Exposure to bacterial DNA before hemorrhagic shock strongly aggravates systemic inflammation and gut barrier loss via an IFN-γ-dependent route

Objective: To investigate the role of bacterial DNA in development of an excessive inflammatory response and loss of gut barrier loss following systemic hypotension. Summary Background Data: Bacterial infection may contribute to development of inflammatory complications following major surgery: however, the pathogenesis is not clear. A common denominator of bacterial infection is bacterial DNA characterized by unmethylated CpG motifs. Recently, it has been shown that bacterial DNA or synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) are immunostimulatory leading to release of inflammatory mediators. Methods: Rats were exposed to CpG-ODN prior to a nonlethal hemorrhagic shock. The role of interferon-gamma (IFN-gamma) was investigated by administration of anti IFN-gamma antibodies. Results: Exposure to CpG-ODN prior to hemorrhagic shock significantly augmented shock-induced release of IFN-gamma, tumor necrosis factor-alpha (TNF-alpha) (P < 0.05), interleukin (IL)-6 (P < 0.05), and nitrite levels (P < 0.05), while there was a defective IL-10 response (P < 0.05). Simultaneously, expression of Toll-like receptor (TLR) 4 in the liver was markedly enhanced. Furthermore, intestinal permeability for HRP significantly increased and bacterial translocation was enhanced in hemorrhagic shock rats pretreated with CpG-ODN. Interestingly, inhibition of IFN-gamma in CpG-treated animals reduced TNF-alpha (P < 0.05), IL-6 (P < 0.05), nitrite (P < 0.05), and intestinal permeability following hemorrhagic shock (P < 0.05) and down-regulated expression of TLR4. Conclusion: Exposure to bacterial DNA strongly aggravates the inflammatory response, disrupts the intestinal barrier, and up-regulates TLR4 expression in the liver following hemorrhagic shock. These effects are mediated via an IFN-gamma-dependent route. In the clinical setting, bacterial DNA may be important in development of inflammatory complications in surgical patients with bacterial infection.