Upper GI and Oncology 05

Abstract

Aims: NFκB and p38 MAP kinase are critical intracellular signal transduction pathways which mediate the systemic inflammatory response syndrome. Antibiotic induces bacterial lysis, also contributes to cytokine production and the inflammatory response by activating NFκB and p38 kinase. In this study, we set out to examine the effects of inhibition of p38 and NFκB translation in in-vivo models of sepsis. Methods: Intraperitoneal lipopolysaccharide (LPS) (45 mg kg−1), tail vein injection of bacteria (Staphlococcus and Salmonella: 5 × 10−8 cfu kg−1) and caecal ligation and puncture (CLP) with or without antibiotics (Co-amoxyclav, 100 mg kg−1) were the septic models employed. Animals received control, SB-202190 a p38 inhibitor or SN-50 an NFκB inhibitor (±antibiotics for CLP), and mortality was assessed by log-rank analysis. Blood was collected at different time points for cytokine analysis and splenic tissue for cytoplasmic protein extraction to assess kinase activation analysis by Western blot. Results: SB-202190 and SN-50 resulted in significant survival benefit in the LPS model (P = 0.0006) but not bacterial or CLP model (P = 0.9; 0.3). SB-202190 and SN-50, in combination with antibiotic, resulted in a significant survival benefit in the CLP model (P = 0.0001; 0.006). Circulating levels of TNF-α and IL-6 were significantly reduced at 2 h (P = 0.047; 0.036*) but not at 6 h (P = 0.18; 0.024) post-CLP (Table 1). Western blot demonstrated down-regulation of p38 kinase 2 h after CLP. Conclusions: We have demonstrated that p38 and NFκB inhibition improves survival in endotoxin shock, whereas the survival benefit in polymicrobial sepsis requires coexistent antibiotic treatment. Our findings suggest that p38 and NFκB inhibition may provide novel strategies in preventing and treating sepsis in clinical practice.