, significantly reduced survival, while chlorpromazine (CPZ) and TNF did not affect it. Only the antibiotics and pentoxifylli ne significantly increased survival in mice with CLP. However, CPZ and DEX protected the mice from LPS mortality. On inhibiting TNF-alpha wi th DEX, PZ, or pentoxifylline, survival was reduced, unchanged, and in creased, respectively, and on increasing TNF-alpha with IBU and TNF, s urvival was decreased or unchanged, respectively, suggesting that the modulation of this cytokine does not play a significant role in sepsis induced by CLP, unlike treatment with LPS. The negative effects of IB U and N-G-nitro-L-arginine suggest a protective role by prostaglandins and nitric oxide in sepsis induced by CLP.