Logo: to the web site of Uppsala University

Sepsis is characterized by a dysregulated host response to infection. The liver and spleen are essential for bacterial elimination, and the liver acts as a gatekeeper limiting systemic exposure to gut-derived bacteria and microbial products. The effects of systemic inflammation on hepatic and splenic bacterial and endotoxin elimination remain incompletely understood. As inflammatory responses in sepsis may differ between organs, regional immunomodulation could attenuate harmful inflammation while limiting systemic effects. This thesis aimed to investigate bacterial and endotoxin elimination in the liver and spleen during experimental sepsis, and to explore regional hepatic immunomodulation and mechanisms of hepatic bacterial elimination. Studies were performed in a porcine intensive care model of Escherichia coli infusion.

Paper I demonstrated that pre-existing systemic inflammation, induced by endotoxin, impaired both hepatic bacterial and endotoxin elimination. These changes were accompanied by an attenuated inflammatory and physiological response to the bacterial infusion.

Paper II showed that pre-existing systemic inflammation impaired splenic bacterial elimination and dampened the inflammatory response to the bacterial challenge. No measurable endotoxin elimination across the spleen was demonstrated.

Paper III evaluated regional hepatic immunomodulation using portal venous administration of budesonide compared with systemic administration. Hepatic bacterial and endotoxin elimination remained preserved in both groups. However, portal budesonide enhanced anti-inflammatory responses without the increase in circulating bacterial levels observed following systemic administration.

Paper IV investigated the roles of Kupffer cells and Toll-like receptor 4 (TLR4) in hepatic bacterial elimination. Neither Kupffer cell nor TLR4 inhibition impaired hepatic bacterial or endotoxin elimination. Kupffer cell inhibition increased hepatic bacterial growth and attenuated IL-10 responses, whereas TLR4 inhibition delayed systemic bacterial clearance and attenuated pro-inflammatory cytokine responses.

In conclusion, systemic inflammation impaired bacterial elimination in both the liver and spleen and impaired hepatic endotoxin elimination. In contrast, selective inhibition of Kupffer cell function, TLR4 signaling, and regional hepatic immunosuppression altered host inflammatory responses without impairing hepatic bacterial elimination. These findings suggest that inflammatory activation and bacterial elimination can be regulated partly independently and that hepatic bacterial elimination is maintained by robust defense mechanisms. Regional hepatic immunomodulation may represent a strategy to modify harmful inflammation while preserving bacterial elimination.