Matrix Metalloproteinase-8 Augments Bacterial Clearance in a Juvenile Sepsis Model

Genetic ablation or pharmacologic inhibition of matrix metalloproteinase-8 ( ) improves survival in an adult murine sepsis model. Because developmental age influences the host inflammatory response, we hypothesized that developmental age influences the role of in sepsis. First, we compared sepsis survival between wild type (WT, C57BL/6) and null juvenile-aged mice (12-14 days) after intraperitoneal injection of a standardized cecal slurry. Second, peritoneal lavages collected at 6 and 18 hours after cecal slurry injection were analyzed for bacterial burden, leukocyte subsets, and inflammatory cytokines. Third, juvenile WT mice were pretreated with an inhibitor prior to cecal slurry injection; analysis of their bacterial burden was compared to vehicle-injected animals. Fourth, the phagocytic capacity of WT and null peritoneal macrophages was compared. Finally, peritoneal neutrophil extracellular traps (NETs) were compared using immunofluorescent imaging and quantitative image analysis. We found that juvenile null mice had greater mortality and higher bacterial burden than WT mice. Leukocyte counts and cytokine concentrations in the peritoneal fluid were increased in the null mice, relative to the wild type mice. Peritoneal macrophages from null mice had reduced phagocytic capacity compared to WT macrophages. There was no quantitative difference in NET formation, but fewer bacteria were adherent to NETs from null animals. In conclusion, in contrast to septic adult mice, genetic ablation of increased mortality following bacterial peritonitis in juvenile mice. The increase in mortality in null juvenile mice was associated with reduced bacterial clearance and reduced NET efficiency. We conclude that developmental age influences the role of in sepsis.