The development of liver disease during the course of sepsis is associated with increased mortality. We hypothesized that worsening liver function would result in decreased bacterial clearance and be associated with increased dysfunction of other organs and increased mortality.
Mild and severe sepsis were generated in C57BL/6 mice via intratracheal inoculation with 103 or 104 organisms of Pseudomonas aeruginosa, respectively. To evaluate bacterial clearance by the liver, portal vein and right ventricle bacterial concentrations were measured using quantitative real-time PCR with primers specific for P. aeruginosa. Liver and cardiac injury was assessed by ALT and CK levels. Organ apoptosis was evaluated with a caspase-3 activity assay. Levels of IL-1 beta and TNF-alpha were measured by ELISA. To inhibit apoptosis, a subset of mice was pre-treated with the caspase inhibitor z-VAD-fmk.
Mild and severe sepsis resulted in 20% and 60% mortality at 36 hours, respectively. Mild sepsis triggered a short but significant hepatic inflammatory response and some liver injury that returned to baseline by 24 hours. Effective bacterial clearance was not lost in this model. Severe sepsis caused a prolonged hepatic inflammatory response and liver injury that continued to worsen over time. Effective bacterial clearance was eventually lost in this model and was associated with increased injury to other organs, as well as increased mortality. Pretreatment with z-VAD-fmk resulted in preservation of hepatic bacterial clearance and increased survival 24 hours after infection with the severe sepsis model.
We conclude that liver injury in sepsis is associated with decreased bacterial clearance, increased end-organ damage, and mortality. Inhibition of apoptosis preserves hepatic bacterial clearance and improves survival.
This study suggests that bacterial clearance by the liver may be an important determinant of the outcome of sepsis.
Alix Ashare, None.